@article {pmid40578318, year = {2025}, author = {Kerdoncuff, E and Skov, L and Patterson, N and Banerjee, J and Khobragade, P and Chakrabarti, SS and Chakrawarty, A and Chatterjee, P and Dhar, M and Gupta, M and John, JP and Koul, PA and Lehl, SS and Mohanty, RR and Padmaja, M and Perianayagam, A and Rajguru, C and Sankhe, L and Talukdar, A and Varghese, M and Yadati, SR and Zhao, W and Leung, YY and Schellenberg, GD and Wang, YZ and Smith, JA and Dey, S and Ganna, A and Dey, AB and Kardia, SLR and Lee, J and Moorjani, P}, title = {50,000 years of evolutionary history of India: Impact on health and disease variation.}, journal = {Cell}, volume = {188}, number = {13}, pages = {3389-3404.e6}, doi = {10.1016/j.cell.2025.04.027}, pmid = {40578318}, issn = {1097-4172}, mesh = {Humans ; India ; Animals ; *Genetic Variation ; Neanderthals/genetics ; Genome, Human/genetics ; Gene Flow ; Human Migration ; Biological Evolution ; Asian People/genetics ; Genetics, Population ; }, abstract = {India has been underrepresented in genomic surveys. We generated whole-genome sequences from 2,762 individuals in India, capturing the genetic diversity across most geographic regions, linguistic groups, and historically underrepresented communities. We find most Indians harbor ancestry primarily from three ancestral groups: South Asian hunter-gatherers, Eurasian Steppe pastoralists, and Neolithic farmers related to Iranian and Central Asian cultures. The extensive homozygosity and identity-by-descent sharing among individuals reflects strong founder events due to a recent shift toward endogamy. We uncover that most of the genetic variation in Indians stems from a single major migration out of Africa that occurred around 50,000 years ago, followed by 1%-2% gene flow from Neanderthals and Denisovans. Notably, Indians exhibit the largest variation and possess the highest amount of population-specific Neanderthal ancestry segments among worldwide groups. Finally, we discuss how this complex evolutionary history has shaped the functional and disease variation on the subcontinent.}, }
@article {pmid40537588, year = {2025}, author = {Lewis, D}, title = {First ever skull from 'Denisovan' reveals what ancient people looked like.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40537588}, issn = {1476-4687}, }
@article {pmid40531192, year = {2025}, author = {Fu, Q and Bai, F and Rao, H and Chen, S and Ji, Y and Liu, A and Bennett, EA and Liu, F and Ji, Q}, title = {The proteome of the late Middle Pleistocene Harbin individual.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eadu9677}, doi = {10.1126/science.adu9677}, pmid = {40531192}, issn = {1095-9203}, abstract = {Denisovans are a hominin group primarily known through genomes or proteins, but the precise morphological features of Denisovans remain elusive due to the fragmentary nature of discovered fossils. Here we report ninety-five endogenous proteins retrieved from a nearly complete cranium from Harbin, China, dating to at least 146,000 years ago and previous assigned to a new species, Homo longi. This individual has three Denisovan derived amino acid variants and clusters with Denisova 3, suggesting the Harbin individual belongs to a Denisovan population. This study fills the gap between morphological and molecular evidence, enhancing our understanding of Denisovans' spatiotemporal dispersal and evolutionary history.}, }
@article {pmid40413751, year = {2025}, author = {Denisova, K and Wolpert, DM}, title = {Protocol to investigate sensorimotor features in young children with autism using functional and resting-state fMRI data from the NIMH Data Archive.}, journal = {STAR protocols}, volume = {6}, number = {2}, pages = {103827}, doi = {10.1016/j.xpro.2025.103827}, pmid = {40413751}, issn = {2666-1667}, abstract = {Head movements cause artifacts in infant neuroimaging that can often render acquired data unusable. Here, we present a protocol that harnesses head motion from fMRI and resting-state (rs)-fMRI NIMH Data Archive (NDA) data to obtain quantitative measures of sensorimotor function in young children and associate them with future cognitive and autism outcomes. We describe steps for downloading, organizing, and pre-processing fMRI data to yield data on in-scan head motion. We then detail procedures for preparing phenotypic data to link with sensorimotor data. For complete details on the use and execution of this protocol, please refer to Denisova and Wolpert.[1].}, }
@article {pmid40399313, year = {2025}, author = {Jacobs, Z and Zavala, EI and Li, B and O'Gorman, K and Shunkov, MV and Kozlikin, MB and Derevianko, AP and Uliyanov, VA and Goldberg, P and Agadjanian, AK and Vasiliev, SK and Brink, F and Peyrégne, S and Slon, V and Pääbo, S and Kelso, J and Meyer, M and Roberts, RG}, title = {Pleistocene chronology and history of hominins and fauna at Denisova Cave.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4738}, pmid = {40399313}, issn = {2041-1723}, support = {FT140100384//Department of Education and Training | Australian Research Council (ARC)/ ; FT150100138//Department of Education and Training | Australian Research Council (ARC)/ ; FL130100116//Department of Education and Training | Australian Research Council (ARC)/ ; 24-18-00069//Russian Science Foundation (RSF)/ ; 24-18-00069//Russian Science Foundation (RSF)/ ; 24-18-00069//Russian Science Foundation (RSF)/ ; 24-18-00069//Russian Science Foundation (RSF)/ ; 24-18-00069//Russian Science Foundation (RSF)/ ; }, mesh = {Animals ; *Caves ; Siberia ; *Hominidae/genetics ; DNA, Mitochondrial/genetics ; Fossils ; Humans ; Neanderthals/genetics ; Geologic Sediments ; Archaeology ; DNA, Ancient/analysis ; Mammals/genetics ; History, Ancient ; }, abstract = {Denisova Cave in southern Siberia is the only site known to have been occupied by Denisovans, Neanderthals and modern humans. The cave consists of three chambers (Main, East and South), with the archaeological assemblages and remains of hominins, fauna and flora recovered from Main and East Chambers being the most thoroughly investigated to date. Here we report the results of analyses of the Palaeolithic artefacts, faunal remains and hominin and mammalian mitochondrial (mt) DNA recovered from renewed excavations in South Chamber. We construct a calendar-year time scale for the stratified Pleistocene deposits from optical dating of the sediments. The timing of hominin occupation and major turnovers in the mtDNA of Denisovans and large mammals largely accords with the patterns detected in Main and East Chambers. Time gaps in those sequences are partly filled by the South Chamber data and the sediment DNA record of Denisovans after 80,000 years ago is more than doubled in size. We combine the sediment dating and DNA records for all three chambers to reveal the whole-of-cave history of this unique site and the climatic conditions experienced by hominins and fauna over the past 300,000 years, including potential changes in habitat suitability for Denisovans and Neanderthals.}, }
@article {pmid40369069, year = {2025}, author = {He, Y and Zhang, X and Peng, MS and Li, YC and Liu, K and Zhang, Y and Mao, L and Guo, Y and Ma, Y and Zhou, B and Zheng, W and Yue, T and Liao, Y and Liang, SA and Chen, L and Zhang, W and Chen, X and Tang, B and Yang, X and Ye, K and Gao, S and Lu, Y and Wang, Y and Wan, S and Hao, R and Wang, X and Mao, Y and Dai, S and Gao, Z and Yang, LQ and Guo, J and Li, J and Liu, C and Wang, J and Sovannary, T and Bunnath, L and Kampuansai, J and Inta, A and Srikummool, M and Kutanan, W and Ho, HQ and Pham, KD and Singthong, S and Sochampa, S and Kyaing, UW and Pongamornkul, W and Morlaeku, C and Rattanakrajangsri, K and ,  and Kong, QP and Zhang, YP and Su, B}, title = {Genome diversity and signatures of natural selection in mainland Southeast Asia.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40369069}, issn = {1476-4687}, abstract = {Mainland Southeast Asia (MSEA) has rich ethnic and cultural diversity with a population of nearly 300 million[1,2]. However, people from MSEA are underrepresented in the current human genomic databases. Here we present the SEA3K genome dataset (phase I), generated by deep short-read whole-genome sequencing of 3,023 individuals from 30 MSEA populations, and long-read whole-genome sequencing of 37 representative individuals. We identified 79.59 million small variants and 96,384 structural variants, among which 22.83 million small variants and 24,622 structural variants are unique to this dataset. We observed a high genetic heterogeneity across MSEA populations, reflected by the varied combinations of genetic components. We identified 44 genomic regions with strong signatures of Darwinian positive selection, covering 89 genes involved in varied physiological systems such as physical traits and immune response. Furthermore, we observed varied patterns of archaic Denisovan introgression in MSEA populations, supporting the proposal of at least two distinct instances of Denisovan admixture into modern humans in Asia[3]. We also detected genomic regions that suggest adaptive archaic introgressions in MSEA populations. The large number of novel genomic variants in MSEA populations highlight the necessity of studying regional populations that can help answer key questions related to prehistory, genetic adaptation and complex diseases.}, }
@article {pmid40362558, year = {2025}, author = {Aleshina, YA and Zavileyskiy, LG and Aleshin, VA}, title = {Neanderthal and Denisovan Glutamate Dehydrogenase 2 Evolution and Clinical Significance.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, doi = {10.3390/ijms26094322}, pmid = {40362558}, issn = {1422-0067}, support = {23-74-10036//Russian Science Foundation/ ; }, mesh = {*Neanderthals/genetics ; Animals ; Humans ; *Glutamate Dehydrogenase/genetics/chemistry/metabolism ; *Evolution, Molecular ; *Hominidae/genetics ; Phylogeny ; Mutation, Missense ; Clinical Relevance ; }, abstract = {Mammalian glutamate dehydrogenase (GDH) is an indispensable metabolic enzyme. GDH duplication has led to the presence of two paralogs, GDH1 and GDH2, in apes. Multiple GDH pseudogenes are also present in the human genome. The novel GDH2, supposed to be a target of positive selection, differs from GDH1 in regulation and is believed to be tightly linked to brain development. Although the differences of modern human GDH2 from GDH2 of other apes have been studied, the evolution of ancient human GDH2 remains a blank space. The goal of this work was to elucidate GDH2 evolution in the genus Homo using the accumulated data on the ancient genomes with high coverage-three Neanderthal and one Denisovan genome. Such analysis clarifies the difference between GDH2 of the last common ancestor of humans and chimpanzees and all Homo to be in M468L substitution, localized in the regulatory "antenna" region of the protein. A few novel missense mutations have been found in Denisovan and Altai Neanderthal GDH2, namely R76H, present in both genomes, and Denisovan-specific T154P, I358L, and S498A substitutions. Another mutation, R352K, has likely occurred independently in modern humans and later Neanderthals. The potential impact of these mutations was estimated using GDH2 structural data and evidence from contemporary medical data. All substitutions are supposed to be benign, with only the S498A GDH2 substitution connected to Parkinson's disease with late onset. Additionally, the ancient genomes were revealed to have all GDH pseudogenes present in modern humans, including the RNA-coding ones. The GLUD1P3 RNA expression was found to correlate negatively with GDH1 in human tissues. A possible regulatory role has been proposed, and the GLUD1P3 RNA sequence identity in all the studied human genomes suggests its conservation in the genus Homo.}, }
@article {pmid40229476, year = {2025}, author = {Graham, F}, title = {Daily briefing: Mysterious Taiwan fossil is Denisovan.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/d41586-025-01213-w}, pmid = {40229476}, issn = {1476-4687}, }
@article {pmid40211080, year = {2025}, author = {Lewis, D}, title = {Mysterious human fossil found in Taiwan was a Denisovan.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40211080}, issn = {1476-4687}, }
@article {pmid40208980, year = {2025}, author = {Tsutaya, T and Sawafuji, R and Taurozzi, AJ and Fagernäs, Z and Patramanis, I and Troché, G and Mackie, M and Gakuhari, T and Oota, H and Tsai, CH and Olsen, JV and Kaifu, Y and Chang, CH and Cappellini, E and Welker, F}, title = {A male Denisovan mandible from Pleistocene Taiwan.}, journal = {Science (New York, N.Y.)}, volume = {388}, number = {6743}, pages = {176-180}, doi = {10.1126/science.ads3888}, pmid = {40208980}, issn = {1095-9203}, mesh = {Animals ; *Mandible/anatomy & histology ; *Fossils ; Taiwan ; Male ; *Hominidae/anatomy & histology/genetics/classification ; }, abstract = {Denisovans are an extinct hominin group defined by ancient genomes of Middle to Late Pleistocene fossils from southern Siberia. Although genomic evidence suggests their widespread distribution throughout eastern Asia and possibly Oceania, so far only a few fossils from the Altai and Tibet are confidently identified molecularly as Denisovan. We identified a hominin mandible (Penghu 1) from Taiwan (10,000 to 70,000 years ago or 130,000 to 190,000 years ago) as belonging to a male Denisovan by applying ancient protein analysis. We retrieved 4241 amino acid residues and identified two Denisovan-specific variants. The increased fossil sample of Denisovans demonstrates their wider distribution, including warm and humid regions, as well as their shared distinct robust dentognathic traits that markedly contrast with their sister group, Neanderthals.}, }
@article {pmid40102687, year = {2025}, author = {Cousins, T and Scally, A and Durbin, R}, title = {A structured coalescent model reveals deep ancestral structure shared by all modern humans.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {40102687}, issn = {1546-1718}, support = {207492/Z/17/Z//Wellcome Trust (Wellcome)/ ; 108864/B/15/Z//Wellcome Trust (Wellcome)/ ; }, abstract = {Understanding the history of admixture events and population size changes leading to modern humans is central to human evolutionary genetics. Here we introduce a coalescence-based hidden Markov model, cobraa, that explicitly represents an ancestral population split and rejoin, and demonstrate its application on simulated and real data across multiple species. Using cobraa, we present evidence for an extended period of structure in the history of all modern humans, in which two ancestral populations that diverged ~1.5 million years ago came together in an admixture event ~300 thousand years ago, in a ratio of ~80:20%. Immediately after their divergence, we detect a strong bottleneck in the major ancestral population. We inferred regions of the present-day genome derived from each ancestral population, finding that material from the minority correlates strongly with distance to coding sequence, suggesting it was deleterious against the majority background. Moreover, we found a strong correlation between regions of majority ancestry and human-Neanderthal or human-Denisovan divergence, suggesting the majority population was also ancestral to those archaic humans.}, }
@article {pmid39962554, year = {2025}, author = {Liang, SA and Ren, T and Zhang, J and He, J and Wang, X and Jiang, X and He, Y and McCoy, RC and Fu, Q and Akey, JM and Mao, Y and Chen, L}, title = {A refined analysis of Neanderthal-introgressed sequences in modern humans with a complete reference genome.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {32}, pmid = {39962554}, issn = {1474-760X}, mesh = {*Neanderthals/genetics ; Humans ; Animals ; *Genome, Human ; Genetic Introgression ; }, abstract = {BACKGROUND: Leveraging long-read sequencing technologies, the first complete human reference genome, T2T-CHM13, corrects assembly errors in previous references and resolves the remaining 8% of the genome. While studies on archaic admixture in modern humans have so far relied on the GRCh37 reference due to the availability of archaic genome data, the impact of T2T-CHM13 in this field remains unexplored.<br><br>RESULTS: We remap the sequencing reads of the high-quality Altai Neanderthal and Denisovan genomes onto GRCh38 and T2T-CHM13. Compared to GRCh37, we find that T2T-CHM13 significantly improves read mapping quality in archaic samples. We then apply IBDmix to identify Neanderthal-introgressed sequences in 2504 individuals from 26 geographically diverse populations using different reference genomes. We observe that commonly used pre-phasing filtering strategies in public datasets substantially influence archaic ancestry determination, underscoring the need for careful filter selection. Our analysis identifies&#x2009;approximately&#x2009;51&#xa0;Mb of Neanderthal sequences unique to T2T-CHM13, predominantly in genomic regions where GRCh38 and T2T-CHM13 assemblies diverge. Additionally, we uncover novel instances of population-specific archaic introgression in diverse populations, spanning genes involved in metabolism, olfaction, and ion-channel function. Finally, to facilitate the exploration of archaic alleles and adaptive signals in human genomics and evolutionary research, we integrate these introgressed sequences and adaptive signals across all reference genomes into a visualization database, ASH (www.arcseqhub.com).<br><br>CONCLUSIONS: Our study enhances the detection of archaic variations in modern humans, highlights the importance of utilizing the T2T-CHM13 reference, and provides novel insights into the functional consequences of archaic hominin admixture.}, }
@article {pmid39953642, year = {2025}, author = {Abood, S and Oota, H}, title = {Human dispersal into East Eurasia: ancient genome insights and the need for research on physiological adaptations.}, journal = {Journal of physiological anthropology}, volume = {44}, number = {1}, pages = {5}, pmid = {39953642}, issn = {1880-6805}, mesh = {Humans ; *Human Migration ; Animals ; *Adaptation, Physiological/genetics ; Genome, Human/genetics ; Neanderthals/genetics ; Anthropology, Physical ; Biological Evolution ; }, abstract = {Humans have long pondered their genesis. The answer to the great question of where Homo sapiens come from has evolved in conjunction with biotechnologies that have allowed us to more brightly illuminate our distant past. The "Multiregional Evolution" model was once the hegemonic theory of Homo sapiens origins, but in the last 30 years, it has been supplanted by the "Out of Africa" model. Here, we review the major findings that have resulted in this paradigmatic shift. These include hominin brain expansion, classical insight from the mitochondrial genome (mtDNA) regarding the timing of the divergence point between Africans and non-Africans, and next-generation sequencing (NGS) of the Neanderthal and Denisovan genomes. These findings largely bolstered the "Out of Africa" model, although they also revealed a small degree of introgression of the Neanderthal and Denisovan genomes into those of non-African Homo sapiens. We also review paleogenomic studies for which migration route, north or south, early migrants to East Eurasia most likely traversed. Whichever route was taken, the migrants moved to higher latitudes, which necessitated adaptation for lower light conditions, colder clines, and pro-adipogenic mechanisms to counteract food scarcity. Further genetic and epigenetic investigations of these physiological adaptations constitute an integral aspect of the story of human origins and human migration to East Asia.}, }
@article {pmid39848961, year = {2025}, author = {Mazières, S and Condemi, S and El Nemer, W and Chiaroni, J}, title = {Rapid change in red cell blood group systems after the main Out of Africa of Homo sapiens.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1597}, pmid = {39848961}, issn = {2045-2322}, support = {ANR-20-CE03-0002//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; Animals ; *Blood Group Antigens/genetics ; *Neanderthals/genetics ; *Genetic Variation ; Haplotypes ; Phylogeny ; Erythrocytes ; Alleles ; Africa ; }, abstract = {Despite the advances in paleogenomics, red cell blood group systems in ancient human populations remain scarcely known. Pioneer attempts showed that Neandertal and Denisova, two archaic hominid populations inhabiting Eurasia, expressed blood groups currently found in sub-Saharans and a rare "rhesus", part of which is found in Oceanians. Herein we fully pictured the blood group genetic diversity of 22 Homo sapiens and 14 Neandertals from Eurasia living between 120,000 and 20,000 years before present (yBP). From the ABO, Rh, Kell, Duffy, Kidd, MNS, Diego, H, secretor and Indian systems, we noted that the blood group allele diversity in the Neandertals remained unchanged since 120,000 yBP, while H. sapiens conquered Eurasia with blood group alleles presently exclusive to non-African populations, suggesting they may have differentiated right after the Out of Africa, between 70,000 and 45,000 yBP. Notably, Ust'Ishim possessed unknown alleles that may illustrate the lost genetic heritage of the early Eurasians. Lastly, Neandertals shared a unique Rh haplotype from which we updated the current RHD phylogeny. The contribution of this study is twofold. It enlightens the expansion patterns of H sapiens and recalls the anthropological effectiveness of genetic polymorphisms currently being surveyed for transfusion safety and pregnancy monitoring.}, }
@article {pmid39801370, year = {2025}, author = {Sandroni, V and Chaumette, B}, title = {Understanding the Emergence of Schizophrenia in the Light of Human Evolution: New Perspectives in Genetics.}, journal = {Genes, brain, and behavior}, volume = {24}, number = {1}, pages = {e70013}, doi = {10.1111/gbb.70013}, pmid = {39801370}, issn = {1601-183X}, support = {//Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale/ ; //Agence R&#xe9;gionale de Sant&#xe9; &#xce;le-de-France/ ; //Agence Nationale de la Recherche/ ; //French Congress of Psychiatry/ ; }, mesh = {Humans ; *Schizophrenia/genetics ; Animals ; Biological Evolution ; Evolution, Molecular ; Hominidae/genetics ; }, abstract = {Schizophrenia is a frequent and disabling disease. The persistence of the disorder despite its harmful consequences represents an evolutionary paradox. Based on recent discoveries in genetics, scientists have formulated the "price-to-pay" hypothesis: schizophrenia would be intimately related to human evolution, particularly to brain development and human-specific higher cognitive functions. The objective of the present work is to question scientific literature about the relationship between schizophrenia and human evolution from a genetic point of view. In the last two decades, research investigated the association between schizophrenia and a few genetic evolutionary markers: Human accelerated regions, segmental duplications, and highly repetitive DNA such as the Olduvai domain. Other studies focused on the action of natural selection on schizophrenia-associated genetic variants, also thanks to the complete sequencing of archaic hominins' genomes (Neanderthal, Denisova). Results suggested that a connection between human evolution and schizophrenia may exist; nonetheless, much research is still needed, and it is possible that a definitive answer to the evolutionary paradox of schizophrenia will never be found.}, }
@article {pmid39672950, year = {2024}, author = {Tournebize, R and Chikhi, L}, title = {Ignoring population structure in hominin evolutionary models can lead to the inference of spurious admixture events.}, journal = {Nature ecology &amp; evolution}, volume = {}, number = {}, pages = {}, pmid = {39672950}, issn = {2397-334X}, support = {ANR-10-LABX-25-01//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-10-LABX-25-01//Agence Nationale de la Recherche (French National Research Agency)/ ; }, abstract = {Genomic and ancient DNA data have revolutionized palaeoanthropology and our vision of human evolution, with indisputable landmarks like the sequencing of Neanderthal and Denisovan genomes. Yet, using genetic data to identify, date and quantify evolutionary events-such as ancient bottlenecks or admixture-is not straightforward, as inferences may depend on model assumptions. In the last two decades, the idea that Neanderthals and members of the Homo sapiens lineage interbred has gained momentum. From the status of unlikely theory, it has reached consensus among human evolutionary biologists. This theory is mainly supported by statistical approaches that depend on demographic models minimizing or ignoring population structure, despite its widespread occurrence and the fact that, when ignored, population structure can lead to the inference of spurious demographic events. We simulated genomic data under a structured and admixture-free model of human evolution, and found that all the tested admixture approaches identified long Neanderthal fragments in our simulated genomes and an admixture event that never took place. We also observed that several published admixture models failed to predict important empirical diversity or admixture statistics, and that we could identify several scenarios from our structured model that better predicted these statistics jointly. Using a simulated time series of ancient DNA, the structured scenarios could also predict the trajectory of the empirical D statistics. Our results suggest that models accounting for population structure are fundamental to improve our understanding of human evolution, and that admixture between Neanderthals and H. sapiens needs to be re-evaluated in the light of structured models. Beyond the Neanderthal case, we argue that ancient hybridization events, which are increasingly documented in many species, including with other hominins, may also benefit from such re-evaluation.}, }
@article {pmid39577372, year = {2024}, author = {Tagore, D and Akey, JM}, title = {Archaic hominin admixture and its consequences for modern humans.}, journal = {Current opinion in genetics &amp; development}, volume = {90}, number = {}, pages = {102280}, doi = {10.1016/j.gde.2024.102280}, pmid = {39577372}, issn = {1879-0380}, abstract = {As anatomically modern humans dispersed out of Africa, they encountered and mated with now extinct hominins, including Neanderthals and Denisovans. It is now well established that all non-African individuals derive approximately 2% of their genome from Neanderthal ancestors and individuals of Melanesian and Australian aboriginal ancestry inherited an additional 2%-5% of their genomes from Denisovan ancestors. Attention has started to shift from documenting amounts of archaic admixture and identifying introgressed segments to understanding their molecular, phenotypic, and evolutionary consequences and refining models of human history. Here, we review recent insights into admixture between modern and archaic humans, emphasizing methodological innovations and the functional and phenotypic effects Neanderthal and Denisovan sequences have in contemporary individuals.}, }
@article {pmid39513938, year = {2024}, author = {Ferraretti, G and Abondio, P and Alberti, M and Dezi, A and Sherpa, PT and Cocco, P and Tiriticco, M and Di Marcello, M and Gnecchi-Ruscone, GA and Natali, L and Corcelli, A and Marinelli, G and Peluzzi, D and Sarno, S and Sazzini, M}, title = {Archaic introgression contributed to shape the adaptive modulation of angiogenesis and cardiovascular traits in human high-altitude populations from the Himalayas.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, doi = {10.7554/eLife.89815}, pmid = {39513938}, issn = {2050-084X}, support = {2019.0552//Fondazione Cassa di Risparmio in Bologna/ ; }, mesh = {Humans ; *Altitude ; Tibet ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Neovascularization, Physiologic/genetics ; Genetic Introgression ; Adaptation, Physiological/genetics ; Gene Flow ; Selection, Genetic ; Angiogenesis ; Himalayas ; }, abstract = {It is well established that several Homo sapiens populations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by the EPAS1 gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan/Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan WGS data and to shortlist those presenting Denisovan-like derived alleles that participate to the same functional pathways and are absent in populations of African ancestry, which are supposed to do not have experienced Denisovan admixture. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regards TBC1D1, RASGRF2, PRKAG2, and KRAS, have plausibly contributed to shape the adaptive modulation of angiogenesis and of certain cardiovascular traits in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment.}, }
@article {pmid39501127, year = {2024}, author = {Ongaro, L and Huerta-Sanchez, E}, title = {A history of multiple Denisovan introgression events in modern humans.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39501127}, issn = {1546-1718}, abstract = {The identification of a new hominin group in the Altai mountains called Denisovans was one of the most exciting discoveries in human evolution in the last decade. Unlike Neanderthal remains, the Denisovan fossil record consists of only a finger bone, jawbone, teeth and skull fragments. Leveraging the surviving Denisovan segments in modern human genomes has uncovered evidence of at least three introgression events from distinct Denisovan populations into modern humans in the past. Each of them presents different levels of relatedness to the sequenced Altai Denisovan, indicating a complex relationship between these sister lineages. Here we review the evidence suggesting that several Denisovan populations, who likely had an extensive geographical range, were adapted to distinct environments and introgressed into modern humans multiple times. We further discuss how archaic variants have been affected by demographic history, negative and positive selection and close by proposing possible new lines of future research.}, }
@article {pmid39390557, year = {2024}, author = {Sawyer, S and Gelabert, P and Yakir, B and Llanos-Lizcano, A and Sperduti, A and Bondioli, L and Cheronet, O and Neugebauer-Maresch, C and Teschler-Nicola, M and Novak, M and Pap, I and Szikossy, I and Hajdu, T and Moiseyev, V and Gromov, A and Zariņa, G and Meshorer, E and Carmel, L and Pinhasi, R}, title = {Improved detection of methylation in ancient DNA.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {261}, pmid = {39390557}, issn = {1474-760X}, abstract = {Reconstructing premortem DNA methylation levels in ancient DNA has led to breakthrough studies such as the prediction of anatomical features of the Denisovan. These studies rely on computationally inferring methylation levels from damage signals in naturally deaminated cytosines, which requires expensive high-coverage genomes. Here, we test two methods for direct methylation measurement developed for modern DNA based on either bisulfite or enzymatic methylation treatments. Bisulfite treatment shows the least reduction in DNA yields as well as the least biases during methylation conversion, demonstrating that this method can be successfully applied to ancient DNA.}, }
@article {pmid39336789, year = {2024}, author = {Santourlidis, S}, title = {Phylo-Epigenetics in Phylogeny Analyses and Evolution.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, doi = {10.3390/genes15091198}, pmid = {39336789}, issn = {2073-4425}, mesh = {Animals ; *Phylogeny ; Humans ; *CpG Islands/genetics ; *Epigenesis, Genetic ; *Evolution, Molecular ; Hominidae/genetics ; Pan troglodytes/genetics ; DNA Methylation/genetics ; Gorilla gorilla/genetics ; }, abstract = {Long-standing, continuous blurring and controversies in the field of phylogenetic interspecies relations, associated with insufficient explanations for dynamics and variability of speeds of evolution in mammals, hint at a crucial missing link. It has been suggested that transgenerational epigenetic inheritance and the concealed mechanisms behind play a distinct role in mammalian evolution. Here, a comprehensive sequence alignment approach in hominid species, i.e., Homo sapiens, Homo neanderthalensis, Denisovan human, Pan troglodytes, Pan paniscus, Gorilla gorilla, and Pongo pygmaeus, comprising conserved CpG islands of housekeeping genes, uncover evidence for a distinct variability of CpG dinucleotides. Applying solely these evolutionary consistent and inconsistent CpG sites in a classic phylogenetic analysis, calibrated by the divergence time point of the common chimpanzee (P. troglodytes) and the bonobo or pygmy chimpanzee (P. paniscus), a "phylo-epigenetic" tree has been generated, which precisely recapitulates branch points and branch lengths, i.e., divergence events and relations, as they have been broadly suggested in the current literature, based on comprehensive molecular phylogenomics and fossil records of many decades. It is suggested here that CpG dinucleotide changes at CpG islands are of superior importance for evolutionary developments. These changes are successfully inherited through the germ line, determining emerging methylation profiles, and they are a central component of transgenerational epigenetic inheritance. It is hidden in the DNA, what will happen on it later.}, }
@article {pmid39024443, year = {2024}, author = {Gibbons, A}, title = {Oldest human genome comes from a Denisovan.}, journal = {Science (New York, N.Y.)}, volume = {385}, number = {6706}, pages = {240-241}, doi = {10.1126/science.adr8007}, pmid = {39024443}, issn = {1095-9203}, mesh = {Animals ; Female ; Humans ; Male ; *DNA, Ancient ; Fossils ; *Genome, Human ; *Neanderthals/genetics ; Siberia ; }, abstract = {200,000-year-old DNA shows our now-extinct cousins mated with Neanderthals.}, }
@article {pmid39002897, year = {2024}, author = {Du, S and Chen, J and Li, J and Qian, W and Wu, S and Peng, Q and Liu, Y and Pan, T and Li, Y and Hadi, SS and Tan, J and Yuan, Z and Wang, J and Tang, K and Wang, Z and Wen, Y and Dong, X and Zhou, W and Ruiz-Linares, A and Shi, Y and Jin, L and Liu, F and Zhang, M and Wang, S}, title = {A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features.}, journal = {Journal of genetics and genomics = Yi chuan xue bao}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jgg.2024.07.005}, pmid = {39002897}, issn = {1673-8527}, abstract = {Facial morphology, a complex trait influenced by genetics, holds great significance in evolutionary research. However, due to limited fossil evidence, the facial characteristics of Neanderthals and Denisovans have remained largely unknown. In this study, we conducted a large-scale multi-ethnic meta-analysis of Genome-Wide Association Study (GWAS), including 9674 East Asians and 10,115 Europeans, quantitatively assessing 78 facial traits using 3D facial images. We identified 71 genomic loci associated with facial features, including 21 novel loci. We developed a facial polygenic score (FPS) that enables the prediction of facial features based on genetic information. Interestingly, the distribution of FPSs among populations from diverse continental groups exhibited significant correlations with observed facial features. Furthermore, we applied the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA, and aligned predictions with the fossil records. Our results suggested that Neanderthals and Denisovans likely shared similar facial features, such as a wider but shorter nose and a wider endocanthion distance. The decreased mouth width was characterized specifically in Denisovan. The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.}, }
@article {pmid38961285, year = {2024}, author = {Xia, H and Zhang, D and Wang, J and Fagernäs, Z and Li, T and Li, Y and Yao, J and Lin, D and Troché, G and Smith, GM and Chen, X and Cheng, T and Shen, X and Han, Y and Olsen, JV and Shen, Z and Pei, Z and Hublin, JJ and Chen, F and Welker, F}, title = {Middle and Late Pleistocene Denisovan subsistence at Baishiya Karst Cave.}, journal = {Nature}, volume = {632}, number = {8023}, pages = {108-113}, pmid = {38961285}, issn = {1476-4687}, mesh = {Animals ; *Caves ; *Fossils ; *Proteomics ; *Hominidae/classification/genetics ; History, Ancient ; Humans ; Mandible/anatomy &amp; histology ; China ; DNA, Mitochondrial/genetics ; Bone and Bones/chemistry/anatomy &amp; histology ; Archaeology ; Phylogeny ; }, abstract = {Genetic and fragmented palaeoanthropological data suggest that Denisovans were once widely distributed across eastern Eurasia[1-3]. Despite limited archaeological evidence, this indicates that Denisovans were capable of adapting to a highly diverse range of environments. Here we integrate zooarchaeological and proteomic analyses of the late Middle to Late Pleistocene faunal assemblage from Baishiya Karst Cave on the Tibetan Plateau, where a Denisovan mandible and Denisovan sedimentary mitochondrial DNA were found[3,4]. Using zooarchaeology by mass spectrometry, we identify a new hominin rib specimen that dates to approximately 48-32 thousand years ago (layer 3). Shotgun proteomic analysis taxonomically assigns this specimen to the Denisovan lineage, extending their presence at Baishiya Karst Cave well into the Late Pleistocene. Throughout the stratigraphic sequence, the faunal assemblage is dominated by Caprinae, together with megaherbivores, carnivores, small mammals and birds. The high proportion of anthropogenic modifications on the bone surfaces suggests that Denisovans were the primary agent of faunal accumulation. The chaîne opératoire of carcass processing indicates that animal taxa were exploited for their meat, marrow and hides, while bone was also used as raw material for the production of tools. Our results shed light on the behaviour of Denisovans and their adaptations to the diverse and fluctuating environments of the late Middle and Late Pleistocene of eastern Eurasia.}, }
@article {pmid38889149, year = {2024}, author = {Yermakovich, D and André, M and Brucato, N and Kariwiga, J and Leavesley, M and Pankratov, V and Mondal, M and Ricaut, FX and Dannemann, M}, title = {Denisovan admixture facilitated environmental adaptation in Papua New Guinean populations.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {26}, pages = {e2405889121}, pmid = {38889149}, issn = {1091-6490}, support = {TK214//HM | Estonian Research Competency Council (Research Competency Council)/ ; 810645//EC | Horizon Europe | WPSERA | HORIZON EUROPE Reforming and enhancing the European Research and Innovation system (REERIS)/ ; MOBEC008//EC | European Regional Development Fund (ERDF)/ ; PAPUAEVOL 20-CE12-0003-01//Association Nationale de la Recherche et de la Technologie (ANRT)/ ; NA//French Ministry of Foreign and European Affairs/ ; NA//Laboratoire d'Excellence TULIP (Labex TULIP)/ ; NA//Leakey Foundation (The Leakey Foundation)/ ; }, mesh = {Papua New Guinea ; Humans ; Animals ; *Haplotypes ; *Neanderthals/genetics ; Adaptation, Physiological/genetics ; Genetics, Population ; }, abstract = {Neandertals and Denisovans, having inhabited distinct regions in Eurasia and possibly Oceania for over 200,000 y, experienced ample time to adapt to diverse environmental challenges these regions presented. Among present-day human populations, Papua New Guineans (PNG) stand out as one of the few carrying substantial amounts of both Neandertal and Denisovan DNA, a result of past admixture events with these archaic human groups. This study investigates the distribution of introgressed Denisovan and Neandertal DNA within two distinct PNG populations, residing in the highlands of Mt Wilhelm and the lowlands of Daru Island. These locations exhibit unique environmental features, some of which may parallel the challenges that archaic humans once confronted and adapted to. Our results show that PNG highlanders carry higher levels of Denisovan DNA compared to PNG lowlanders. Among the Denisovan-like haplotypes with higher frequencies in highlander populations, those exhibiting the greatest frequency difference compared to lowlander populations also demonstrate more pronounced differences in population frequencies than frequency-matched nonarchaic variants. Two of the five most highly differentiated of those haplotypes reside in genomic areas linked to brain development genes. Conversely, Denisovan-like haplotypes more frequent in lowlanders overlap with genes associated with immune response processes. Our findings suggest that Denisovan DNA has provided genetic variation associated with brain biology and immune response to PNG genomes, some of which might have facilitated adaptive processes to environmental challenges.}, }
@article {pmid38802968, year = {2024}, author = {Roca-Ayats, N and Maceda, I and Bruque, CD and Martínez-Gil, N and Garcia-Giralt, N and Cozar, M and Mellibovsky, L and Van Hul, W and Lao, O and Grinberg, D and Balcells, S}, title = {Evolutionary and functional analyses of LRP5 in archaic and extant modern humans.}, journal = {Human genomics}, volume = {18}, number = {1}, pages = {53}, pmid = {38802968}, issn = {1479-7364}, support = {SAF 2016-75948R and PID2019-107188RB-C21//Ministerio de Ciencia e Innovaci&#xf3;n/ ; GRC 2017 SGR 937//Generalitat de Catalunya/ ; 2017SGR:00738//Catalan Government/ ; PGC2018-098574-B-I00//Ministerio de Econom&#xed;a y Competitividad/ ; }, mesh = {Humans ; *Low Density Lipoprotein Receptor-Related Protein-5/genetics ; *Evolution, Molecular ; Animals ; *Neanderthals/genetics ; Selection, Genetic/genetics ; Hominidae/genetics ; Haplotypes/genetics ; Bone Density/genetics ; Genome, Human/genetics ; }, abstract = {BACKGROUND: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced.<br><br>RESULTS: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first &#x3b2;-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation.<br><br>CONCLUSIONS: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant&#xa0;modern humans and archaic Homo populations.}, }
@article {pmid38782905, year = {2024}, author = {Yee, SW and Ferrández-Peral, L and Alentorn-Moron, P and Fontsere, C and Ceylan, M and Koleske, ML and Handin, N and Artegoitia, VM and Lara, G and Chien, HC and Zhou, X and Dainat, J and Zalevsky, A and Sali, A and Brand, CM and Wolfreys, FD and Yang, J and Gestwicki, JE and Capra, JA and Artursson, P and Newman, JW and Marquès-Bonet, T and Giacomini, KM}, title = {Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4380}, pmid = {38782905}, issn = {2041-1723}, support = {GM117163//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 EY032161/EY/NEI NIH HHS/United States ; R01 GM139875/GM/NIGMS NIH HHS/United States ; GM139875//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 GM117163/GM/NIGMS NIH HHS/United States ; EY032161//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; }, mesh = {Animals ; Humans ; Amino Acid Sequence ; Estradiol/metabolism ; HEK293 Cells ; Hominidae/genetics/metabolism ; Mutation, Missense ; Organic Cation Transport Proteins/metabolism/genetics ; *Primates/genetics ; Pseudogenes ; Substrate Specificity ; }, abstract = {SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.}, }
@article {pmid38630824, year = {2024}, author = {Liu, X and Koyama, S and Tomizuka, K and Takata, S and Ishikawa, Y and Ito, S and Kosugi, S and Suzuki, K and Hikino, K and Koido, M and Koike, Y and Horikoshi, M and Gakuhari, T and Ikegawa, S and Matsuda, K and Momozawa, Y and Ito, K and Kamatani, Y and Terao, C}, title = {Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing.}, journal = {Science advances}, volume = {10}, number = {16}, pages = {eadi8419}, pmid = {38630824}, issn = {2375-2548}, mesh = {Humans ; Japan ; *Diabetes Mellitus, Type 2 ; Selection, Genetic ; Whole Genome Sequencing ; Exome ; }, abstract = {We generated Japanese Encyclopedia of Whole-Genome/Exome Sequencing Library (JEWEL), a high-depth whole-genome sequencing dataset comprising 3256 individuals from across Japan. Analysis of JEWEL revealed genetic characteristics of the Japanese population that were not discernible using microarray data. First, rare variant-based analysis revealed an unprecedented fine-scale genetic structure. Together with population genetics analysis, the present-day Japanese can be decomposed into three ancestral components. Second, we identified unreported loss-of-function (LoF) variants and observed that for specific genes, LoF variants appeared to be restricted to a more limited set of transcripts than would be expected by chance, with PTPRD as a notable example. Third, we identified 44 archaic segments linked to complex traits, including a Denisovan-derived segment at NKX6-1 associated with type 2 diabetes. Most of these segments are specific to East Asians. Fourth, we identified candidate genetic loci under recent natural selection. Overall, our work provided insights into genetic characteristics of the Japanese population.}, }
@article {pmid38558123, year = {2024}, author = {Aneli, S and Ceccatelli Berti, C and Gilea, AI and Birolo, G and Mutti, G and Pavesi, A and Baruffini, E and Goffrini, P and Capelli, C}, title = {Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae.}, journal = {Human molecular genetics}, volume = {33}, number = {13}, pages = {1152-1163}, doi = {10.1093/hmg/ddae057}, pmid = {38558123}, issn = {1460-2083}, support = {//Departments of Excellence/ ; //Italian Ministry for University and Research (MIUR, 2018-2022 and MUR, 2023-2027)/ ; //Programma Nazionale della Ricerca PNR 2021-2027 e PON "Ricerca e Innovazione" 2014-2020-progetti di ricerca su tematiche "Innovazione" e "Green"/ ; RF-2016-02361241//Italian Ministry of Health/ ; //University of Parma/ ; GGP19287A//Italian Telethon Foundation/ ; }, mesh = {Humans ; *Saccharomyces cerevisiae/genetics ; *Neanderthals/genetics ; Animals ; Genetic Variation ; Mitochondria/genetics/metabolism ; Alleles ; Genetic Introgression ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; }, abstract = {Neanderthal and Denisovan hybridisation with modern humans has generated a non-random genomic distribution of introgressed regions, the result of drift and selection dynamics. Cross-species genomic incompatibility and more efficient removal of slightly deleterious archaic variants have been proposed as selection-based processes involved in the post-hybridisation purge of archaic introgressed regions. Both scenarios require the presence of functionally different alleles across Homo species onto which selection operated differently according to which populations hosted them, but only a few of these variants have been pinpointed so far. In order to identify functionally divergent archaic variants removed in humans, we focused on mitonuclear genes, which are underrepresented in the genomic landscape of archaic humans. We searched for non-synonymous, fixed, archaic-derived variants present in mitonuclear genes, rare or absent in human populations. We then compared the functional impact of archaic and human variants in the model organism Saccharomyces cerevisiae. Notably, a variant within the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) gene exhibited a significant decrease in respiratory activity and a substantial reduction of Cox2 levels, a proxy for mitochondrial protein biosynthesis, coupled with the accumulation of the YARS2 protein precursor and a lower amount of mature enzyme. Our work suggests that this variant is associated with mitochondrial functionality impairment, thus contributing to the purging of archaic introgression in YARS2. While different molecular mechanisms may have impacted other mitonuclear genes, our approach can be extended to the functional screening of mitonuclear genetic variants present across species and populations.}, }
@article {pmid38458749, year = {2024}, author = {Geier, A and Trost, J and Wang, K and Schmid, C and Krawczyk, M and Schiffels, S}, title = {PNPLA3 fatty liver allele was fixed in Neanderthals and segregates neutrally in humans.}, journal = {Gut}, volume = {73}, number = {6}, pages = {1008-1014}, doi = {10.1136/gutjnl-2023-331594}, pmid = {38458749}, issn = {1468-3288}, support = {851511/ERC_/European Research Council/International ; }, mesh = {Animals ; Humans ; *Acyltransferases/genetics ; *Alleles ; DNA, Ancient/analysis ; *Fatty Liver/genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; *Neanderthals/genetics ; *Phospholipases A2, Calcium-Independent/genetics ; }, abstract = {OBJECTIVE: Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date.<br><br>DESIGN: Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed.<br><br>RESULTS: We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15&#x2009;000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10&#x2009;000 years.<br><br>CONCLUSION: Archaic human individuals exclusively carried a fixed PNPLA3 allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3 p.I148M.}, }
@article {pmid38405782, year = {2024}, author = {Kerdoncuff, E and Skov, L and Patterson, N and Zhao, W and Lueng, YY and Schellenberg, GD and Smith, JA and Dey, S and Ganna, A and Dey, AB and Kardia, SLR and Lee, J and Moorjani, P}, title = {50,000 years of Evolutionary History of India: Insights from ~2,700 Whole Genome Sequences.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38405782}, issn = {2692-8205}, support = {R01 AG051125/AG/NIA NIH HHS/United States ; R35 GM142978/GM/NIGMS NIH HHS/United States ; RF1 AG055273/AG/NIA NIH HHS/United States ; }, abstract = {India has been underrepresented in whole genome sequencing studies. We generated 2,762 high coverage genomes from India-including individuals from most geographic regions, speakers of all major languages, and tribal and caste groups-providing a comprehensive survey of genetic variation in India. With these data, we reconstruct the evolutionary history of India through space and time at fine scales. We show that most Indians derive ancestry from three ancestral groups related to ancient Iranian farmers, Eurasian Steppe pastoralists and South Asian hunter-gatherers. We uncover a common source of Iranian-related ancestry from early Neolithic cultures of Central Asia into the ancestors of Ancestral South Indians (ASI), Ancestral North Indians (ANI), Austro-asiatic-related and East Asian-related groups in India. Following these admixtures, India experienced a major demographic shift towards endogamy, resulting in extensive homozygosity and identity-by-descent sharing among individuals. At deep time scales, Indians derive around 1-2% of their ancestry from gene flow from archaic hominins, Neanderthals and Denisovans. By assembling the surviving fragments of archaic ancestry in modern Indians, we recover ~1.5 Gb (or 50%) of the introgressing Neanderthal and ~0.6 Gb (or 20%) of the introgressing Denisovan genomes, more than any other previous archaic ancestry study. Moreover, Indians have the largest variation in Neanderthal ancestry, as well as the highest amount of population-specific Neanderthal segments among worldwide groups. Finally, we demonstrate that most of the genetic variation in Indians stems from a single major migration out of Africa that occurred around 50,000 years ago, with minimal contribution from earlier migration waves. Together, these analyses provide a detailed view of the population history of India and underscore the value of expanding genomic surveys to diverse groups outside Europe.}, }
@article {pmid38337062, year = {2024}, author = {Végh, EI and Douka, K}, title = {SpecieScan: semi-automated taxonomic identification of bone collagen peptides from MALDI-ToF-MS.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {3}, pages = {}, pmid = {38337062}, issn = {1367-4811}, support = {/ERC_/European Research Council/International ; }, mesh = {Animals ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; *Algorithms ; *Peptides/chemistry ; Databases, Factual ; Automation ; Mammals ; }, abstract = {MOTIVATION: Zooarchaeology by Mass Spectrometry (ZooMS) is a palaeoproteomics method for the taxonomic determination of collagen, which traditionally involves challenging manual spectra analysis with limitations in quantitative results. As the ZooMS reference database expands, a faster and reproducible identification tool is necessary. Here we present SpecieScan, an open-access algorithm for automating taxa identification from raw MALDI-ToF mass spectrometry (MS) data.<br><br>RESULTS: SpecieScan was developed using R (pre-processing) and Python (automation). The algorithm's output includes identified peptide markers, closest matching taxonomic group (taxon, family, order), correlation scores with the reference databases, and contaminant peaks present in the spectra. Testing on original MS data from bones discovered at Palaeothic archaeological sites, including Denisova Cave in Russia, as well as using publicly-available, externally produced data, we achieved >90% accuracy at the genus-level and &#x223c;92% accuracy at the family-level for mammalian bone collagen previously analysed manually.<br><br>The SpecieScan algorithm, along with the raw data used in testing, results, reference database, and common contaminants lists are freely available on Github (https://github.com/mesve/SpecieScan).}, }
@article {pmid38213708, year = {2023}, author = {Borodko, DD and Zhenilo, SV and Sharko, FS}, title = {Search for differentially methylated regions in ancient and modern genomes.}, journal = {Vavilovskii zhurnal genetiki i selektsii}, volume = {27}, number = {7}, pages = {820-828}, doi = {10.18699/VJGB-23-95}, pmid = {38213708}, issn = {2500-0462}, abstract = {Currently, active research is focused on investigating the mechanisms that regulate the development of various pathologies and their evolutionary dynamics. Epigenetic mechanisms, such as DNA methylation, play a significant role in evolutionary processes, as their changes have a faster impact on the phenotype compared to mutagenesis. In this study, we attempted to develop an algorithm for identifying differentially methylated regions associated with metabolic syndrome, which have undergone methylation changes in humans during the transition from a hunter-gatherer to a sedentary lifestyle. The application of existing whole-genome bisulfite sequencing methods is limited for ancient samples due to their low quality and fragmentation, and the approach to obtaining DNA methylation profiles differs significantly between ancient hunter-gatherer samples and modern tissues. In this study, we validated DamMet, an algorithm for reconstructing ancient methylomes. Application of DamMet to Neanderthal and Denisovan genomes showed a moderate level of correlation with previously published methylation profiles and demonstrated an underestimation of methylation levels in the reconstructed profiles by an average of 15-20 %. Additionally, we developed a new Python-based algorithm that allows for the comparison of methylomes in ancient and modern samples, despite the absence of methylation profiles in modern bone tissue within the context of obesity. This analysis involves a two-step data processing approach, where the first step involves the identification and filtration of tissue-specific methylation regions, and the second step focuses on the direct search for differentially methylated regions in specific areas associated with the researcher's target condition. By applying this algorithm to test data, we identified 38 differentially methylated regions associated with obesity, the majority of which were located in promoter regions. The pipeline demonstrated sufficient efficiency in detecting these regions. These results confirm the feasibility of reconstructing DNA methylation profiles in ancient samples and comparing them with modern methylomes. Furthermore, possibilities for further methodological development and the implementation of a new step for studying differentially methylated positions associated with evolutionary processes are discussed.}, }
@article {pmid38189581, year = {2024}, author = {Ziv, I and Avni, I and Dinstein, I and Meiri, G and Bonneh, YS}, title = {Oculomotor randomness is higher in autistic children and increases with the severity of symptoms.}, journal = {Autism research : official journal of the International Society for Autism Research}, volume = {17}, number = {2}, pages = {249-265}, doi = {10.1002/aur.3083}, pmid = {38189581}, issn = {1939-3806}, support = {657/21//Israel Science Foundation/ ; 1150/20//Israel Science Foundation/ ; }, mesh = {Child ; Humans ; Infant ; Child, Preschool ; Eye Movements ; *Autism Spectrum Disorder/psychology ; *Autistic Disorder ; Saccades ; }, abstract = {A variety of studies have suggested that at least some children with autism spectrum disorder (ASD) view the world differently. Differences in gaze patterns as measured by eye tracking have been demonstrated during visual exploration of images and natural viewing of movies with social content. Here we analyzed the temporal randomness of saccades and blinks during natural viewing of movies, inspired by a recent measure of "randomness" applied to micro-movements of the hand and head in ASD (Torres et al., 2013; Torres &amp; Denisova, 2016). We analyzed a large eye-tracking dataset of 189 ASD and 41 typically developing (TD) children (1-11 years old) who watched three movie clips with social content, each repeated twice. We found that oculomotor measures of randomness, obtained from gamma parameters of inter-saccade intervals (ISI) and blink duration distributions, were significantly higher in the ASD group compared with the TD group and were correlated with the ADOS comparison score, reflecting increased "randomness" in more severe cases. Moreover, these measures of randomness decreased with age, as well as with higher cognitive scores in both groups and were consistent across repeated viewing of each movie clip. Highly "random" eye movements in ASD children could be associated with high "neural variability" or noise, poor sensory-motor control, or weak engagement with the movies. These findings could contribute to the future development of oculomotor biomarkers as part of an integrative diagnostic tool for ASD.}, }
@article {pmid38166646, year = {2024}, author = {Levinstein Hallak, K and Rosset, S}, title = {Dating ancient splits in phylogenetic trees, with application to the human-Neanderthal split.}, journal = {BMC genomic data}, volume = {25}, number = {1}, pages = {4}, pmid = {38166646}, issn = {2730-6844}, support = {2180/20//Israeli Science Foundation grant/ ; }, mesh = {Animals ; Humans ; *Neanderthals/genetics ; Phylogeny ; Pan troglodytes/genetics ; Bayes Theorem ; *Hominidae/genetics ; DNA, Mitochondrial/genetics ; }, abstract = {BACKGROUND: We tackle the problem of estimating species TMRCAs (Time to Most Recent Common Ancestor), given a genome sequence from each species and a large known phylogenetic tree with a known structure (typically from one of the species). The number of transitions at each site from the first sequence to the other is assumed to be Poisson distributed, and only the parity of the number of transitions is observed. The detailed phylogenetic tree contains information about the transition rates in each site. We use this formulation to develop and analyze multiple estimators of the species' TMRCA. To test our methods, we use mtDNA substitution statistics from the well-established Phylotree as a baseline for data simulation such that the substitution rate per site mimics the real-world observed rates.<br><br>RESULTS: We evaluate our methods using simulated data and compare them to the Bayesian optimizing software BEAST2, showing that our proposed estimators are accurate for a wide range of TMRCAs and significantly outperform BEAST2. We then apply the proposed estimators on Neanderthal, Denisovan, and Chimpanzee mtDNA genomes to better estimate their TMRCA with modern humans and find that their TMRCA is substantially later, compared to values cited recently in the literature.<br><br>CONCLUSIONS: Our methods utilize the transition statistics from the entire known human mtDNA phylogenetic tree (Phylotree), eliminating the requirement to reconstruct a tree encompassing the specific sequences of interest. Moreover, they demonstrate notable improvement in both running speed and accuracy compared to BEAST2, particularly for earlier TMRCAs like the human-Chimpanzee split. Our results date the human - Neanderthal TMRCA to be [Formula: see text] years ago, considerably later than values cited in other recent studies.}, }
@article {pmid38051947, year = {2023}, author = {Wroblewski, TH and Witt, KE and Lee, SB and Malhi, RS and Peede, D and Huerta-Sánchez, E and Villanea, FA and Claw, KG}, title = {Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications.}, journal = {Genome biology and evolution}, volume = {15}, number = {12}, pages = {}, pmid = {38051947}, issn = {1759-6653}, support = {R35 GM128946/GM/NIGMS NIH HHS/United States ; R35 HG011319/HG/NHGRI NIH HHS/United States ; R35HG011319/HG/NHGRI NIH HHS/United States ; 1R35GM128946-01/NH/NIH HHS/United States ; T32 GM128596/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Neanderthals/genetics ; Pharmacogenetics ; Genome, Human ; *Hominidae/genetics ; Biological Evolution ; }, abstract = {Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes-genes responsible for the processing of exogenous substances such as food, pollutants, and medications-as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore 11 key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these 11 CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.}, }
@article {pmid38020913, year = {2023}, author = {Agata, A and Ohtsuka, S and Noji, R and Gotoh, H and Ono, K and Nomura, T}, title = {A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1247361}, pmid = {38020913}, issn = {2296-634X}, abstract = {Changes in genomic structures underlie phenotypic diversification in organisms. Amino acid-changing mutations affect pleiotropic functions of proteins, although little is known about how mutated proteins are adapted in existing developmental programs. Here we investigate the biological effects of a variant of the GLI3 transcription factor (GLI3[R1537C]) carried in Neanderthals and Denisovans, which are extinct hominins close to modern humans. R1537C does not compromise protein stability or GLI3 activator-dependent transcriptional activities. In contrast, R1537C affects the regulation of downstream target genes associated with developmental processes. Furthermore, genome-edited mice carrying the Neanderthal/Denisovan GLI3 mutation exhibited various alterations in skeletal morphology. Our data suggest that an extinct hominin-type GLI3 contributes to species-specific anatomical variations, which were tolerated by relaxed constraint in developmental programs during human evolution.}, }
@article {pmid37853790, year = {2023}, author = {Sokolov, S and Shchenkov, S and Frolov, E and Denisova, S and Gordeev, I}, title = {Molecular and morphological screening of Podocotyle spp. (Trematoda: Opecoelidae) sheds light on their diversity in Northwest Pacific and eastern European Arctic.}, journal = {Journal of helminthology}, volume = {97}, number = {}, pages = {e78}, doi = {10.1017/S0022149X23000603}, pmid = {37853790}, issn = {1475-2697}, mesh = {Animals ; Phylogeny ; *Trematoda ; Fishes ; Life Cycle Stages ; DNA, Ribosomal/genetics ; }, abstract = {Podocotyle is a genus of marine opecoelid digeneans that parasitize a wide variety of fish as adults. We present the first phylogenetic analysis of several Podocotyle isolates using nuclear 28S rDNA and mitochondrial cox1 DNA regions. New sequences were obtained for Podocotyle specimens from fish caught in the Sea of Okhotsk and the White Sea. Based on morphological and molecular data, eight Podocotyle lineages of species rank were revealed. However, this diversity is poorly formalized within the current taxonomic model of the genus. As a result, we identified Podocotyle cf. angulata, Podocotyle cf. atomon, Podocotyle cf. reflexa, Podocotyle atomon of Sokolov et al., 2019, Podocotyle sp. of Denisova et al., 2023, Podocotyle sp. 1, Podocotyle sp. 2 and Podocotyle sp. 3. We also highlight the unresolved question of the life cycles of representatives of Podocotyle whose intramolluscan stages parasitize the intertidal snails Littorina spp.}, }
@article {pmid37808839, year = {2023}, author = {Villanea, FA and Peede, D and Kaufman, EJ and Añorve-Garibay, V and Witt, KE and Villa-Islas, V and Zeloni, R and Marnetto, D and Moorjani, P and Jay, F and Valdmanis, PN and Ávila-Arcos, MC and Huerta-Sánchez, E}, title = {The MUC19 gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37808839}, issn = {2692-8205}, support = {R01 NS122766/NS/NINDS NIH HHS/United States ; R35 GM128946/GM/NIGMS NIH HHS/United States ; R35 GM142978/GM/NIGMS NIH HHS/United States ; T32 GM128596/GM/NIGMS NIH HHS/United States ; }, abstract = {All humans carry a small fraction of archaic ancestry across the genome, the legacy of gene flow from Neanderthals, Denisovans, and other hominids into the ancestors of modern humans. While the effects of Neanderthal ancestry on human fitness and health have been explored more thoroughly, there are fewer examples of adaptive introgression of Denisovan variants. Here, we study the gene MUC19, for which some modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions, from lubrication to immunity. We find the diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed Latin American individuals among global population, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that some Neanderthals--Vindija and Chagyrskaya--carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. Finally, we find that the Denisovan-like MUC19 haplotype carries a higher copy number of a 30 base-pair variable number tandem repeat relative to the Human-like haplotype, and that copy numbers of this repeat are exceedingly high in American populations. Our results suggest that the Denisovan-like MUC19 haplotype served as the raw genetic material for positive selection as American populations adapted to novel environments during their movement from Beringia into North and then South America.}, }
@article {pmid37790518, year = {2023}, author = {Yee, SW and Ferrández-Peral, L and Alentorn, P and Fontsere, C and Ceylan, M and Koleske, ML and Handin, N and Artegoitia, VM and Lara, G and Chien, HC and Zhou, X and Dainat, J and Zalevsky, A and Sali, A and Brand, CM and Capra, JA and Artursson, P and Newman, JW and Marques-Bonet, T and Giacomini, KM}, title = {Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37790518}, issn = {2693-5015}, support = {R01 GM117163/GM/NIGMS NIH HHS/United States ; R01 GM139875/GM/NIGMS NIH HHS/United States ; }, abstract = {SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17β-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.}, }
@article {pmid37758744, year = {2023}, author = {Bacon, AM and Bourgon, N and Dufour, E and Demeter, F and Zanolli, C and Westaway, KE and Joannes-Boyau, R and Duringer, P and Ponche, JL and Morley, MW and Suzzoni, E and Frangeul, S and Boesch, Q and Antoine, PO and Boualaphane, S and Sichanthongtip, P and Sihanam, D and Huong, NTM and Tuan, NA and Fiorillo, D and Tombret, O and Patole-Edoumba, E and Zachwieja, A and Luangkhoth, T and Souksavatdy, V and Dunn, TE and Shackelford, L and Hublin, JJ}, title = {Palaeoenvironments and hominin evolutionary dynamics in southeast Asia.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {16165}, pmid = {37758744}, issn = {2045-2322}, mesh = {Animals ; Laos ; *Forests ; *Biological Evolution ; Caves ; China ; }, abstract = {Secure environmental contexts are crucial for hominin interpretation and comparison. The discovery of a Denisovan individual and associated fauna at Tam Ngu Hao 2 (Cobra) Cave, Laos, dating back to 164-131 ka, allows for environmental comparisons between this (sub)tropical site and the Palearctic Denisovan sites of Denisova Cave (Russia) and Baishiya Karst Cave (China). Denisovans from northern latitudes foraged in a mix of forested and open landscapes, including tundra and steppe. Using stable isotope values from the Cobra Cave assemblage, we demonstrate that, despite the presence of nearby canopy forests, the Denisovan individual from Cobra Cave primarily consumed plants and/or animals from open forests and savannah. Using faunal evidence and proxy indicators of climates, results herein highlight a local expansion of rainforest at ~ 130 ka, raising questions about how Denisovans responded to this local climate change. Comparing the diet and habitat of the archaic hominin from Cobra Cave with those of early Homo sapiens from Tam Pà Ling Cave (46-43 ka), Laos, it appears that only our species was able to exploit rainforest resources.}, }
@article {pmid37747921, year = {2023}, author = {Roca-Umbert, A and Garcia-Calleja, J and Vogel-González, M and Fierro-Villegas, A and Ill-Raga, G and Herrera-Fernández, V and Bosnjak, A and Muntané, G and Gutiérrez, E and Campelo, F and Vicente, R and Bosch, E}, title = {Human genetic adaptation related to cellular zinc homeostasis.}, journal = {PLoS genetics}, volume = {19}, number = {9}, pages = {e1010950}, pmid = {37747921}, issn = {1553-7404}, mesh = {Animals ; Humans ; HEK293 Cells ; *Hominidae/genetics ; Homeostasis/genetics ; Zinc ; Human Genetics ; Selection, Genetic ; Haplotypes ; Genome, Human ; }, abstract = {SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.}, }
@article {pmid37723347, year = {2024}, author = {Peyrégne, S and Slon, V and Kelso, J}, title = {More than a decade of genetic research on the Denisovans.}, journal = {Nature reviews. Genetics}, volume = {25}, number = {2}, pages = {83-103}, pmid = {37723347}, issn = {1471-0064}, mesh = {Animals ; Humans ; *Neanderthals/genetics ; *Hominidae ; Biological Evolution ; DNA ; Genetic Research ; Genome, Human ; }, abstract = {Denisovans, a group of now extinct humans who lived in Eastern Eurasia in the Middle and Late Pleistocene, were first identified from DNA sequences just over a decade ago. Only ten fragmentary remains from two sites have been attributed to Denisovans based entirely on molecular information. Nevertheless, there has been great interest in using genetic data to understand Denisovans and their place in human history. From the reconstruction of a single high-quality genome, it has been possible to infer their population history, including events of admixture with other human groups. Additionally, the identification of Denisovan DNA in the genomes of present-day individuals has provided insights into the timing and routes of dispersal of ancient modern humans into Asia and Oceania, as well as the contributions of archaic DNA to the physiology of present-day people. In this Review, we synthesize more than a decade of research on Denisovans, reconcile controversies and summarize insights into their population history and phenotype. We also highlight how our growing knowledge about Denisovans has provided insights into our own evolutionary history.}, }
@article {pmid37713634, year = {2023}, author = {Ge, X and Lu, Y and Chen, S and Gao, Y and Ma, L and Liu, L and Liu, J and Ma, X and Kang, L and Xu, S}, title = {Genetic Origins and Adaptive Evolution of the Deng People on the Tibetan Plateau.}, journal = {Molecular biology and evolution}, volume = {40}, number = {10}, pages = {}, pmid = {37713634}, issn = {1537-1719}, mesh = {Humans ; Adaptor Proteins, Signal Transducing ; Altitude ; *Asian People/genetics ; Haplotypes ; Tibet ; }, abstract = {The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30-60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700-7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000-14,000 years; TIB-HAN, 7,200-10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.}, }
@article {pmid37616382, year = {2024}, author = {Denisova, K}, title = {English translation of the first study reporting cyclical periods of increased respiration and eye and body motility during sleep in infants in 1926, with commentary.}, journal = {Sleep}, volume = {47}, number = {1}, pages = {}, doi = {10.1093/sleep/zsad219}, pmid = {37616382}, issn = {1550-9109}, support = {R01 MH121605/MH/NIMH NIH HHS/United States ; R01MH121605/MH/NIMH NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Infant ; Child ; Humans ; *Sleep/physiology ; *Sleep, REM/physiology ; Sleep Stages/physiology ; Respiration ; Eye Movements ; }, abstract = {This is the first English translation of the work Periodic phenomena in the sleep in children, published in 1926 in the Journal Novoe v refleksologii i fiziologii nervnoi sistemy (Vol. 2, pp. 338-345) by Maria Denisova and Nicholai Figurin; it is the first study to report data on what is currently termed rapid eye movement (REM) sleep. The authors acquired continuous quantitative respiration data, as well as, eye and body movements during sleep in children for up to 6 hours, and discovered several novel features of sleep cycles in healthy infants from birth to about 1 year of age. First, the study reports cyclical periods of increased respiration and eye and body movements, with rapid ocular movements visible under relaxed eyelids (separation: 0.5-1 mm). These observations suggest atonia of REM sleep. Second, the length of the complete cycle (alternating active and quiet sleep phases or states) is about 50 minutes, an estimate that is consistent with later work. Third, the study identifies infant-specific ordering of sleep states, with the active phase beginning after sleep onset, followed by the quiescence phase. Importantly, these published data on sleep cycles precede all published studies related to the state now termed REM sleep by about 30 years (i.e. publishing in Science and in the Journal of Applied Physiology in the 1950s by Eugene Aserinski and Nathaniel Kleitman). In the historical commentary accompanying this translation, the findings of those later works are carefully compared to the original data on respiration and ocular and body motility cycles during sleep in infants, first reported and published by Denisova and Figurin (1926).}, }
@article {pmid37609337, year = {2023}, author = {Yee, SW and Ferrández-Peral, L and Alentorn, P and Fontsere, C and Ceylan, M and Koleske, ML and Handin, N and Artegoitia, VM and Lara, G and Chien, HC and Zhou, X and Dainat, J and Zalevsky, A and Sali, A and Brand, CM and Capra, JA and Artursson, P and Newman, JW and Marques-Bonet, T and Giacomini, KM}, title = {Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37609337}, issn = {2692-8205}, support = {R01 GM117163/GM/NIGMS NIH HHS/United States ; R01 GM139875/GM/NIGMS NIH HHS/United States ; }, abstract = {SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17β-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.}, }
@article {pmid37589132, year = {2023}, author = {Essel, E}, title = {Releasing secrets bound to ancient remains with modern DNA extraction techniques: an interview with Elena Essel.}, journal = {BioTechniques}, volume = {75}, number = {2}, pages = {42-46}, doi = {10.2144/btn-2023-0067}, pmid = {37589132}, issn = {1940-9818}, mesh = {Humans ; Female ; *DNA, Ancient ; *Anthropology ; Body Remains ; Sequence Analysis, DNA ; Universities ; }, abstract = {Elena Essel (Msc) spoke to Ebony Torrington, Managing Editor of BioTechniques. Essel is a molecular biologist in Matthias Meyer's Advanced DNA Sequencing Techniques group at the Max Planck Institute for Evolutionary Anthropology in Leipzig (Germany). Essel studied biology at University of Erlangen-Nuremberg (Erlangen, Germany) for her bachelor's and in Martin-Luther-University Halle-Wittenberg (Halle an der Saale, Germany) for her master's. Essel worked in Meyer's group on DNA extraction of very degraded material for her master's thesis. Meyer is an expert in developing new cutting-edge methods for researching ancient DNA, with a focus on skeletal remains, and more recently on sediment remains. Essel now focusses on DNA sampling and extraction aspects of the pipeline at Meyer's lab for the ancient DNA workflow.}, }
@article {pmid37561879, year = {2023}, author = {Ruan, J and Timmermann, A and Raia, P and Yun, KS and Zeller, E and Mondanaro, A and Di Febbraro, M and Lemmon, D and Castiglione, S and Melchionna, M}, title = {Climate shifts orchestrated hominin interbreeding events across Eurasia.}, journal = {Science (New York, N.Y.)}, volume = {381}, number = {6658}, pages = {699-704}, doi = {10.1126/science.add4459}, pmid = {37561879}, issn = {1095-9203}, mesh = {Animals ; Humans ; Fossils ; Gene Flow ; *Neanderthals/genetics ; *Climate Change ; }, abstract = {When, where, and how often hominin interbreeding happened is largely unknown. We study the potential for Neanderthal-Denisovan admixture using species distribution models that integrate extensive fossil, archaeological, and genetic data with transient coupled general circulation model simulations of global climate and biomes. Our Pleistocene hindcast of past hominins' habitat suitability reveals pronounced climate-driven zonal shifts in the main overlap region of Denisovans and Neanderthals in central Eurasia. These shifts, which influenced the timing and intensity of potential interbreeding events, can be attributed to the response of climate and vegetation to past variations in atmospheric carbon dioxide and Northern Hemisphere ice-sheet volume. Therefore, glacial-interglacial climate swings likely played an important role in favoring gene flow between archaic humans.}, }
@article {pmid37516110, year = {2023}, author = {Maasch, JRMA and Torres, MDT and Melo, MCR and de la Fuente-Nunez, C}, title = {Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning.}, journal = {Cell host &amp; microbe}, volume = {31}, number = {8}, pages = {1260-1274.e6}, doi = {10.1016/j.chom.2023.07.001}, pmid = {37516110}, issn = {1934-6069}, support = {R35 GM138201/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Antimicrobial Peptides ; *Anti-Infective Agents ; Peptides/pharmacology ; Anti-Bacterial Agents/pharmacology ; Machine Learning ; Peptide Hydrolases ; Microbial Sensitivity Tests ; }, abstract = {Molecular de-extinction could offer avenues for drug discovery by reintroducing bioactive molecules that are no longer encoded by extant organisms. To prospect for antimicrobial peptides encrypted within extinct and extant human proteins, we introduce the panCleave random forest model for proteome-wide cleavage site prediction. Our model outperformed multiple protease-specific cleavage site classifiers for three modern human caspases, despite its pan-protease design. Antimicrobial activity was observed in vitro for modern and archaic protein fragments identified with panCleave. Lead peptides showed resistance to proteolysis and exhibited variable membrane permeabilization. Additionally, representative modern and archaic protein fragments showed anti-infective efficacy against A. baumannii in both a skin abscess infection model and a preclinical murine thigh infection model. These results suggest that machine-learning-based encrypted peptide prospection can identify stable, nontoxic peptide antibiotics. Moreover, we establish molecular de-extinction through paleoproteome mining as a framework for antibacterial drug discovery.}, }
@article {pmid37452091, year = {2023}, author = {Yang, C and Zhou, Y and Song, Y and Wu, D and Zeng, Y and Nie, L and Liu, P and Zhang, S and Chen, G and Xu, J and Zhou, H and Zhou, L and Qian, X and Liu, C and Tan, S and Zhou, C and Dai, W and Xu, M and Qi, Y and Wang, X and Guo, L and Fan, G and Wang, A and Deng, Y and Zhang, Y and Jin, J and He, Y and Guo, C and Guo, G and Zhou, Q and Xu, X and Yang, H and Wang, J and Xu, S and Mao, Y and Jin, X and Ruan, J and Zhang, G}, title = {The complete and fully-phased diploid genome of a male Han Chinese.}, journal = {Cell research}, volume = {33}, number = {10}, pages = {745-761}, pmid = {37452091}, issn = {1748-7838}, mesh = {Humans ; Male ; Asian People/genetics ; *Diploidy ; *East Asian People/ethnology/genetics ; *Genome, Human/genetics ; Genomics ; *Telomere/genetics ; }, abstract = {Since the release of the complete human genome, the priority of human genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid human genome from a Han Chinese male individual (CN1), in which the assemblies of both haploids achieve the telomere-to-telomere (T2T) level. Comparison of this diploid genome with the CHM13 haploid T2T genome revealed significant variations in the centromere. Outside the centromere, we discovered 11,413 structural variations, including numerous novel ones. We also detected thousands of CN1 alleles that have accumulated high substitution rates and a few that have been under positive selection in the East Asian population. Further, we found that CN1 outperforms CHM13 as a reference genome in mapping and variant calling for the East Asian population owing to the distinct structural variants of the two references. Comparison of SNP calling for a large cohort of 8869 Chinese genomes using CN1 and CHM13 as reference respectively showed that the reference bias profoundly impacts rare SNP calling, with nearly 2 million rare SNPs miss-called with different reference genomes. Finally, applying the CN1 as a reference, we discovered 5.80 Mb and 4.21 Mb putative introgression sequences from Neanderthal and Denisovan, respectively, including many East Asian specific ones undetected using CHM13 as the reference. Our analyses reveal the advances of using CN1 as a reference for population genomic studies and paleo-genomic studies. This complete genome will serve as an alternative reference for future genomic studies on the East Asian population.}, }
@article {pmid37304756, year = {2023}, author = {Kou, SH and Li, J and Tam, B and Lei, H and Zhao, B and Xiao, F and Wang, SM}, title = {TP53 germline pathogenic variants in modern humans were likely originated during recent human history.}, journal = {NAR cancer}, volume = {5}, number = {3}, pages = {zcad025}, pmid = {37304756}, issn = {2632-8674}, abstract = {TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158 550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.}, }
@article {pmid37269363, year = {2023}, author = {Garcia-Heras, J}, title = {The 2022 Nobel Prize in Physiology or Medicine.}, journal = {Journal of the Association of Genetic Technologists}, volume = {49}, number = {2}, pages = {56-67}, pmid = {37269363}, issn = {1523-7834}, abstract = {The Nobel Assembly at the Karolinska Institute awarded the 2022 Nobel Prize in Physiology or Medicine to Svante Pääbo (Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany). This award acknowledged his discoveries about the genomes of extinct hominins (Neandertal man and the Denisovans), the molecular genetic insights of human origin and evolutionary history, and the understanding of phylogenetic relationships between archaic hominins and modern humans. The scientific advances included detection of Neandertal and Denisovan DNA carried by modern humans due to past admixture events, which in turn stimulated active research about the functional and phenotypic significance of such archaic ancestry on non-disease and disease phenotypic features in modern populations. In addition, comparative genomic studies started to delineate the genes and genetic regulation mechanisms that distinguish modern-day humans from the archaic hominins and our immediate ancestors, the anatomically modern humans. These breakthroughs allowed a more thorough understanding of ancestral and modern human population genetics, and propelled the take-off of human paleogenomics as a new scientific discipline in its own right.}, }
@article {pmid37192163, year = {2023}, author = {Rong, S and Neil, CR and Welch, A and Duan, C and Maguire, S and Meremikwu, IC and Meyerson, M and Evans, BJ and Fairbrother, WG}, title = {Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {21}, pages = {e2218308120}, pmid = {37192163}, issn = {1091-6490}, support = {R01 GM127472/GM/NIGMS NIH HHS/United States ; }, mesh = {Male ; Animals ; Humans ; *Neanderthals/genetics ; Semen ; *Hominidae/genetics ; Alleles ; Gene Expression Regulation ; Genome, Human ; }, abstract = {Humans coexisted and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here, we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 962 exonic splicing mutations that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than that in Neanderthals. Adaptively introgressed variants were enriched for moderate-effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a unique tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a unique Neanderthal introgressed alternative splicing variant in the gene HSPG2 that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide unique insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.}, }
@article {pmid37142741, year = {2023}, author = {Brand, CM and Colbran, LL and Capra, JA}, title = {Resurrecting the alternative splicing landscape of archaic hominins using machine learning.}, journal = {Nature ecology &amp; evolution}, volume = {7}, number = {6}, pages = {939-953}, pmid = {37142741}, issn = {2397-334X}, support = {R35 GM127087/GM/NIGMS NIH HHS/United States ; T32 HG009495/HG/NHGRI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Hominidae/genetics ; *Neanderthals/genetics ; Alternative Splicing ; Genome, Human ; Population Density ; }, abstract = {Alternative splicing contributes to adaptation and divergence in many species. However, it has not been possible to directly compare splicing between modern and archaic hominins. Here, we unmask the recent evolution of this previously unobservable regulatory mechanism by applying SpliceAI, a machine-learning algorithm that identifies splice-altering variants (SAVs), to high-coverage genomes from three Neanderthals and a Denisovan. We discover 5,950 putative archaic SAVs, of which 2,186 are archaic-specific and 3,607 also occur in modern humans via introgression (244) or shared ancestry (3,520). Archaic-specific SAVs are enriched in genes that contribute to traits potentially relevant to hominin phenotypic divergence, such as the epidermis, respiration and spinal rigidity. Compared to shared SAVs, archaic-specific SAVs occur in sites under weaker selection and are more common in genes with tissue-specific expression. Further underscoring the importance of negative selection on SAVs, Neanderthal lineages with low effective population sizes are enriched for SAVs compared to Denisovan and shared SAVs. Finally, we find that nearly all introgressed SAVs in humans were shared across the three Neanderthals, suggesting that older SAVs were more tolerated in human genomes. Our results reveal the splicing landscape of archaic hominins and identify potential contributions of splicing to phenotypic differences among hominins.}, }
@article {pmid37138083, year = {2023}, author = {Essel, E and Zavala, EI and Schulz-Kornas, E and Kozlikin, MB and Fewlass, H and Vernot, B and Shunkov, MV and Derevianko, AP and Douka, K and Barnes, I and Soulier, MC and Schmidt, A and Szymanski, M and Tsanova, T and Sirakov, N and Endarova, E and McPherron, SP and Hublin, JJ and Kelso, J and Pääbo, S and Hajdinjak, M and Soressi, M and Meyer, M}, title = {Ancient human DNA recovered from a Palaeolithic pendant.}, journal = {Nature}, volume = {618}, number = {7964}, pages = {328-332}, pmid = {37138083}, issn = {1476-4687}, mesh = {Animals ; Female ; Humans ; Archaeology/methods ; *Bone and Bones/chemistry ; Deer/genetics ; *DNA, Ancient/analysis/isolation &amp; purification ; DNA, Mitochondrial/analysis/isolation &amp; purification ; History, Ancient ; Siberia ; *Tooth/chemistry ; Caves ; Russia ; }, abstract = {Artefacts made from stones, bones and teeth are fundamental to our understanding of human subsistence strategies, behaviour and culture in the Pleistocene. Although these resources are plentiful, it is impossible to associate artefacts to specific human individuals[1] who can be morphologically or genetically characterized, unless they are found within burials, which are rare in this time period. Thus, our ability to discern the societal roles of Pleistocene individuals based on their biological sex or genetic ancestry is limited[2-5]. Here we report the development of a non-destructive method for the gradual release of DNA trapped in ancient bone and tooth artefacts. Application of the method to an Upper Palaeolithic deer tooth pendant from Denisova Cave, Russia, resulted in the recovery of ancient human and deer mitochondrial genomes, which allowed us to estimate the age of the pendant at approximately 19,000-25,000 years. Nuclear DNA analysis identifies the presumed maker or wearer of the pendant as a female individual with strong genetic affinities to a group of Ancient North Eurasian individuals who lived around the same time but were previously found only further east in Siberia. Our work redefines how cultural and genetic records can be linked in prehistoric archaeology.}, }
@article {pmid37103242, year = {2023}, author = {Witt, KE and Funk, A and Añorve-Garibay, V and Fang, LL and Huerta-Sánchez, E}, title = {The Impact of Modern Admixture on Archaic Human Ancestry in Human Populations.}, journal = {Genome biology and evolution}, volume = {15}, number = {5}, pages = {}, pmid = {37103242}, issn = {1759-6653}, support = {R35 GM128946/GM/NIGMS NIH HHS/United States ; T32 GM128596/GM/NIGMS NIH HHS/United States ; EHS 1R35GM128946-01/NH/NIH HHS/United States ; }, mesh = {Animals ; Humans ; DNA ; Genome, Human ; *Hominidae/genetics ; *Neanderthals/genetics ; }, abstract = {Admixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, which have shaped genetic ancestry in modern humans. For example, populations in the Americas are often mosaics of different ancestries due to recent admixture events as part of European colonization. Admixed individuals also often have introgressed DNA from Neanderthals and Denisovans that may have come from multiple ancestral populations, which may affect how archaic ancestry is distributed across an admixed genome. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual's archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight increase of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.}, }
@article {pmid36980999, year = {2023}, author = {Toncheva, D and Marinova, M and Chobanov, T and Serbezov, D}, title = {Pathogenic Variants Associated with Rare Monogenic Diseases Established in Ancient Neanderthal and Denisovan Genome-Wide Data.}, journal = {Genes}, volume = {14}, number = {3}, pages = {}, pmid = {36980999}, issn = {2073-4425}, mesh = {Animals ; Humans ; Infant, Newborn ; *Neanderthals/genetics ; Rare Diseases/genetics ; *Hominidae/genetics ; Genome, Human ; DNA ; }, abstract = {Ancient anatomically modern humans (AMHs) encountered other archaic human species, most notably Neanderthals and Denisovans, when they left Africa and spread across Europe and Asia ~60,000 years ago. They interbred with them, and modern human genomes retain DNA inherited from these interbreeding events. High quality (high coverage) ancient human genomes have recently been sequenced allowing for a direct estimation of individual heterozygosity, which has shown that genetic diversity in these archaic human groups was very low, indicating low population sizes. In this study, we analyze ten ancient human genome-wide data, including four sequenced with high-coverage. We screened these ancient genome-wide data for pathogenic mutations associated with monogenic diseases, and established unusual aggregation of pathogenic mutations in individual subjects, including quadruple homozygous cases of pathogenic variants in the PAH gene associated with the condition phenylketonuria in a ~120,000 years old Neanderthal. Such aggregation of pathogenic mutations is extremely rare in contemporary populations, and their existence in ancient humans could be explained by less significant clinical manifestations coupled with small community sizes, leading to higher inbreeding levels. Our results suggest that pathogenic variants associated with rare diseases might be the result of introgression from other archaic human species, and archaic admixture thus could have influenced disease risk in modern humans.}, }
@article {pmid36823244, year = {2023}, author = {Wang, PY and Yang, Y and Shi, XQ and Chen, Y and Liu, SD and Wang, HY and Peng, T and Shi, Q and Zhang, W and Sun, C}, title = {Distilling functional variations for human UGT2B4 upstream region based on selection signals and implications for phenotypes of Neanderthal and Denisovan.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {3134}, pmid = {36823244}, issn = {2045-2322}, mesh = {Animals ; Female ; Humans ; Breast Neoplasms/genetics ; *Genetics, Population ; Genome, Human ; *Glucuronosyltransferase/genetics ; Hominidae/genetics ; Neanderthals/genetics ; Phenotype ; }, abstract = {Our previous work identified one region upstream human UGT2B4 (UDP glucuronosyltransferase family 2 member B4) which is associated with breast cancer and under balancing selection. However, the distribution, functional variation and molecular mechanism underlying breast cancer and balancing selection remain unclear. In current study, the two haplotypes with deep divergence are described by analyzing 1000 genomes project data and observed to be with high frequencies in all human populations. Through population genetics analysis and genome annotation, the potential functional region is identified and verified by reporter gene assay. Further mutagenesis indicates that the functional mutations are rs66862535 and rs68096061. Both SNPs can alter the interaction efficiency of transcription factor POU2F1 (POU class 2 homeobox 1). Through chromosome conformation capture, it is identified that the enhancer containing these two SNPs can interact with UGT2B4 promoter. Expression quantitative trait loci analysis indicates that UGT2B4 expression is dependent on the genotype of this locus. The common haplotype in human is lost in four genomes of archaic hominins, which suggests that Neanderthal and Denisovan should present relatively lower UGT2B4 expression and further higher steroid hormone level. This study provides new insight into the contribution of ancient population structure to human phenotypes.}, }
@article {pmid36776693, year = {2023}, author = {Hagymási, K}, title = {The Nobel prize in physiology and medicine - 2022.}, journal = {Structural chemistry}, volume = {34}, number = {2}, pages = {733-736}, pmid = {36776693}, issn = {1040-0400}, abstract = {The Nobel Assembly at Karolinska Institutet awarded the 2022 Nobel Prize in Physiology or Medicine to a Swedish geneticist, Svante Pääbo, for his discoveries concerning the genomes of extinct hominins and human evolution, for the sequencing of the genome of the Neanderthal, the discovery of a previously unknown hominin, Denisova, and the establishment of a new scientific discipline, paleogenomics.}, }
@article {pmid36711776, year = {2023}, author = {Witt, KE and Funk, A and Fang, LL and Huerta-Sanchez, E}, title = {The impact of modern admixture on archaic human ancestry in human populations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36711776}, issn = {2692-8205}, abstract = {Admixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, as well as introgression between humans and archaic humans, Neanderthals and Denisovans. One example are genomes from populations in the Americas, as these are often mosaics of different ancestries due to recent admixture events as part of European colonization. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual’s archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight enrichment of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.}, }
@article {pmid36691623, year = {2023}, author = {de March, CA and Matsunami, H and Abe, M and Cobb, M and Hoover, KC}, title = {Genetic and functional odorant receptor variation in the Homo lineage.}, journal = {iScience}, volume = {26}, number = {1}, pages = {105908}, pmid = {36691623}, issn = {2589-0042}, abstract = {Humans, Neanderthals, and Denisovans independently adapted to a wide range of geographic environments and their associated food odors. Using ancient DNA sequences, we explored the in vitro function of thirty odorant receptor genes in the genus Homo. Our extinct relatives had highly conserved olfactory receptor sequence, but humans did not. Variations in odorant receptor protein sequence and structure may have produced variation in odor detection and perception. Variants led to minimal changes in specificity but had more influence on functional sensitivity. The few Neanderthal variants disturbed function, whereas Denisovan variants increased sensitivity to sweet and sulfur odors. Geographic adaptations may have produced greater functional variation in our lineage, increasing our olfactory repertoire and expanding our adaptive capacity. Our survey of olfactory genes and odorant receptors suggests that our genus has a shared repertoire with possible local ecological adaptations.}, }
@article {pmid36681659, year = {2022}, author = {Zhou, Z and M A Swagemakers, S and S Lourens, M and Suratannon, N and J van der Spek, P and A S H Dalm, V and A Dik, W and IJspeert, H and van Hagen, PM}, title = {Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals?.}, journal = {Asian Pacific journal of allergy and immunology}, volume = {40}, number = {4}, pages = {422-434}, doi = {10.12932/AP-251022-1489}, pmid = {36681659}, issn = {0125-877X}, mesh = {Humans ; Animals ; *Neanderthals/genetics ; Genome ; Genome, Human ; Membrane Proteins/genetics ; }, abstract = {BACKGROUND: Neanderthals were a species of archaic humans that became extinct around 40,000 years ago. Modern humans have inherited 1-6% of Neanderthal DNA as a result of interbreeding. These inherited Neanderthal genes have paradoxical influences, while some can provide protection to viral infections, some others are associated with autoimmune/auto-inflammatory diseases.<br><br>OBJECTIVE: We aim to investigate whether genetic variants with strong detrimental effects on the function of the immune system could have potentially contributed to the extinction of the Neanderthal population.<br><br>METHODS: We used the publically available genome information from an Altai Neanderthal and filtered for potentially damaging variants present in genes associated with inborn errors of immunity (IEI) and checked whether these variants were present in the genomes of the Denisovan, Vindija and Chagyrskaya Neanderthals.<br><br>RESULTS: We identified 24 homozygous variants and 15 heterozygous variants in IEI-related genes in the Altai Neanderthal. Two homozygous variants in the UNC13D gene and one variant in the MOGS gene were present in all archaic genomes. Defects in the UNC13D gene are known to cause a severe and often fatal disease called hemophagocytic lymphohistiocystosis (HLH). One of these variants p.(N943S) has been reported in patients with HLH. Variants in MOGS are associated with glycosylation defects in the immune system affecting the susceptibility for infections.<br><br>CONCLUSIONS: Although the exact functional impact of these three variants needs further elucidation, we speculate that they could have resulted in an increased susceptibility to severe diseases and may have contributed to the extinction of Neanderthals after exposure to specific infections.}, }
@article {pmid36480515, year = {2022}, author = {Vespasiani, DM and Jacobs, GS and Cook, LE and Brucato, N and Leavesley, M and Kinipi, C and Ricaut, FX and Cox, MP and Gallego Romero, I}, title = {Denisovan introgression has shaped the immune system of present-day Papuans.}, journal = {PLoS genetics}, volume = {18}, number = {12}, pages = {e1010470}, pmid = {36480515}, issn = {1553-7404}, mesh = {Humans ; *Immune System ; *Hominidae/genetics ; *Neanderthals/genetics ; Papua New Guinea ; *Evolution, Molecular ; }, abstract = {Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans.}, }
@article {pmid36344982, year = {2022}, author = {Koller, D and Wendt, FR and Pathak, GA and De Lillo, A and De Angelis, F and Cabrera-Mendoza, B and Tucci, S and Polimanti, R}, title = {Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations.}, journal = {BMC biology}, volume = {20}, number = {1}, pages = {249}, pmid = {36344982}, issn = {1741-7007}, support = {MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; R21 DC018098/DC/NIDCD NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; F32 MH122058/MH/NIMH NIH HHS/United States ; R33 DA047527/DA/NIDA NIH HHS/United States ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Animals ; *Neanderthals/genetics ; Multifactorial Inheritance ; Genome-Wide Association Study ; Genome, Human ; Asian People ; }, abstract = {BACKGROUND: Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations.<br><br>RESULTS: Leveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=-0.17, p=3.57&#xd7;10[-7]). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1&#xd7;10[-7]), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69&#xd7;10[-116]) and red hair color (rs60733936 beta=-0.86, p=4.49&#xd7;10[-165]) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide - rs732632 beta=-2.38, p=5.22&#xd7;10[-7]).<br><br>CONCLUSIONS: Our study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.}, }
@article {pmid36322514, year = {2022}, author = {Campelo Dos Santos, AL and Owings, A and Sullasi, HSL and Gokcumen, O and DeGiorgio, M and Lindo, J}, title = {Genomic evidence for ancient human migration routes along South America's Atlantic coast.}, journal = {Proceedings. Biological sciences}, volume = {289}, number = {1986}, pages = {20221078}, pmid = {36322514}, issn = {1471-2954}, support = {R35 GM128590/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; History, Ancient ; Animals ; *Human Migration ; Genomics ; Genome, Human ; *Neanderthals ; Brazil ; }, abstract = {An increasing body of archaeological and genomic evidence has hinted at a complex settlement process of the Americas by humans. This is especially true for South America, where unexpected ancestral signals have raised perplexing scenarios for the early migrations into different regions of the continent. Here, we present ancient human genomes from the archaeologically rich Northeast Brazil and compare them to ancient and present-day genomic data. We find a distinct relationship between ancient genomes from Northeast Brazil, Lagoa Santa, Uruguay and Panama, representing evidence for ancient migration routes along South America's Atlantic coast. To further add to the existing complexity, we also detect greater Denisovan than Neanderthal ancestry in ancient Uruguay and Panama individuals. Moreover, we find a strong Australasian signal in an ancient genome from Panama. This work sheds light on the deep demographic history of eastern South America and presents a starting point for future fine-scale investigations on the regional level.}, }
@article {pmid36253794, year = {2022}, author = {Bergman, J and Schierup, MH}, title = {Evolutionary dynamics of pseudoautosomal region 1 in humans and great apes.}, journal = {Genome biology}, volume = {23}, number = {1}, pages = {215}, pmid = {36253794}, issn = {1474-760X}, mesh = {Animals ; Female ; *Hominidae/genetics ; Humans ; Male ; Nucleotides ; *Pseudoautosomal Regions ; Receptor, PAR-1/genetics ; Y Chromosome/genetics ; }, abstract = {BACKGROUND: The pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. PAR1 has a crucial role in ensuring proper segregation of sex chromosomes during male meiosis, exposing it to extreme recombination and mutation processes. We investigate PAR1 evolution using population genomic datasets of extant humans, eight populations of great apes, and two archaic human genome sequences.<br><br>RESULTS: We find that PAR1 is fast evolving and closer to evolutionary nucleotide equilibrium than autosomal telomeres. We detect a difference between substitution patterns and extant diversity in PAR1, mainly driven by the conflict between strong mutation and recombination-associated fixation bias at CpG sites. We detect excess C-to-G mutations in PAR1 of all great apes, specific to the mutagenic effect of male recombination. Despite recent evidence for Y chromosome introgression from humans into Neanderthals, we find that the Neanderthal PAR1 retained similarity to the Denisovan sequence. We find differences between substitution spectra of these archaics suggesting rapid evolution of PAR1 in recent hominin history. Frequency analysis of alleles segregating in females and males provided no evidence for recent sexual antagonism in this region. We study repeat content and double-strand break hotspot regions in PAR1 and find that they may play roles in ensuring the obligate X-Y recombination event during male meiosis.<br><br>CONCLUSIONS: Our study provides an unprecedented quantification of population genetic forces governing PAR1 biology across extant and extinct hominids. PAR1 evolutionary dynamics are predominantly governed by recombination processes with a strong impact on mutation patterns across all species.}, }
@article {pmid36181428, year = {2022}, author = {Huang, X and Kruisz, P and Kuhlwilm, M}, title = {sstar: A Python Package for Detecting Archaic Introgression from Population Genetic Data with S.}, journal = {Molecular biology and evolution}, volume = {39}, number = {11}, pages = {}, pmid = {36181428}, issn = {1537-1719}, mesh = {Humans ; Animals ; *Genome, Human ; *Neanderthals/genetics ; Genetics, Population ; }, abstract = {S* is a widely used statistic for detecting archaic admixture from population genetic data. Previous studies used freezing-archer to apply S*, which is only directly applicable to the specific case of Neanderthal and Denisovan introgression in Papuans. Here, we implemented sstar for a more general purpose. Compared with several tools, including SPrime, SkovHMM, and ArchaicSeeker2.0, for detecting introgressed fragments with simulations, our results suggest that sstar is robust to differences in demographic models, including ghost introgression and two-source introgression. We believe sstar will be a useful tool for detecting introgressed fragments in various scenarios and in non-human species.}, }
@article {pmid36044840, year = {2022}, author = {Kaczanowska, J and Ganglberger, F and Chernomor, O and Kargl, D and Galik, B and Hess, A and Moodley, Y and von Haeseler, A and Bühler, K and Haubensak, W}, title = {Molecular archaeology of human cognitive traits.}, journal = {Cell reports}, volume = {40}, number = {9}, pages = {111287}, doi = {10.1016/j.celrep.2022.111287}, pmid = {36044840}, issn = {2211-1247}, mesh = {Animals ; Archaeology ; Cognition/physiology ; Evolution, Molecular ; Genome, Human ; *Hominidae/genetics ; Humans ; Mammals ; *Neanderthals/genetics ; Phenotype ; }, abstract = {The brains and minds of our human ancestors remain inaccessible for experimental exploration. Therefore, we reconstructed human cognitive evolution by projecting nonsynonymous/synonymous rate ratios (ω values) in mammalian phylogeny onto the anatomically modern human (AMH) brain. This atlas retraces human neurogenetic selection and allows imputation of ancestral evolution in task-related functional networks (FNs). Adaptive evolution (high ω values) is associated with excitatory neurons and synaptic function. It shifted from FNs for motor control in anthropoid ancestry (60-41 mya) to attention in ancient hominoids (26-19 mya) and hominids (19-7.4 mya). Selection in FNs for language emerged with an early hominin ancestor (7.4-1.7 mya) and was later accompanied by adaptive evolution in FNs for strategic thinking during recent (0.8 mya-present) speciation of AMHs. This pattern mirrors increasingly complex cognitive demands and suggests that co-selection for language alongside strategic thinking may have separated AMHs from their archaic Denisovan and Neanderthal relatives.}, }
@article {pmid35927700, year = {2022}, author = {Lee, B and Cyrill, SL and Lee, W and Melchiotti, R and Andiappan, AK and Poidinger, M and Rötzschke, O}, title = {Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination.}, journal = {BMC biology}, volume = {20}, number = {1}, pages = {173}, pmid = {35927700}, issn = {1741-7007}, mesh = {Alleles ; CpG Islands ; *DNA Methylation ; *Epigenesis, Genetic ; Haplotypes ; Humans ; }, abstract = {BACKGROUND: Non-crossover (NCO) refers to a mechanism of homologous recombination in which short tracks of DNA are copied between homologue chromatids. The allelic changes are typically restricted to one or few SNPs, which potentially allow for the gradual adaptation and maturation of haplotypes. It is assumed to be a stochastic process but the analysis of archaic and modern human haplotypes revealed a striking variability in local NCO recombination rates.<br><br>METHODS: NCO recombination rates of 1.9 million archaic SNPs shared with Denisovan hominids were defined by a linkage study and correlated with functional and genomic annotations as well as ChIP-Seq data from modern humans.<br><br>RESULTS: We detected a strong correlation between NCO recombination rates and the function of the respective region: low NCO rates were evident in introns and quiescent intergenic regions but high rates in splice sites, exons, 5'- and 3'-UTRs, as well as CpG islands. Correlations with ChIP-Seq data from ENCODE and other public sources further identified epigenetic modifications that associated directly with these recombination events. A particularly strong association was observed for 5-hydroxymethylcytosine marks (5hmC), which were enriched in virtually all of the functional regions associated with elevated NCO rates, including CpG islands and 'poised' bivalent regions.<br><br>CONCLUSION: Our results suggest that 5hmC marks may guide the NCO machinery specifically towards functionally relevant regions and, as an intermediate of oxidative demethylation, may open a pathway for environmental influence by specifically targeting recently opened gene loci.}, }
@article {pmid35880026, year = {2022}, author = {Brucato, N and André, M and Hudjashov, G and Mondal, M and Cox, MP and Leavesley, M and Ricaut, FX}, title = {Chronology of natural selection in Oceanian genomes.}, journal = {iScience}, volume = {25}, number = {7}, pages = {104583}, pmid = {35880026}, issn = {2589-0042}, abstract = {As human populations left Asia to first settle in Oceania around 50,000 years ago, they entered a territory ecologically separated from the Old World for millions of years. We analyzed genomic data of 239 modern Oceanian individuals to detect and date signals of selection specific to this region. Combining both relative and absolute dating approaches, we identified a strong selection pattern between 52,000 and 54,000 years ago in the genomes of descendants of the first settlers of Sahul. This strikingly corresponds to the dates of initial settlement as inferred from archaeological evidence. Loci under selection during this period, some showing enrichment in Denisovan ancestry, overlap genes involved in the immune response and diet, especially based on plants. Pathogens and natural resources, especially from endemic plants, therefore appear to have acted as strong selective pressures on the genomes of the first settlers of Sahul.}, }
@article {pmid35757177, year = {2022}, author = {Theofanopoulou, C and Andirkó, A and Boeckx, C and Jarvis, ED}, title = {Oxytocin and vasotocin receptor variation and the evolution of human prosociality.}, journal = {Comprehensive psychoneuroendocrinology}, volume = {11}, number = {}, pages = {100139}, pmid = {35757177}, issn = {2666-4976}, abstract = {Modern human lifestyle strongly depends on complex social traits like empathy, tolerance and cooperation. These diverse facets of social cognition have been associated with variation in the oxytocin receptor (OTR) and its sister genes, the vasotocin/vasopressin receptors (VTR1A/AVPR1A and AVPR1B/VTR1B). Here, we compared the available genomic sequences of these receptors between modern humans, archaic humans, and 12 non-human primate species, and identified sites that show heterozygous variation in modern humans and archaic humans distinct from variation in other primates, and for which we could find association studies with clinical implications. On these sites, we performed a range of analyses (variant clustering, pathogenicity prediction, regulation, linkage disequilibrium frequency), and reviewed the literature on selection data in different modern-human populations. We found five sites with modern human specific variation, where the modern human allele is the major allele in the global population (OTR: rs1042778, rs237885, rs6770632; VTR1A: rs10877969; VTR1B: rs33985287). Among them, variation in the OTR-rs6770632 site was predicted to be the most functional. Two alleles (OTR: rs59190448 and rs237888) present only in modern humans and archaic humans were putatively under positive selection in modern humans, with rs237888 predicted to be a highly functional site. Three sites showed convergent evolution between modern humans and bonobos (OTR: rs2228485 and rs237897; VTR1A: rs1042615), with OTR-rs2228485 ranking highly in terms of functionality and reported to be under balancing selection in modern humans (Schaschl, 2015) [1]. Our findings have implications for understanding hominid prosociality, as well as the similarities between modern human and bonobo social behavior.}, }
@article {pmid35581187, year = {2022}, author = {Demeter, F and Zanolli, C and Westaway, KE and Joannes-Boyau, R and Duringer, P and Morley, MW and Welker, F and Rüther, PL and Skinner, MM and McColl, H and Gaunitz, C and Vinner, L and Dunn, TE and Olsen, JV and Sikora, M and Ponche, JL and Suzzoni, E and Frangeul, S and Boesch, Q and Antoine, PO and Pan, L and Xing, S and Zhao, JX and Bailey, RM and Boualaphane, S and Sichanthongtip, P and Sihanam, D and Patole-Edoumba, E and Aubaile, F and Crozier, F and Bourgon, N and Zachwieja, A and Luangkhoth, T and Souksavatdy, V and Sayavongkhamdy, T and Cappellini, E and Bacon, AM and Hublin, JJ and Willerslev, E and Shackelford, L}, title = {A Middle Pleistocene Denisovan molar from the Annamite Chain of northern Laos.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {2557}, pmid = {35581187}, issn = {2041-1723}, mesh = {Animals ; Bayes Theorem ; Female ; Fossils ; *Hominidae/anatomy &amp; histology ; Humans ; Laos ; Molar ; }, abstract = {The Pleistocene presence of the genus Homo in continental Southeast Asia is primarily evidenced by a sparse stone tool record and rare human remains. Here we report a Middle Pleistocene hominin specimen from Laos, with the discovery of a molar from the Tam Ngu Hao 2 (Cobra Cave) limestone cave in the Annamite Mountains. The age of the fossil-bearing breccia ranges between 164-131 kyr, based on the Bayesian modelling of luminescence dating of the sedimentary matrix from which it was recovered, U-series dating of an overlying flowstone, and U-series-ESR dating of associated faunal teeth. Analyses of the internal structure of the molar in tandem with palaeoproteomic analyses of the enamel indicate that the tooth derives from a young, likely female, Homo individual. The close morphological affinities with the Xiahe specimen from China indicate that they belong to the same taxon and that Tam Ngu Hao 2 most likely represents a Denisovan.}, }
@article {pmid35440148, year = {2022}, author = {Brand, CM and Colbran, LL and Capra, JA}, title = {Predicting Archaic Hominin Phenotypes from Genomic Data.}, journal = {Annual review of genomics and human genetics}, volume = {23}, number = {}, pages = {591-612}, pmid = {35440148}, issn = {1545-293X}, support = {R35 GM127087/GM/NIGMS NIH HHS/United States ; T32 HG009495/HG/NHGRI NIH HHS/United States ; }, mesh = {Animals ; DNA, Ancient ; Genome, Human ; Genomics ; *Hominidae/genetics ; Humans ; *Neanderthals/genetics ; Phenotype ; }, abstract = {Ancient DNA provides a powerful window into the biology of extant and extinct species, including humans' closest relatives: Denisovans and Neanderthals. Here, we review what is known about archaic hominin phenotypes from genomic data and how those inferences have been made. We contend that understanding the influence of variants on lower-level molecular phenotypes-such as gene expression and protein function-is a promising approach to using ancient DNA to learn about archaic hominin traits. Molecular phenotypes have simpler genetic architectures than organism-level complex phenotypes, and this approach enables moving beyond association studies by proposing hypotheses about the effects of archaic variants that are testable in model systems. The major challenge to understanding archaic hominin phenotypes is broadening our ability to accurately map genotypes to phenotypes, but ongoing advances ensure that there will be much more to learn about archaic hominin phenotypes from their genomes.}, }
@article {pmid35359699, year = {2022}, author = {Molodtseva, AS and Makunin, AI and Salomashkina, VV and Kichigin, IG and Vorobieva, NV and Vasiliev, SK and Shunkov, MV and Tishkin, AA and Grushin, SP and Anijalg, P and Tammeleht, E and Keis, M and Boeskorov, GG and Mamaev, N and Okhlopkov, IM and Kryukov, AP and Lyapunova, EA and Kholodova, MV and Seryodkin, IV and Saarma, U and Trifonov, VA and Graphodatsky, AS}, title = {Phylogeography of ancient and modern brown bears from eastern Eurasia.}, journal = {Biological journal of the Linnean Society. Linnean Society of London}, volume = {135}, number = {4}, pages = {722-733}, pmid = {35359699}, issn = {0024-4066}, support = {/WT_/Wellcome Trust/United Kingdom ; 206194/WT_/Wellcome Trust/United Kingdom ; }, abstract = {The brown bear (Ursus arctos) is an iconic carnivoran species of the Northern Hemisphere. Its population history has been studied extensively using mitochondrial markers, which demonstrated signatures of multiple waves of migration, arguably connected with glaciation periods. Among Eurasian brown bears, Siberian populations remain understudied. We have sequenced complete mitochondrial genomes of four ancient (~4.5-40 kya) bears from South Siberia and 19 modern bears from South Siberia and the Russian Far East. Reconstruction of phylogenetic relationships between haplotypes and evaluation of modern population structure have demonstrated that all the studied samples belong to the most widespread Eurasian clade 3. One of the ancient haplotypes takes a basal position relative to the whole of clade 3; the second is basal to the haplogroup 3a (the most common subclade), and two others belong to clades 3a1 and 3b. Modern Siberian bears retain at least some of this diversity; apart from the most common haplogroup 3a, we demonstrate the presence of clade 3b, which was previously found mainly in mainland Eurasia and Northern Japan. Our findings highlight the importance of South Siberia as a refugium for northern Eurasian brown bears and further corroborate the hypothesis of several waves of migration in the Pleistocene.}, }
@article {pmid35143674, year = {2022}, author = {Göllner, T and Larena, M and Kutanan, W and Lukas, H and Fieder, M and Schaschl, H}, title = {Unveiling the Genetic History of the Maniq, a Primary Hunter-Gatherer Society.}, journal = {Genome biology and evolution}, volume = {14}, number = {4}, pages = {}, pmid = {35143674}, issn = {1759-6653}, mesh = {Animals ; Asia, Southeastern ; *Asian People ; Genetics, Population ; Humans ; *Neanderthals/genetics ; Polymorphism, Single Nucleotide ; Thailand ; }, abstract = {The Maniq of southern Thailand is one of the last remaining practicing hunter-gatherer communities in the world. However, our knowledge on their genetic origins and demographic history is still largely limited. We present here the genotype data covering ∼2.3 million single nucleotide polymorphisms of 11 unrelated Maniq individuals. Our analyses reveal the Maniq to be closely related to the Semang populations of Malaysia (Malay Negritos), who altogether carry an Andamanese-related ancestry linked to the ancient Hòabìnhian hunter-gatherers of Mainland Southeast Asia (MSEA). Moreover, the Maniq possess ∼35% East Asian-related ancestry, likely brought about by recent admixture with surrounding agriculturist communities in the region. In addition, the Maniq exhibit one of the highest levels of genetic differentiation found among living human populations, indicative of their small population size and historical practice of endogamy. Similar to other hunter-gatherer populations of MSEA, we also find the Maniq to possess low levels of Neanderthal ancestry and undetectable levels of Denisovan ancestry. Altogether, we reveal the Maniq to be a Semang group that experienced intense genetic drift and exhibits signs of ancient Hòabìnhian ancestry.}, }
@article {pmid35075148, year = {2022}, author = {Morley, MW and Goldberg, P and Uliyanov, VA and Kozlikin, MB and Shunkov, MV and Derevianko, AP and Jacobs, Z and Roberts, RG}, title = {Author Correction: Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {1545}, doi = {10.1038/s41598-021-03251-6}, pmid = {35075148}, issn = {2045-2322}, }
@article {pmid34969841, year = {2022}, author = {Massilani, D and Morley, MW and Mentzer, SM and Aldeias, V and Vernot, B and Miller, C and Stahlschmidt, M and Kozlikin, MB and Shunkov, MV and Derevianko, AP and Conard, NJ and Wurz, S and Henshilwood, CS and Vasquez, J and Essel, E and Nagel, S and Richter, J and Nickel, B and Roberts, RG and Pääbo, S and Slon, V and Goldberg, P and Meyer, M}, title = {Microstratigraphic preservation of ancient faunal and hominin DNA in Pleistocene cave sediments.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {1}, pages = {}, pmid = {34969841}, issn = {1091-6490}, mesh = {Animals ; *Caves ; *DNA, Ancient ; *Fossils ; Hominidae/*genetics ; Neanderthals/*genetics ; }, abstract = {Ancient DNA recovered from Pleistocene sediments represents a rich resource for the study of past hominin and environmental diversity. However, little is known about how DNA is preserved in sediments and the extent to which it may be translocated between archaeological strata. Here, we investigate DNA preservation in 47 blocks of resin-impregnated archaeological sediment collected over the last four decades for micromorphological analyses at 13 prehistoric sites in Europe, Asia, Africa, and North America and show that such blocks can preserve DNA of hominins and other mammals. Extensive microsampling of sediment blocks from Denisova Cave in the Altai Mountains reveals that the taxonomic composition of mammalian DNA differs drastically at the millimeter-scale and that DNA is concentrated in small particles, especially in fragments of bone and feces (coprolites), suggesting that these are substantial sources of DNA in sediments. Three microsamples taken in close proximity in one of the blocks yielded Neanderthal DNA from at least two male individuals closely related to Denisova 5, a Neanderthal toe bone previously recovered from the same layer. Our work indicates that DNA can remain stably localized in sediments over time and provides a means of linking genetic information to the archaeological and ecological records on a microstratigraphic scale.}, }
@article {pmid34937535, year = {2021}, author = {Zhur, KV and Trifonov, VA and Prokhortchouk, EB}, title = {Progress and Prospects in Epigenetic Studies of Ancient DNA.}, journal = {Biochemistry. Biokhimiia}, volume = {86}, number = {12}, pages = {1563-1571}, doi = {10.1134/S0006297921120051}, pmid = {34937535}, issn = {1608-3040}, mesh = {Animals ; *DNA Methylation ; *DNA, Ancient ; *Epigenesis, Genetic ; Epigenomics/trends ; *Evolution, Molecular ; Human Migration ; Humans ; Neanderthals/*genetics ; }, abstract = {Development of technologies for high-throughput whole-genome sequencing and improvement of sample preparation techniques made it possible to study ancient DNA (aDNA) from archaeological samples over a million year old. The studies of aDNA have shed light on the history of human migration, replacement of populations, interbreeding of Cro-Magnons with Neanderthals and Denisovans, evolution of human pathogens, etc. Equally important is the possibility to investigate epigenetic modifications of ancient genomes, which has allowed to obtain previously inaccessible information on gene expression, nucleosome positioning, and DNA methylation. Analysis of methylation status of certain genomic sites can predict an individual's age at death and reconstruct some phenotypic features, as it was done for the Denisovan genome, and even to elucidate unfavorable environmental factors that had affected this archaic individual. In this review, we discuss current progress in epigenetic studies of aDNA, including methodological approaches and promising research directions in this field.}, }
@article {pmid34919805, year = {2022}, author = {Natri, HM and Hudjashov, G and Jacobs, G and Kusuma, P and Saag, L and Darusallam, CC and Metspalu, M and Sudoyo, H and Cox, MP and Gallego Romero, I and Banovich, NE}, title = {Genetic architecture of gene regulation in Indonesian populations identifies QTLs associated with global and local ancestries.}, journal = {American journal of human genetics}, volume = {109}, number = {1}, pages = {50-65}, pmid = {34919805}, issn = {1537-6605}, mesh = {Computational Biology/methods ; DNA Methylation ; Databases, Genetic ; *Gene Expression Regulation ; *Genetics, Population ; *Genome, Human ; Genome-Wide Association Study ; Genomics/methods ; High-Throughput Nucleotide Sequencing ; Humans ; Indonesia ; Male ; Models, Genetic ; Molecular Sequence Annotation ; Multifactorial Inheritance ; *Quantitative Trait Loci ; Quantitative Trait, Heritable ; Selection, Genetic ; Whole Genome Sequencing ; }, abstract = {Lack of diversity in human genomics limits our understanding of the genetic underpinnings of complex traits, hinders precision medicine, and contributes to health disparities. To map genetic effects on gene regulation in the underrepresented Indonesian population, we have integrated genotype, gene expression, and CpG methylation data from 115 participants across three island populations that capture the major sources of genomic diversity in the region. In a comparison with European datasets, we identify eQTLs shared between Indonesia and Europe as well as population-specific eQTLs that exhibit differences in allele frequencies and/or overall expression levels between populations. By combining local ancestry and archaic introgression inference with eQTLs and methylQTLs, we identify regulatory loci driven by modern Papuan ancestry as well as introgressed Denisovan and Neanderthal variation. GWAS colocalization connects QTLs detected here to hematological traits, and further comparison with European datasets reflects the poor overall transferability of GWAS statistics across diverse populations. Our findings illustrate how population-specific genetic architecture, local ancestry, and archaic introgression drive variation in gene regulation across genetically distinct and in admixed populations and highlight the need for performing association studies on non-European populations.}, }
@article {pmid34872977, year = {2022}, author = {Hubert, L and Paganini, J and Picard, C and Chiaroni, J and Abi-Rached, L and Pontarotti, P and Di Cristofaro, J}, title = {HLA-H*02:07 Is a Membrane-Bound Ligand of Denisovan Origin That Protects against Lysis by Activated Immune Effectors.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {208}, number = {1}, pages = {49-53}, doi = {10.4049/jimmunol.2100358}, pmid = {34872977}, issn = {1550-6606}, mesh = {Alleles ; Asian People ; Cell Membrane/*metabolism ; Cytotoxicity, Immunologic ; Evolution, Molecular ; Gene Frequency ; *Genotype ; HLA-A11 Antigen/genetics ; Haplotypes ; Hemochromatosis Protein/*genetics/metabolism ; Homeostasis ; Humans ; Immune Tolerance ; K562 Cells ; Killer Cells, Natural/*immunology ; Lymphocyte Activation ; Pseudogenes/*genetics ; White People ; }, abstract = {The biological relevance of genes initially categorized as "pseudogenes" is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, HLA-H is one such pseudogene; yet, it is transcribed, and its variation is associated with immune properties. Furthermore, two HLA-H alleles, H*02:07 and H*02:14, putatively encode a complete, membrane-bound HLA protein. Here we thus hypothesized that HLA-H contributes to immune homeostasis similarly to tolerogenic molecules HLA-G, -E, and -F. We tested if HLA-H*02:07 encodes a membrane-bound protein that can inhibit the cytotoxicity of effector cells. We used an HLA-null human erythroblast cell line transduced with HLA-H*02:07 cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 HLA-H*02:07 inhibits human effector IL-2-activated PBMCs and human IL-2-independent NK92-MI cell line activity. Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived HLA-A*11, we also show that H*02:07 is of archaic origin. Hence, admixture with archaic humans brought a functional HLA-H allele into modern European and Asian populations.}, }
@article {pmid34863581, year = {2022}, author = {Zhang, P and Zhang, X and Zhang, X and Gao, X and Huerta-Sanchez, E and Zwyns, N}, title = {Denisovans and Homo sapiens on the Tibetan Plateau: dispersals and adaptations.}, journal = {Trends in ecology &amp; evolution}, volume = {37}, number = {3}, pages = {257-267}, pmid = {34863581}, issn = {1872-8383}, support = {K99 GM143466/GM/NIGMS NIH HHS/United States ; R35 GM119856/GM/NIGMS NIH HHS/United States ; R35 GM128946/GM/NIGMS NIH HHS/United States ; }, mesh = {Acclimatization/genetics ; *Adaptation, Physiological/genetics ; *Altitude ; Archaeology ; Humans ; Tibet ; }, abstract = {Recent archaeological discoveries suggest that both archaic Denisovans and Homo sapiens occupied the Tibetan Plateau earlier than expected. Genetic studies show that a pulse of Denisovan introgression was involved in the adaptation of Tibetan populations to high-altitude hypoxia. These findings challenge the traditional view that the plateau was one of the last places on earth colonized by H. sapiens and warrant a reappraisal of the population history of this highland. Here, we integrate archaeological and genomic evidence relevant to human dispersal, settlement, and adaptation in the region. We propose two testable models to address the peopling of the plateau in the broader context of H. sapiens dispersal and their encounters with Denisovans in Asia.}, }
@article {pmid34824388, year = {2022}, author = {Brown, S and Massilani, D and Kozlikin, MB and Shunkov, MV and Derevianko, AP and Stoessel, A and Jope-Street, B and Meyer, M and Kelso, J and Pääbo, S and Higham, T and Douka, K}, title = {The earliest Denisovans and their cultural adaptation.}, journal = {Nature ecology &amp; evolution}, volume = {6}, number = {1}, pages = {28-35}, pmid = {34824388}, issn = {2397-334X}, support = {694707/ERC_/European Research Council/International ; 715069/ERC_/European Research Council/International ; 324139/ERC_/European Research Council/International ; }, mesh = {Animals ; Archaeology ; Caves ; DNA, Mitochondrial/genetics ; *Hominidae/genetics ; *Neanderthals/genetics ; }, abstract = {Since the initial identification of the Denisovans a decade ago, only a handful of their physical remains have been discovered. Here we analysed ~3,800 non-diagnostic bone fragments using collagen peptide mass fingerprinting to locate new hominin remains from Denisova Cave (Siberia, Russia). We identified five new hominin bones, four of which contained sufficient DNA for mitochondrial analysis. Three carry mitochondrial DNA of the Denisovan type and one was found to carry mtDNA of the Neanderthal type. The former come from the same archaeological layer near the base of the cave's sequence and are the oldest securely dated evidence of Denisovans at 200 ka (thousand years ago) (205-192 ka at 68.2% or 217-187 ka at 95% probability). The stratigraphic context in which they were located contains a wealth of archaeological material in the form of lithics and faunal remains, allowing us to determine the material culture associated with these early hominins and explore their behavioural and environmental adaptations. The combination of bone collagen fingerprinting and genetic analyses has so far more-than-doubled the number of hominin bones at Denisova Cave and has expanded our understanding of Denisovan and Neanderthal interactions, as well as their archaeological signatures.}, }
@article {pmid34795445, year = {2021}, author = {Liston, A and Humblet-Baron, S and Duffy, D and Goris, A}, title = {Human immune diversity: from evolution to modernity.}, journal = {Nature immunology}, volume = {22}, number = {12}, pages = {1479-1489}, pmid = {34795445}, issn = {1529-2916}, support = {BBS/E/B/000C0427/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BBS/E/B/000C0428/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Age Factors ; Diet ; *Evolution, Molecular ; Female ; Gene-Environment Interaction ; *Genetic Variation ; Host-Pathogen Interactions ; Humans ; Immune System/immunology/metabolism/*physiology ; Male ; Microbiota/immunology ; Sex Factors ; Species Specificity ; }, abstract = {The extreme diversity of the human immune system, forged and maintained throughout evolutionary history, provides a potent defense against opportunistic pathogens. At the same time, this immune variation is the substrate upon which a plethora of immune-associated diseases develop. Genetic analysis suggests that thousands of individually weak loci together drive up to half of the observed immune variation. Intense selection maintains this genetic diversity, even selecting for the introgressed Neanderthal or Denisovan alleles that have reintroduced variation lost during the out-of-Africa migration. Variations in age, sex, diet, environmental exposure, and microbiome each potentially explain the residual variation, with proof-of-concept studies demonstrating both plausible mechanisms and correlative associations. The confounding interaction of many of these variables currently makes it difficult to assign definitive contributions. Here, we review the current state of play in the field, identify the key unknowns in the causality of immune variation, and identify the multidisciplinary pathways toward an improved understanding.}, }
@article {pmid34718708, year = {2022}, author = {Saitou, M and Masuda, N and Gokcumen, O}, title = {Similarity-Based Analysis of Allele Frequency Distribution among Multiple Populations Identifies Adaptive Genomic Structural Variants.}, journal = {Molecular biology and evolution}, volume = {39}, number = {3}, pages = {}, pmid = {34718708}, issn = {1537-1719}, mesh = {Alleles ; Gene Frequency ; *Genetics, Population ; *Genomic Structural Variation ; Haplotypes ; Phenotype ; *Selection, Genetic ; }, abstract = {Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a similarity-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 576 structural variants that show unusual population differentiation. Of these putatively adaptive structural variants, we further showed that 24 variants are multiallelic and overlap with coding sequences, and 20 variants are significantly associated with GWAS traits. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to: 1) population differentiation of rapidly evolving multiallelic variants, 2) incomplete sweeps, and 3) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants.}, }
@article {pmid34716352, year = {2021}, author = {Di Pietro, L and Barba, M and Palacios, D and Tiberio, F and Prampolini, C and Baranzini, M and Parolini, O and Arcovito, A and Lattanzi, W}, title = {Shaping modern human skull through epigenetic, transcriptional and post-transcriptional regulation of the RUNX2 master bone gene.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {21316}, pmid = {34716352}, issn = {2045-2322}, support = {Linea D1 - 2018//Universit&#xe0; Cattolica del Sacro Cuore/ ; Linea D1 - 2017//Universit&#xe0; Cattolica del Sacro Cuore/ ; }, mesh = {Animals ; *Biological Evolution ; Core Binding Factor Alpha 1 Subunit/*genetics/metabolism ; Cranial Sutures/growth &amp; development ; Craniosynostoses/genetics ; Epigenesis, Genetic ; Genome, Human ; Hominidae/anatomy &amp; histology/genetics ; Humans ; Mesenchymal Stem Cells ; MicroRNAs/genetics ; Neanderthals/anatomy &amp; histology/genetics ; Osteogenesis/genetics ; RNA, Long Noncoding/genetics ; Skull/*anatomy &amp; histology ; }, abstract = {RUNX2 encodes the master bone transcription factor driving skeletal development in vertebrates, and playing a specific role in craniofacial and skull morphogenesis. The anatomically modern human (AMH) features sequence changes in the RUNX2 locus compared with archaic hominins' species. We aimed to understand how these changes may have contributed to human skull globularization occurred in recent evolution. We compared in silico AMH and archaic hominins' genomes, and used mesenchymal stromal cells isolated from skull sutures of craniosynostosis patients for in vitro functional assays. We detected 459 and 470 nucleotide changes in noncoding regions of the AMH RUNX2 locus, compared with the Neandertal and Denisovan genomes, respectively. Three nucleotide changes in the proximal promoter were predicted to alter the binding of the zinc finger protein Znf263 and long-distance interactions with other cis-regulatory regions. By surface plasmon resonance, we selected nucleotide substitutions in the 3'UTRs able to affect miRNA binding affinity. Specifically, miR-3150a-3p and miR-6785-5p expression inversely correlated with RUNX2 expression during in vitro osteogenic differentiation. The expression of two long non-coding RNAs, AL096865.1 and RUNX2-AS1, within the same locus, was modulated during in vitro osteogenic differentiation and correlated with the expression of specific RUNX2 isoforms. Our data suggest that RUNX2 may have undergone adaptive phenotypic evolution caused by epigenetic and post-transcriptional regulatory mechanisms, which may explain the delayed suture fusion leading to the present-day globular skull shape.}, }
@article {pmid34716342, year = {2021}, author = {Yuan, K and Ni, X and Liu, C and Pan, Y and Deng, L and Zhang, R and Gao, Y and Ge, X and Liu, J and Ma, X and Lou, H and Wu, T and Xu, S}, title = {Refining models of archaic admixture in Eurasia with ArchaicSeeker 2.0.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {6232}, pmid = {34716342}, issn = {2041-1723}, mesh = {Algorithms ; Animals ; Asia ; DNA-Binding Proteins/genetics ; Europe ; *Genetic Introgression ; Genome, Human ; Hominidae/*genetics ; Humans ; Metagenomics/*methods ; *Models, Genetic ; Neanderthals/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Siberia ; }, abstract = {We developed a method, ArchaicSeeker 2.0, to identify introgressed hominin sequences and model multiple-wave admixture. The new method enabled us to discern two waves of introgression from both Denisovan-like and Neanderthal-like hominins in present-day Eurasian populations and an ancient Siberian individual. We estimated that an early Denisovan-like introgression occurred in Eurasia around 118.8-94.0 thousand years ago (kya). In contrast, we detected only one single episode of Denisovan-like admixture in indigenous peoples eastern to the Wallace-Line. Modeling ancient admixtures suggested an early dispersal of modern humans throughout Asia before the Toba volcanic super-eruption 74 kya, predating the initial peopling of Asia as proposed by the traditional Out-of-Africa model. Survived archaic sequences are involved in various phenotypes including immune and body mass (e.g., ZNF169), cardiovascular and lung function (e.g., HHAT), UV response and carbohydrate metabolism (e.g., HYAL1/HYAL2/HYAL3), while "archaic deserts" are enriched with genes associated with skin development and keratinization.}, }
@article {pmid34433944, year = {2021}, author = {Carlhoff, S and Duli, A and Nägele, K and Nur, M and Skov, L and Sumantri, I and Oktaviana, AA and Hakim, B and Burhan, B and Syahdar, FA and McGahan, DP and Bulbeck, D and Perston, YL and Newman, K and Saiful, AM and Ririmasse, M and Chia, S and Hasanuddin,  and Pulubuhu, DAT and Suryatman,  and Supriadi,  and Jeong, C and Peter, BM and Prüfer, K and Powell, A and Krause, J and Posth, C and Brumm, A}, title = {Genome of a middle Holocene hunter-gatherer from Wallacea.}, journal = {Nature}, volume = {596}, number = {7873}, pages = {543-547}, pmid = {34433944}, issn = {1476-4687}, mesh = {Asia, Southeastern ; Australia ; Bone and Bones/metabolism ; Caves ; DNA, Ancient/*analysis ; Female ; *Fossils ; Genome, Human/*genetics ; *Genomics ; History, Ancient ; Human Migration/history ; Humans ; Indonesia/ethnology ; Islands/*ethnology ; New Guinea ; *Phylogeny ; }, abstract = {Much remains unknown about the population history of early modern humans in southeast Asia, where the archaeological record is sparse and the tropical climate is inimical to the preservation of ancient human DNA[1]. So far, only two low-coverage pre-Neolithic human genomes have been sequenced from this region. Both are from mainland Hòabìnhian hunter-gatherer sites: Pha Faen in Laos, dated to 7939-7751 calibrated years before present (yr cal BP; present taken as AD 1950), and Gua Cha in Malaysia (4.4-4.2 kyr cal BP)[1]. Here we report, to our knowledge, the first ancient human genome from Wallacea, the oceanic island zone between the Sunda Shelf (comprising mainland southeast Asia and the continental islands of western Indonesia) and Pleistocene Sahul (Australia-New Guinea). We extracted DNA from the petrous bone of a young female hunter-gatherer buried 7.3-7.2 kyr cal BP at the limestone cave of Leang Panninge[2] in South Sulawesi, Indonesia. Genetic analyses show that this pre-Neolithic forager, who is associated with the 'Toalean' technocomplex[3,4], shares most genetic drift and morphological similarities with present-day Papuan and Indigenous Australian groups, yet represents a previously unknown divergent human lineage that branched off around the time of the split between these populations approximately 37,000 years ago[5]. We also describe Denisovan and deep Asian-related ancestries in the Leang Panninge genome, and infer their large-scale displacement from the region today.}, }
@article {pmid34388371, year = {2021}, author = {Larena, M and McKenna, J and Sanchez-Quinto, F and Bernhardsson, C and Ebeo, C and Reyes, R and Casel, O and Huang, JY and Hagada, KP and Guilay, D and Reyes, J and Allian, FP and Mori, V and Azarcon, LS and Manera, A and Terando, C and Jamero, L and Sireg, G and Manginsay-Tremedal, R and Labos, MS and Vilar, RD and Latiph, A and Saway, RL and Marte, E and Magbanua, P and Morales, A and Java, I and Reveche, R and Barrios, B and Burton, E and Salon, JC and Kels, MJT and Albano, A and Cruz-Angeles, RB and Molanida, E and Granehäll, L and Vicente, M and Edlund, H and Loo, JH and Trejaut, J and Ho, SYW and Reid, L and Lambeck, K and Malmström, H and Schlebusch, C and Endicott, P and Jakobsson, M}, title = {Philippine Ayta possess the highest level of Denisovan ancestry in the world.}, journal = {Current biology : CB}, volume = {31}, number = {19}, pages = {4219-4230.e10}, pmid = {34388371}, issn = {1879-0445}, mesh = {Animals ; Asia ; Asia, Southeastern ; Australia ; *Hominidae/genetics ; Humans ; *Neanderthals/genetics ; Philippines ; Racial Groups ; }, abstract = {Multiple lines of evidence show that modern humans interbred with archaic Denisovans. Here, we report an account of shared demographic history between Australasians and Denisovans distinctively in Island Southeast Asia. Our analyses are based on ∼2.3 million genotypes from 118 ethnic groups of the Philippines, including 25 diverse self-identified Negrito populations, along with high-coverage genomes of Australopapuans and Ayta Magbukon Negritos. We show that Ayta Magbukon possess the highest level of Denisovan ancestry in the world-∼30%-40% greater than that of Australians and Papuans-consistent with an independent admixture event into Negritos from Denisovans. Together with the recently described Homo luzonensis, we suggest that there were multiple archaic species that inhabited the Philippines prior to the arrival of modern humans and that these archaic groups may have been genetically related. Altogether, our findings unveil a complex intertwined history of modern and archaic humans in the Asia-Pacific region, where distinct Islander Denisovan populations differentially admixed with incoming Australasians across multiple locations and at various points in time.}, }
@article {pmid34326389, year = {2021}, author = {Brown, S and Wang, N and Oertle, A and Kozlikin, MB and Shunkov, MV and Derevianko, AP and Comeskey, D and Jope-Street, B and Harvey, VL and Chowdhury, MP and Buckley, M and Higham, T and Douka, K}, title = {Zooarchaeology through the lens of collagen fingerprinting at Denisova Cave.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {15457}, pmid = {34326389}, issn = {2045-2322}, mesh = {Animals ; Archaeology/*methods ; Bone and Bones/pathology ; Carnivora ; Caves ; Collagen/*chemistry ; Fossils ; Hominidae ; Humans ; Paleontology/*methods ; Siberia ; }, abstract = {Denisova Cave, a Pleistocene site in the Altai Mountains of Russian Siberia, has yielded significant fossil and lithic evidence for the Pleistocene in Northern Asia. Abundant animal and human bones have been discovered at the site, however, these tend to be highly fragmented, necessitating new approaches to identifying important hominin and faunal fossils. Here we report the results for 8253 bone fragments using ZooMS. Through the integration of this new ZooMS-based data with the previously published macroscopically-identified fauna we aim to create a holistic picture of the zooarchaeological record of the site. We identify trends associated with climate variability throughout the Middle and Upper Pleistocene as well as patterns explaining the process of bone fragmentation. Where morphological analysis of bones from the site have identified a high proportion of carnivore bones (30.2%), we find that these account for only 7.6% of the ZooMS assemblage, with large mammals between 3 and 5 more abundant overall. Our analysis suggests a cyclical pattern in fragmentation of bones which sees initial fragmentation by hominins using percussive tools and secondary carnivore action, such as gnawing and digestion, likely furthering the initial human-induced fragmentation.}, }
@article {pmid34320013, year = {2021}, author = {Condemi, S and Mazières, S and Faux, P and Costedoat, C and Ruiz-Linares, A and Bailly, P and Chiaroni, J}, title = {Blood groups of Neandertals and Denisova decrypted.}, journal = {PloS one}, volume = {16}, number = {7}, pages = {e0254175}, pmid = {34320013}, issn = {1932-6203}, mesh = {Alleles ; Animals ; Blood Group Antigens/*genetics ; Fossils ; Genetic Variation ; Genotype ; Hominidae/*genetics ; INDEL Mutation ; Neanderthals/*genetics ; Phenotype ; Polymorphism, Genetic ; }, abstract = {Blood group systems were the first phenotypic markers used in anthropology to decipher the origin of populations, their migratory movements, and their admixture. The recent emergence of new technologies based on the decoding of nucleic acids from an individual's entire genome has relegated them to their primary application, blood transfusion. Thus, despite the finer mapping of the modern human genome in relation to Neanderthal and Denisova populations, little is known about red cell blood groups in these archaic populations. Here we analyze the available high-quality sequences of three Neanderthals and one Denisovan individuals for 7 blood group systems that are used today in transfusion (ABO including H/Se, Rh (Rhesus), Kell, Duffy, Kidd, MNS, Diego). We show that Neanderthal and Denisova were polymorphic for ABO and shared blood group alleles recurrent in modern Sub-Saharan populations. Furthermore, we found ABO-related alleles currently preventing from viral gut infection and Neanderthal RHD and RHCE alleles nowadays associated with a high risk of hemolytic disease of the fetus and newborn. Such a common blood group pattern across time and space is coherent with a Neanderthal population of low genetic diversity exposed to low reproductive success and with their inevitable demise. Lastly, we connect a Neanderthal RHD allele to two present-day Aboriginal Australian and Papuan, suggesting that a segment of archaic genome was introgressed in this gene in non-Eurasian populations. While contributing to both the origin and late evolutionary history of Neanderthal and Denisova, our results further illustrate that blood group systems are a relevant piece of the puzzle helping to decipher it.}, }
@article {pmid34272242, year = {2021}, author = {Schaefer, NK and Shapiro, B and Green, RE}, title = {An ancestral recombination graph of human, Neanderthal, and Denisovan genomes.}, journal = {Science advances}, volume = {7}, number = {29}, pages = {}, pmid = {34272242}, issn = {2375-2548}, support = {T32 HG008345/HG/NHGRI NIH HHS/United States ; T32 HG00834/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Animals ; Genome, Human ; Genomics ; *Hominidae/genetics ; Humans ; *Neanderthals/genetics ; Recombination, Genetic ; }, abstract = {Many humans carry genes from Neanderthals, a legacy of past admixture. Existing methods detect this archaic hominin ancestry within human genomes using patterns of linkage disequilibrium or direct comparison to Neanderthal genomes. Each of these methods is limited in sensitivity and scalability. We describe a new ancestral recombination graph inference algorithm that scales to large genome-wide datasets and demonstrate its accuracy on real and simulated data. We then generate a genome-wide ancestral recombination graph including human and archaic hominin genomes. From this, we generate a map within human genomes of archaic ancestry and of genomic regions not shared with archaic hominins either by admixture or incomplete lineage sorting. We find that only 1.5 to 7% of the modern human genome is uniquely human. We also find evidence of multiple bursts of adaptive changes specific to modern humans within the past 600,000 years involving genes related to brain development and function.}, }
@article {pmid34210857, year = {2021}, author = {Gibbons, A}, title = {'Dragon Man' may be an elusive Denisovan.}, journal = {Science (New York, N.Y.)}, volume = {373}, number = {6550}, pages = {11-12}, doi = {10.1126/science.373.6550.11}, pmid = {34210857}, issn = {1095-9203}, }
@article {pmid34183844, year = {2021}, author = {Graham, F}, title = {Daily briefing: DNA in Denisova Cave soil records several human species.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/d41586-021-01771-9}, pmid = {34183844}, issn = {1476-4687}, }
@article {pmid34163072, year = {2021}, author = {Zavala, EI and Jacobs, Z and Vernot, B and Shunkov, MV and Kozlikin, MB and Derevianko, AP and Essel, E and de Fillipo, C and Nagel, S and Richter, J and Romagné, F and Schmidt, A and Li, B and O'Gorman, K and Slon, V and Kelso, J and Pääbo, S and Roberts, RG and Meyer, M}, title = {Pleistocene sediment DNA reveals hominin and faunal turnovers at Denisova Cave.}, journal = {Nature}, volume = {595}, number = {7867}, pages = {399-403}, pmid = {34163072}, issn = {1476-4687}, support = {/ERC_/European Research Council/International ; }, mesh = {Animals ; Archaeology ; *Caves ; DNA, Ancient/*analysis ; DNA, Mitochondrial/analysis/genetics ; Fossils ; Geologic Sediments/*chemistry ; History, Ancient ; Hominidae/*genetics ; Neanderthals/genetics ; Siberia ; }, abstract = {Denisova Cave in southern Siberia is the type locality of the Denisovans, an archaic hominin group who were related to Neanderthals[1-4]. The dozen hominin remains recovered from the deposits also include Neanderthals[5,6] and the child of a Neanderthal and a Denisovan[7], which suggests that Denisova Cave was a contact zone between these archaic hominins. However, uncertainties persist about the order in which these groups appeared at the site, the timing and environmental context of hominin occupation, and the association of particular hominin groups with archaeological assemblages[5,8-11]. Here we report the analysis of DNA from 728 sediment samples that were collected in a grid-like manner from layers dating to the Pleistocene epoch. We retrieved ancient faunal and hominin mitochondrial (mt)DNA from 685 and 175 samples, respectively. The earliest evidence for hominin mtDNA is of Denisovans, and is associated with early Middle Palaeolithic stone tools that were deposited approximately 250,000 to 170,000 years ago; Neanderthal mtDNA first appears towards the end of this period. We detect a turnover in the mtDNA of Denisovans that coincides with changes in the composition of faunal mtDNA, and evidence that Denisovans and Neanderthals occupied the site repeatedly-possibly until, or after, the onset of the Initial Upper Palaeolithic at least 45,000 years ago, when modern human mtDNA is first recorded in the sediments.}, }
@article {pmid34150310, year = {2021}, author = {Amos, W}, title = {Correlated and geographically predictable Neanderthal and Denisovan legacies are difficult to reconcile with a simple model based on inter-breeding.}, journal = {Royal Society open science}, volume = {8}, number = {6}, pages = {201229}, pmid = {34150310}, issn = {2054-5703}, abstract = {Although the presence of archaic hominin legacies in humans is taken for granted, little attention has been given as to how the data fit with how humans colonized the world. Here, I show that Neanderthal and Denisovan legacies are strongly correlated and that inferred legacy size, like heterozygosity, exhibits a strong correlation with distance from Africa. Simulations confirm that, once created, legacy size is extremely stable: it may reduce through admixture with lower legacy populations but cannot increase significantly through neutral drift. Consequently, populations carrying the highest legacies are likely to be those whose ancestors inter-bred most with archaics. However, the populations with the highest legacies are globally scattered and are unified, not by having origins within the known Neanderthal range, but instead by living in locations that lie furthest from Africa. Furthermore, the Simons Genome Diversity Project data reveal two distinct correlations between Neanderthal and Denisovan legacies, one that starts in North Africa and increases west to east across Eurasia and into some parts of Oceania, and a second, much steeper trend that starts in Africa, peaking with the San and Ju/'hoansi and which, if extrapolated, predicts the large inferred legacies of both archaics found in Oceania/Australia. Similar 'double' trends are observed for the introgression statistic f 4 in a second large dataset published by Qin and Stoneking (Qin &amp; Stoneking 2015 Mol. Biol. Evol. 32, 2665-2674 (doi:10.1093/molbev/msv141)). These trends appear at odds with simple models of how introgression occurred though more complicated patterns of introgression could potentially generate better fits. Moreover, substituting archaic genomes with those of great apes yields similar but biologically impossible signals of introgression, suggesting that the signals these metrics capture arise within humans and are largely independent of the test group. Interestingly, the data do appear to fit a speculative model in which the loss of diversity that occurred when humans moved further from Africa created a gradient in heterozygosity that in turn progressively reduced mutation rate such that populations furthest from Africa have diverged less from our common ancestor and hence from the archaics. In this light, the two distinct trends could be interpreted in terms of two 'out of Africa' events, an early one ending in Oceania and Australia and a later one that colonized Eurasia and the Americas.}, }
@article {pmid34095864, year = {2021}, author = {Zhou, Y and Browning, SR}, title = {Protocol for detecting introgressed archaic variants with SPrime.}, journal = {STAR protocols}, volume = {2}, number = {2}, pages = {100550}, pmid = {34095864}, issn = {2666-1667}, support = {R01 HG010869/HG/NHGRI NIH HHS/United States ; }, mesh = {Animals ; DNA, Ancient/analysis ; Genetic Introgression/*genetics ; Genomics/*methods ; Hominidae/genetics ; Humans ; Neanderthals/*genetics ; }, abstract = {The SPrime program detects the variants in current-day populations that were introgressed from an archaic source in the past. It is optimized for detecting introgression from Neanderthals and Denisovans in modern humans. We provide a protocol for detecting Neanderthal and Denisovan introgression in 1000 Genomes Project data, specifically focusing on the CHB (Han Chinese in Beijing) population. For complete details on the use and execution of this protocol, please refer to Browning et al. (2018).}, }
@article {pmid34050022, year = {2021}, author = {Zhang, X and Witt, KE and Bañuelos, MM and Ko, A and Yuan, K and Xu, S and Nielsen, R and Huerta-Sanchez, E}, title = {The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {22}, pages = {}, pmid = {34050022}, issn = {1091-6490}, support = {R35 GM119856/GM/NIGMS NIH HHS/United States ; R35 GM128946/GM/NIGMS NIH HHS/United States ; T32 GM128596/GM/NIGMS NIH HHS/United States ; }, mesh = {Adaptation, Physiological/genetics ; Altitude ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; *Evolution, Molecular ; *Haplotypes ; Humans ; Tibet ; }, abstract = {Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000-59,500) y ago, and selection started around 9,000 (2,500-42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.}, }
@article {pmid34028527, year = {2021}, author = {Ahlquist, KD and Bañuelos, MM and Funk, A and Lai, J and Rong, S and Villanea, FA and Witt, KE}, title = {Our Tangled Family Tree: New Genomic Methods Offer Insight into the Legacy of Archaic Admixture.}, journal = {Genome biology and evolution}, volume = {13}, number = {7}, pages = {}, pmid = {34028527}, issn = {1759-6653}, support = {T32 GM007601/GM/NIGMS NIH HHS/United States ; R35 GM139628/GM/NIGMS NIH HHS/United States ; T32 GM128596/GM/NIGMS NIH HHS/United States ; R35 GM128946/GM/NIGMS NIH HHS/United States ; R01 GM127472/GM/NIGMS NIH HHS/United States ; R01 GM118652/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Genome, Human ; Genomics ; *Hominidae/genetics ; Humans ; *Neanderthals/genetics ; Pedigree ; }, abstract = {The archaic ancestry present in the human genome has captured the imagination of both scientists and the wider public in recent years. This excitement is the result of new studies pushing the envelope of what we can learn from the archaic genetic information that has survived for over 50,000 years in the human genome. Here, we review the most recent ten years of literature on the topic of archaic introgression, including the current state of knowledge on Neanderthal and Denisovan introgression, as well as introgression from other as-yet unidentified archaic populations. We focus this review on four topics: 1) a reimagining of human demographic history, including evidence for multiple admixture events between modern humans, Neanderthals, Denisovans, and other archaic populations; 2) state-of-the-art methods for detecting archaic ancestry in population-level genomic data; 3) how these novel methods can detect archaic introgression in modern African populations; and 4) the functional consequences of archaic gene variants, including how those variants were co-opted into novel function in modern human populations. The goal of this review is to provide a simple-to-access reference for the relevant methods and novel data, which has changed our understanding of the relationship between our species and its siblings. This body of literature reveals the large degree to which the genetic legacy of these extinct hominins has been integrated into the human populations of today.}, }
@article {pmid33934123, year = {2021}, author = {Mualim, K and Theunert, C and Slatkin, M}, title = {Estimation of coalescence probabilities and population divergence times from SNP data.}, journal = {Heredity}, volume = {127}, number = {1}, pages = {1-9}, pmid = {33934123}, issn = {1365-2540}, support = {R01 GM040282/GM/NIGMS NIH HHS/United States ; }, mesh = {Alleles ; Animals ; Humans ; *Neanderthals/genetics ; Population Density ; Probability ; }, abstract = {We present a method called the G(A|B) method for estimating coalescence probabilities within population lineages from genome sequences when one individual is sampled from each population. Population divergence times can be estimated from these coalescence probabilities if additional assumptions about the history of population sizes are made. Our method is based on a method presented by Rasmussen et al. (2014) to test whether an archaic genome is from a population directly ancestral to a present-day population. The G(A|B) method does not require distinguishing ancestral from derived alleles or assumptions about demographic history before population divergence. We discuss the relationship of our method to two similar methods, one introduced by Green et al. (2010) and called the F(A|B) method and the other introduced by Schlebusch et al. (2017) and called the TT method. When our method is applied to individuals from three or more populations, it provides a test of whether the population history is treelike because coalescence probabilities are additive on a tree. We illustrate the use of our method by applying it to three high-coverage archaic genomes, two Neanderthals (Vindija and Altai) and a Denisovan.}, }
@article {pmid33892510, year = {2021}, author = {Villanea, FA and Huerta-Sanchez, E and Fox, K}, title = {ABO Genetic Variation in Neanderthals and Denisovans.}, journal = {Molecular biology and evolution}, volume = {38}, number = {8}, pages = {3373-3382}, pmid = {33892510}, issn = {1537-1719}, support = {R35 GM128946/GM/NIGMS NIH HHS/United States ; }, mesh = {ABO Blood-Group System/*genetics ; Animals ; Genetic Variation ; Genome, Human ; Haplotypes ; Humans ; Neanderthals/*genetics ; }, abstract = {Variation at the ABO locus was one of the earliest sources of data in the study of human population identity and history, and to this day remains widely genotyped due to its importance in blood and tissue transfusions. Here, we look at ABO blood type variants in our archaic relatives: Neanderthals and Denisovans. Our goal is to understand the genetic landscape of the ABO gene in archaic humans, and how it relates to modern human ABO variation. We found two Neanderthal variants of the O allele in the Siberian Neanderthals (O1 and O2), one of these variants is shared with an European Neanderthal, who is a heterozygote for this O1 variant and a rare cis-AB variant. The Denisovan individual is heterozygous for two variants of the O1 allele, functionally similar to variants found widely in modern humans. Perhaps more surprisingly, the O2 allele variant found in Siberian Neanderthals can be found at low frequencies in modern Europeans and Southeast Asians, and the O1 allele variant found in Siberian and European Neanderthal is also found at very low frequency in modern East Asians. Our genetic distance analyses suggest both alleles survive in modern humans due to inbreeding with Neanderthals. We find that the sequence backgrounds of the surviving Neanderthal-like O alleles in modern humans retain a higher sequence divergence than other surviving Neanderthal genome fragments, supporting a view of balancing selection operating in the Neanderthal ABO alleles by retaining highly diverse haplotypes compared with portions of the genome evolving neutrally.}, }
@article {pmid33885362, year = {2021}, author = {Weiss, CV and Harshman, L and Inoue, F and Fraser, HB and Petrov, DA and Ahituv, N and Gokhman, D}, title = {The cis-regulatory effects of modern human-specific variants.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, pmid = {33885362}, issn = {2050-084X}, support = {U01 MH116438/MH/NIMH NIH HHS/United States ; 1U01MH116438/MH/NIMH NIH HHS/United States ; UM1 HG009408/HG/NHGRI NIH HHS/United States ; P01 HD084387/HD/NICHD NIH HHS/United States ; R01 MH109907/MH/NIMH NIH HHS/United States ; 1R01MH109907/MH/NIMH NIH HHS/United States ; R01 MH116438/MH/NIMH NIH HHS/United States ; R35 GM118165/GM/NIGMS NIH HHS/United States ; 1UM1HG009408/HG/NHGRI NIH HHS/United States ; F31 HG011568/HG/NHGRI NIH HHS/United States ; }, mesh = {Embryonic Stem Cells/*metabolism ; *Gene Expression Regulation ; Genome, Human ; Humans ; Osteoblasts/*metabolism ; *Polymorphism, Single Nucleotide ; Stem Cells/*metabolism ; Transcription Factors/*metabolism ; }, abstract = {The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.}, }
@article {pmid33883706, year = {2020}, author = {}, title = {Podcast: Denisovan DNA in modern Europeans, and the birth of an unusual celestial object.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/d41586-020-01170-6}, pmid = {33883706}, issn = {1476-4687}, }
@article {pmid33854233, year = {2021}, author = {Choin, J and Mendoza-Revilla, J and Arauna, LR and Cuadros-Espinoza, S and Cassar, O and Larena, M and Ko, AM and Harmant, C and Laurent, R and Verdu, P and Laval, G and Boland, A and Olaso, R and Deleuze, JF and Valentin, F and Ko, YC and Jakobsson, M and Gessain, A and Excoffier, L and Stoneking, M and Patin, E and Quintana-Murci, L}, title = {Genomic insights into population history and biological adaptation in Oceania.}, journal = {Nature}, volume = {592}, number = {7855}, pages = {583-589}, pmid = {33854233}, issn = {1476-4687}, mesh = {Adaptation, Biological/*genetics ; Animals ; Australia ; *Biological Evolution ; Datasets as Topic ; Asia, Eastern ; Genetic Introgression ; *Genetics, Population ; Genome, Human/*genetics ; *Genomics ; History, Ancient ; Human Migration/*history ; Humans ; *Islands ; Native Hawaiian or Other Pacific Islander/*genetics ; Neanderthals/genetics ; Oceania ; Pacific Ocean ; Taiwan ; }, abstract = {The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes[1]. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago[2-4]. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.}, }
@article {pmid33753899, year = {2021}, author = {Teixeira, JC and Jacobs, GS and Stringer, C and Tuke, J and Hudjashov, G and Purnomo, GA and Sudoyo, H and Cox, MP and Tobler, R and Turney, CSM and Cooper, A and Helgen, KM}, title = {Widespread Denisovan ancestry in Island Southeast Asia but no evidence of substantial super-archaic hominin admixture.}, journal = {Nature ecology &amp; evolution}, volume = {5}, number = {5}, pages = {616-624}, pmid = {33753899}, issn = {2397-334X}, mesh = {Animals ; Asia, Southeastern ; Fossils ; *Hominidae/genetics ; Humans ; Islands ; *Neanderthals ; }, abstract = {The hominin fossil record of Island Southeast Asia (ISEA) indicates that at least two endemic 'super-archaic' species-Homo luzonensis and H. floresiensis-were present around the time anatomically modern humans arrived in the region >50,000 years ago. Intriguingly, contemporary human populations across ISEA carry distinct genomic traces of ancient interbreeding events with Denisovans-a separate hominin lineage that currently lacks a fossil record in ISEA. To query this apparent disparity between fossil and genetic evidence, we performed a comprehensive search for super-archaic introgression in >400 modern human genomes, including >200 from ISEA. Our results corroborate widespread Denisovan ancestry in ISEA populations, but fail to detect any substantial super-archaic admixture signals compatible with the endemic fossil record of ISEA. We discuss the implications of our findings for the understanding of hominin history in ISEA, including future research directions that might help to unlock more details about the prehistory of the enigmatic Denisovans.}, }
@article {pmid33574182, year = {2021}, author = {Trujillo, CA and Rice, ES and Schaefer, NK and Chaim, IA and Wheeler, EC and Madrigal, AA and Buchanan, J and Preissl, S and Wang, A and Negraes, PD and Szeto, RA and Herai, RH and Huseynov, A and Ferraz, MSA and Borges, FS and Kihara, AH and Byrne, A and Marin, M and Vollmers, C and Brooks, AN and Lautz, JD and Semendeferi, K and Shapiro, B and Yeo, GW and Smith, SEP and Green, RE and Muotri, AR}, title = {Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment.}, journal = {Science (New York, N.Y.)}, volume = {371}, number = {6530}, pages = {}, pmid = {33574182}, issn = {1095-9203}, support = {R01 HL137223/HL/NHLBI NIH HHS/United States ; K12 GM068524/GM/NIGMS NIH HHS/United States ; R01 MH121487/MH/NIMH NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; S10 OD026929/OD/NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; R01 MH113545/MH/NIMH NIH HHS/United States ; K01 AA026911/AA/NIAAA NIH HHS/United States ; U19 MH107367/MH/NIMH NIH HHS/United States ; T32 HG008345/HG/NHGRI NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; }, mesh = {Alleles ; Alternative Splicing ; Amino Acid Substitution ; Animals ; Binding Sites ; Biological Evolution ; CRISPR-Cas Systems ; Cell Proliferation ; Cerebral Cortex/cytology/*growth &amp; development/*physiology ; Gene Expression Regulation, Developmental ; Genetic Variation ; Genome ; Genome, Human ; Haplotypes ; Hominidae/genetics ; Humans ; Induced Pluripotent Stem Cells ; Neanderthals/*genetics ; Nerve Net/physiology ; Nerve Tissue Proteins/genetics/metabolism ; Neuro-Oncological Ventral Antigen ; Neurons/*physiology ; Organoids ; RNA-Binding Proteins/*genetics/*metabolism ; Synapses/physiology ; }, abstract = {The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function. NOVA1 also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version of NOVA1 Moreover, levels of synaptic markers and synaptic protein coassociations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution in NOVA1, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.}, }
@article {pmid33556445, year = {2021}, author = {Reinscheid, RK and Mafessoni, F and Lüttjohann, A and Jüngling, K and Pape, HC and Schulz, S}, title = {Neandertal introgression and accumulation of hypomorphic mutations in the neuropeptide S (NPS) system promote attenuated functionality.}, journal = {Peptides}, volume = {138}, number = {}, pages = {170506}, doi = {10.1016/j.peptides.2021.170506}, pmid = {33556445}, issn = {1873-5169}, mesh = {Animals ; *Biological Evolution ; Genetic Introgression/*genetics ; Hominidae/genetics ; Humans ; Mutation/genetics ; Neanderthals/genetics ; Neuropeptides/genetics ; Polymorphism, Single Nucleotide/genetics ; Receptors, G-Protein-Coupled/*genetics ; *Selection, Genetic ; }, abstract = {The neuropeptide S (NPS) system plays an important role in fear and fear memory processing but has also been associated with allergic and inflammatory diseases. Genes for NPS and its receptor NPSR1 are found in all tetrapods. Compared to non-human primates, several non-synonymous single-nucleotide polymorphisms (SNPs) occur in both human genes that collectively result in functional attenuation, suggesting adaptive mechanisms in a human context. To investigate historic and geographic origins of these hypomorphic mutations and explore genetic signs of selection, we analyzed ancient genomes and worldwide genotype frequencies of four prototypic SNPs in the NPS system. Neandertal and Denisovan genomes contain exclusively ancestral alleles for NPSR1 while all derived alleles occur in ancient genomes of anatomically modern humans, indicating that they arose in modern Homo sapiens. Worldwide genotype frequencies for three hypomorphic NPSR1 SNPs show significant regional homogeneity but follow a gradient towards increasing derived allele frequencies that supports an out-of-Africa scenario. Increased density of high-frequency polymorphisms around the three NPSR1 loci suggests weak or possibly balancing selection. A hypomorphic mutation in the NPS precursor, however, was detected at high frequency in Eurasian Neandertal genomes and shows genetic signatures indicating that it was introgressed into the human gene pool, particularly in Southern Europe, by interbreeding with Neandertals. We discuss potential evolutionary scenarios including behavior and immune-based natural selection.}, }
@article {pmid33547071, year = {2021}, author = {Bonfante, B and Faux, P and Navarro, N and Mendoza-Revilla, J and Dubied, M and Montillot, C and Wentworth, E and Poloni, L and Varón-González, C and Jones, P and Xiong, Z and Fuentes-Guajardo, M and Palmal, S and Chacón-Duque, JC and Hurtado, M and Villegas, V and Granja, V and Jaramillo, C and Arias, W and Barquera, R and Everardo-Martínez, P and Sánchez-Quinto, M and Gómez-Valdés, J and Villamil-Ramírez, H and Silva de Cerqueira, CC and Hünemeier, T and Ramallo, V and Liu, F and Weinberg, SM and Shaffer, JR and Stergiakouli, E and Howe, LJ and Hysi, PG and Spector, TD and Gonzalez-José, R and Schüler-Faccini, L and Bortolini, MC and Acuña-Alonzo, V and Canizales-Quinteros, S and Gallo, C and Poletti, G and Bedoya, G and Rothhammer, F and Thauvin-Robinet, C and Faivre, L and Costedoat, C and Balding, D and Cox, T and Kayser, M and Duplomb, L and Yalcin, B and Cotney, J and Adhikari, K and Ruiz-Linares, A}, title = {A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.}, journal = {Science advances}, volume = {7}, number = {6}, pages = {}, pmid = {33547071}, issn = {2375-2548}, support = {R01 DE027023/DE/NIDCR NIH HHS/United States ; U01 DE020078/DE/NIDCR NIH HHS/United States ; R00 DE024194/DE/NIDCR NIH HHS/United States ; R01 DE016148/DE/NIDCR NIH HHS/United States ; T90 DE033006/DE/NIDCR NIH HHS/United States ; T90 DE021989/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; *Face/anatomy &amp; histology ; Genome-Wide Association Study ; Genotype ; Hispanic or Latino/genetics ; Humans ; Mice ; Phenotype ; *Polymorphism, Single Nucleotide ; *Vesicular Transport Proteins/genetics ; }, abstract = {To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.}, }
@article {pmid33417716, year = {2021}, author = {Greer, C and Bhakta, H and Ghanem, L and Refai, F and Linn, E and Avella, M}, title = {Deleterious variants in genes regulating mammalian reproduction in Neanderthals, Denisovans and extant humans.}, journal = {Human reproduction (Oxford, England)}, volume = {36}, number = {3}, pages = {734-755}, doi = {10.1093/humrep/deaa347}, pmid = {33417716}, issn = {1460-2350}, mesh = {Animals ; Europe ; Genome, Human ; *Hominidae/genetics ; Humans ; Male ; *Neanderthals/genetics ; Nuclear Proteins ; Reproduction/genetics ; Trans-Activators ; }, abstract = {STUDY QUESTION: Were Neanderthals and Denisovans (referred here also as extinct hominidae) carrying deleterious variants in genes regulating reproduction?<br><br>SUMMARY ANSWER: The majority of extinct hominidae analyzed here, presented a considerable number of deleterious variants per individual in proteins regulating different aspects of reproduction, including gonad and uterine function, and gametogenesis.<br><br>WHAT IS KNOWN ALREADY: Neanderthals, Denisovans and extant humans were interfertile and hybridized while occupying geographically overlapping areas in Europe and Asia. This is evidenced by the small archaic genome component (average &#x223c;2%) present in non-African extant humans.<br><br>STUDY DESIGN, SIZE, DURATION: The genome of eight extinct hominidae, together with five human genome databases, plus 44 mothers and 48 fathers (fertile controls), were screened to look for deleterious variants in 1734 protein-coding genes regulating reproduction.<br><br>Ancient DNA from six Neanderthals and two Denisovans dated between &#x223c;82&#xa0;000 and 43&#xa0;000 calibrated years was retrieved from the public European Nucleotide Archive. The hominins analyzed include Altai, Vindija 33.15, 33.19, 33.25 and 33.26, El Sidron 1253, Denisova 3 and 11. Their DNA was analyzed using the CLC Genomics Workbench 12, by mapping overlapping paired-end reads (Illumina, FASTQ files) to the human genome assembly GRCh37 (hg19) (Vindija 33.19, 33.25, 33.26, Denisova 3 and Denisova 11) or by analyzing BAM files (Altai, El Sidron 1253 and Vindija 33.15) (human genome reference, GRCh37 (hg19)). Non-synonymous reproductive variants were classified as deleterious or tolerated (PolyPhen-2 and SIFT analyses) and were compared to deleterious variants obtained from extant human genome databases (Genome Aggregation Database (GnomAD), 1000 Genomes, the Haplotype Map (HapMap), Single Nucleotide Polymorphism Database (dbSNPs)) across different populations. A genetic intersection between extant or extinct DNA variants and other genetic disorders was evaluated by annotating the obtained variants with the Clinical Variant (ClinVar) database.<br><br>Among the eight extinct hominidae analyzed, a total of 9650 non-synonymous variants (only coverage &#x2265;20 reads included; frameshift mutations were excluded) in 1734 reproductive protein-coding genes were found, 24% of which were classified as deleterious. The majority (73%) of the deleterious alleles present in extant humans that are shared between extant humans and extinct hominidae were found to be rare (<1%) in extant human populations. A set of 8044 variants were found uniquely in extinct hominidae. At the single-gene level, no extinct individual was found to be homozygous for deleterious variants in genes necessary for gamete recognition and fusion, and no higher chance of embryo-lethality (calculated by Mendelian Genetics) was found upon simulated mating between extant human and extinct hominidae compared to extant human-extant human. However, three of the eight extinct hominidae were found to be homozygous for 48-69 deleterious variants in 55 genes controlling ovarian and uterine functions, or oogenesis (AKAP1, BUB1B, CCDC141, CDC73, DUSP6, ESR1, ESR2, PATL2, PSMC3IP, SEMA3A, WT1 and WNT4). Moreover, we report the distribution of nine Neanderthal variants in genes associated with a human fertility phenotype found in extant human populations, one of which has been associated with polycystic ovarian syndrome and primary congenital glaucoma.<br><br>While analyzing archaic DNA, stringent filtering criteria were adopted to screen for deleterious variants in Neanderthals and Denisovans, which could result in missing a number of variants. Such restraints preserve the potential for detection of additional deleterious variants in reproductive proteins in extinct hominidae.<br><br>This study provides a comprehensive overview of putatively deleterious variants in extant human populations and extinct individuals occurring in 1734 protein-coding genes controlling reproduction and provides the fundaments for future functional studies of extinct variants in human reproduction.<br><br>This study was supported by the Department of Biological Science and by the Office of Research and Sponsored Programs at the University of Tulsa (Faculty Research Grant and Faculty Research Summer Fellowship) to M.A. and the University of Tulsa, Tulsa Undergraduate Research Challenge (TURC) program to E.L.; no conflict of interest to declare.<br><br>TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid33180850, year = {2020}, author = {Vorobieva, NV and Makunin, AI and Druzhkova, AS and Kusliy, MA and Trifonov, VA and Popova, KO and Polosmak, NV and Molodin, VI and Vasiliev, SK and Shunkov, MV and Graphodatsky, AS}, title = {High genetic diversity of ancient horses from the Ukok Plateau.}, journal = {PloS one}, volume = {15}, number = {11}, pages = {e0241997}, pmid = {33180850}, issn = {1932-6203}, mesh = {Animals ; Animals, Domestic/*genetics ; Animals, Wild/*genetics ; DNA, Ancient/analysis ; Evolution, Molecular ; Extinction, Biological ; Fossils/history ; Genome, Mitochondrial ; Haplotypes ; High-Throughput Nucleotide Sequencing/veterinary ; History, Ancient ; Horses ; Mitochondria/*genetics ; Phylogeny ; Russia ; Whole Genome Sequencing/*veterinary ; }, abstract = {A growing number of researchers studying horse domestication come to a conclusion that this process happened in multiple locations and involved multiple wild maternal lines. The most promising approach to address this problem involves mitochondrial haplotype comparison of wild and domestic horses from various locations coupled with studies of possible migration routes of the ancient shepherds. Here, we sequenced complete mitochondrial genomes of six horses from burials of the Ukok plateau (Russia, Altai Mountains) dated from 2.7 to 1.4 thousand years before present and a single late Pleistocene wild horse from the neighboring region (Denisova cave). Sequencing data indicates that the wild horse belongs to an extinct pre-domestication lineage. Integration of the domestic horse data with known Eurasian haplotypes of a similar age revealed two distinct groups: the first one widely distributed in Europe and presumably imported to Altai, and the second one specific for Altai Mountains and surrounding area.}, }
@article {pmid33122381, year = {2020}, author = {Zhang, D and Xia, H and Chen, F and Li, B and Slon, V and Cheng, T and Yang, R and Jacobs, Z and Dai, Q and Massilani, D and Shen, X and Wang, J and Feng, X and Cao, P and Yang, MA and Yao, J and Yang, J and Madsen, DB and Han, Y and Ping, W and Liu, F and Perreault, C and Chen, X and Meyer, M and Kelso, J and Pääbo, S and Fu, Q}, title = {Denisovan DNA in Late Pleistocene sediments from Baishiya Karst Cave on the Tibetan Plateau.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6516}, pages = {584-587}, doi = {10.1126/science.abb6320}, pmid = {33122381}, issn = {1095-9203}, mesh = {Animals ; *Caves ; DNA, Ancient/*isolation &amp; purification ; DNA, Mitochondrial/genetics ; Geologic Sediments/*chemistry ; Hominidae/*classification/*genetics ; Humans ; Phylogeny ; Tibet ; }, abstract = {A late Middle Pleistocene mandible from Baishiya Karst Cave (BKC) on the Tibetan Plateau has been inferred to be from a Denisovan, an Asian hominin related to Neanderthals, on the basis of an amino acid substitution in its collagen. Here we describe the stratigraphy, chronology, and mitochondrial DNA extracted from the sediments in BKC. We recover Denisovan mitochondrial DNA from sediments deposited ~100 thousand and ~60 thousand years ago (ka) and possibly as recently as ~45 ka. The long-term occupation of BKC by Denisovans suggests that they may have adapted to life at high altitudes and may have contributed such adaptations to modern humans on the Tibetan Plateau.}, }
@article {pmid33122380, year = {2020}, author = {Massilani, D and Skov, L and Hajdinjak, M and Gunchinsuren, B and Tseveendorj, D and Yi, S and Lee, J and Nagel, S and Nickel, B and Devièse, T and Higham, T and Meyer, M and Kelso, J and Peter, BM and Pääbo, S}, title = {Denisovan ancestry and population history of early East Asians.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6516}, pages = {579-583}, doi = {10.1126/science.abc1166}, pmid = {33122380}, issn = {1095-9203}, support = {324139/ERC_/European Research Council/International ; 694707/ERC_/European Research Council/International ; }, mesh = {Animals ; Asian People/*genetics ; DNA, Ancient ; *Evolution, Molecular ; Female ; Hominidae/*genetics ; Humans ; Mongolia ; Population ; Skull ; }, abstract = {We present analyses of the genome of a ~34,000-year-old hominin skull cap discovered in the Salkhit Valley in northeastern Mongolia. We show that this individual was a female member of a modern human population that, following the split between East and West Eurasians, experienced substantial gene flow from West Eurasians. Both she and a 40,000-year-old individual from Tianyuan outside Beijing carried genomic segments of Denisovan ancestry. These segments derive from the same Denisovan admixture event(s) that contributed to present-day mainland Asians but are distinct from the Denisovan DNA segments in present-day Papuans and Aboriginal Australians.}, }
@article {pmid33122362, year = {2020}, author = {Gibbons, A}, title = {Denisovan DNA found in cave on Tibetan Plateau.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6516}, pages = {512-513}, doi = {10.1126/science.370.6516.512}, pmid = {33122362}, issn = {1095-9203}, mesh = {Altitude ; Animals ; Caves ; Cold Temperature ; DNA, Ancient/*isolation &amp; purification ; DNA, Mitochondrial/*isolation &amp; purification ; Geologic Sediments/*chemistry ; Hominidae/*genetics ; Humans ; Tibet ; }, }
@article {pmid37588361, year = {2020}, author = {Sánchez Goñi, MF}, title = {Regional impacts of climate change and its relevance to human evolution.}, journal = {Evolutionary human sciences}, volume = {2}, number = {}, pages = {e55}, pmid = {37588361}, issn = {2513-843X}, abstract = {The traditional concept of long and gradual, glacial-interglacial climate changes during the Quaternary has been challenged since the 1980s. High temporal resolution analysis of marine, terrestrial and ice geological archives has identified rapid, millennial- to centennial-scale, and large-amplitude climatic cycles throughout the last few million years. These changes were global but have had contrasting regional impacts on the terrestrial and marine ecosystems, with in some cases strong changes in the high latitudes of both hemispheres but muted changes elsewhere. Such a regionalization has produced environmental barriers and corridors that have probably triggered niche contractions/expansions of hominin populations living in Eurasia and Africa. This article reviews the long- and short-timescale ecosystem changes that have punctuated the last few million years, paying particular attention to the environments of the last 650,000 years, which have witnessed key events in the evolution of our lineage in Africa and Eurasia. This review highlights, for the first time, a contemporaneity between the split between Denisovan and Neanderthals, at ~650-400 ka, and the strong Eurasian ice-sheet expansion down to the Black Sea. This ice expansion could form an ice barrier between Europe and Asia that may have triggered the genetic drift between these two populations.}, }
@article {pmid33039881, year = {2020}, author = {Pan, L and Dumoncel, J and Mazurier, A and Zanolli, C}, title = {Hominin diversity in East Asia during the Middle Pleistocene: A premolar endostructural perspective.}, journal = {Journal of human evolution}, volume = {148}, number = {}, pages = {102888}, doi = {10.1016/j.jhevol.2020.102888}, pmid = {33039881}, issn = {1095-8606}, mesh = {Animals ; Bicuspid ; Asia, Eastern ; Fossils ; *Hominidae ; Humans ; *Neanderthals ; }, abstract = {Following the recent studies of East Asian mid-Middle to early Late Pleistocene hominin material, a large spectrum of morphological diversity has been recognized and the coexistence of archaic ('Homo erectus-like') and derived ('modern-like') dental morphological patterns has been highlighted. In fact, for most of these Chinese fossils, generally categorized as 'archaic Homo sapiens' or 'post-H. erectus Homo', the taxonomic attribution is a matter of contention. With the help of μCT techniques and a deformation-based 3D geometric morphometric approach, we focused on the morphological variation in the enamel-dentine junction (EDJ) of 18 upper and lower premolars from Chinese Middle Pleistocene hominins. We then compared our results with a number of fossil and modern human groups, including Early Pleistocene H. erectus from Sangiran; late Early Pleistocene hominins from Tighenif, Algeria; classic Neanderthals; and modern humans. Our results highlight an evolutionary/chronological trend of crown base reduction, elevation of EDJ topography, and EDJ surface simplification in the hominin groups studied here. Moreover, this study brings insights to the taxonomy/phylogeny of 6 late Middle Pleistocene specimens whose evolutionary placement has been debated for decades. Among these specimens, Changyang premolars show features that can be aligned with the Asian H. erectus hypodigm, whereas Panxian Dadong and Tongzi premolars are more similar to Late Pleistocene Homo. Compared with early to mid-Middle Pleistocene hominins in East Asia, late Middle Pleistocene hominins evince an enlarged morphological variation. A persistence of archaic morphotypes and possible admixture among populations during the late Middle Pleistocene are discussed.}, }
@article {pmid32973032, year = {2020}, author = {Petr, M and Hajdinjak, M and Fu, Q and Essel, E and Rougier, H and Crevecoeur, I and Semal, P and Golovanova, LV and Doronichev, VB and Lalueza-Fox, C and de la Rasilla, M and Rosas, A and Shunkov, MV and Kozlikin, MB and Derevianko, AP and Vernot, B and Meyer, M and Kelso, J}, title = {The evolutionary history of Neanderthal and Denisovan Y chromosomes.}, journal = {Science (New York, N.Y.)}, volume = {369}, number = {6511}, pages = {1653-1656}, doi = {10.1126/science.abb6460}, pmid = {32973032}, issn = {1095-9203}, support = {694707/ERC_/European Research Council/International ; }, mesh = {Animals ; Chromosomes, Human, Y/genetics ; DNA, Ancient ; DNA, Mitochondrial/genetics ; *Evolution, Molecular ; Humans ; *Life History Traits ; Male ; Neanderthals/classification/*genetics ; Phylogeny ; Y Chromosome/*genetics ; }, abstract = {Ancient DNA has provided new insights into many aspects of human history. However, we lack comprehensive studies of the Y chromosomes of Denisovans and Neanderthals because the majority of specimens that have been sequenced to sufficient coverage are female. Sequencing Y chromosomes from two Denisovans and three Neanderthals shows that the Y chromosomes of Denisovans split around 700 thousand years ago from a lineage shared by Neanderthals and modern human Y chromosomes, which diverged from each other around 370 thousand years ago. The phylogenetic relationships of archaic and modern human Y chromosomes differ from the population relationships inferred from the autosomal genomes and mirror mitochondrial DNA phylogenies, indicating replacement of both the mitochondrial and Y chromosomal gene pools in late Neanderthals. This replacement is plausible if the low effective population size of Neanderthals resulted in an increased genetic load in Neanderthals relative to modern humans.}, }
@article {pmid32839541, year = {2020}, author = {Telis, N and Aguilar, R and Harris, K}, title = {Selection against archaic hominin genetic variation in regulatory regions.}, journal = {Nature ecology &amp; evolution}, volume = {4}, number = {11}, pages = {1558-1566}, pmid = {32839541}, issn = {2397-334X}, support = {R35 GM133428/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Biological Evolution ; *Hominidae/genetics ; Humans ; *Neanderthals/genetics ; Regulatory Sequences, Nucleic Acid ; Selection, Genetic ; }, abstract = {Traces of Neandertal and Denisovan DNA persist in the modern human gene pool, but have been systematically purged by natural selection from genes and other functionally important regions. This implies that many archaic alleles harmed the fitness of hybrid individuals, but the nature of this harm is poorly understood. Here, we show that enhancers contain less Neandertal and Denisovan variation than expected given the background selection they experience, suggesting that selection acted to purge these regions of archaic alleles that disrupted their gene regulatory functions. We infer that selection acted mainly on young archaic variation that arose in Neandertals or Denisovans shortly before their contact with humans; enhancers are not depleted of older variants found in both archaic species. Some types of enhancer appear to have tolerated introgression better than others; compared with tissue-specific enhancers, pleiotropic enhancers show stronger depletion of archaic single-nucleotide polymorphisms. To some extent, evolutionary constraint is predictive of introgression depletion, but certain tissues' enhancers are more depleted of Neandertal and Denisovan alleles than expected given their comparative tolerance to new mutations. Foetal brain and muscle are the tissues whose enhancers show the strongest depletion of archaic alleles, but only brain enhancers show evidence of unusually stringent purifying selection. We conclude that epistatic incompatibilities between human and archaic alleles are needed to explain the degree of archaic variant depletion from foetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared with humans.}, }
@article {pmid32760067, year = {2020}, author = {Hubisz, MJ and Williams, AL and Siepel, A}, title = {Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph.}, journal = {PLoS genetics}, volume = {16}, number = {8}, pages = {e1008895}, pmid = {32760067}, issn = {1553-7404}, support = {R35 GM127070/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Evolution, Molecular ; *Gene Flow ; Human Migration ; Humans ; *Models, Genetic ; Neanderthals/*genetics ; Population/*genetics ; *Recombination, Genetic ; }, abstract = {The sequencing of Neanderthal and Denisovan genomes has yielded many new insights about interbreeding events between extinct hominins and the ancestors of modern humans. While much attention has been paid to the relatively recent gene flow from Neanderthals and Denisovans into modern humans, other instances of introgression leave more subtle genomic evidence and have received less attention. Here, we present a major extension of the ARGweaver algorithm, called ARGweaver-D, which can infer local genetic relationships under a user-defined demographic model that includes population splits and migration events. This Bayesian algorithm probabilistically samples ancestral recombination graphs (ARGs) that specify not only tree topologies and branch lengths along the genome, but also indicate migrant lineages. The sampled ARGs can therefore be parsed to produce probabilities of introgression along the genome. We show that this method is well powered to detect the archaic migration into modern humans, even with only a few samples. We then show that the method can also detect introgressed regions stemming from older migration events, or from unsampled populations. We apply it to human, Neanderthal, and Denisovan genomes, looking for signatures of older proposed migration events, including ancient humans into Neanderthal, and unknown archaic hominins into Denisovans. We identify 3% of the Neanderthal genome that is putatively introgressed from ancient humans, and estimate that the gene flow occurred between 200-300kya. We find no convincing evidence that negative selection acted against these regions. Finally, we predict that 1% of the Denisovan genome was introgressed from an unsequenced, but highly diverged, archaic hominin ancestor. About 15% of these "super-archaic" regions-comprising at least about 4Mb-were, in turn, introgressed into modern humans and continue to exist in the genomes of people alive today.}, }
@article {pmid32750315, year = {2020}, author = {Course, MM and Gudsnuk, K and Smukowski, SN and Winston, K and Desai, N and Ross, JP and Sulovari, A and Bourassa, CV and Spiegelman, D and Couthouis, J and Yu, CE and Tsuang, DW and Jayadev, S and Kay, MA and Gitler, AD and Dupre, N and Eichler, EE and Dion, PA and Rouleau, GA and Valdmanis, PN}, title = {Evolution of a Human-Specific Tandem Repeat Associated with ALS.}, journal = {American journal of human genetics}, volume = {107}, number = {3}, pages = {445-460}, pmid = {32750315}, issn = {1537-6605}, support = {T32 GM007454/GM/NIGMS NIH HHS/United States ; U24 AG041689/AG/NIA NIH HHS/United States ; R01 DK078424/DK/NIDDK NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; R01 HG010169/HG/NHGRI NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Aged ; Alzheimer Disease/genetics/pathology ; Amyotrophic Lateral Sclerosis/*genetics/pathology ; DNA Repeat Expansion/genetics ; *Evolution, Molecular ; Female ; Gene Expression Regulation/genetics ; Humans ; Male ; Minisatellite Repeats/genetics ; Phenotype ; Species Specificity ; Tandem Repeat Sequences/*genetics ; }, abstract = {Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.}, }
@article {pmid32745133, year = {2020}, author = {Örd, T and Puurand, T and Örd, D and Annilo, T and Möls, M and Remm, M and Örd, T}, title = {A human-specific VNTR in the TRIB3 promoter causes gene expression variation between individuals.}, journal = {PLoS genetics}, volume = {16}, number = {8}, pages = {e1008981}, pmid = {32745133}, issn = {1553-7404}, support = {HHSN268201000029C/HL/NHLBI NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {Cell Cycle Proteins/*genetics ; Estonia/epidemiology ; Female ; Gene Expression Regulation/genetics ; *Genetic Heterogeneity ; *Genetics, Population ; Genotype ; Humans ; Male ; Minisatellite Repeats/*genetics ; Promoter Regions, Genetic ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors/genetics ; RNA-Seq ; Repressor Proteins/*genetics ; Whole Genome Sequencing ; }, abstract = {Tribbles homolog 3 (TRIB3) is pseudokinase involved in intracellular regulatory processes and has been implicated in several diseases. In this article, we report that human TRIB3 promoter contains a 33-bp variable number tandem repeat (VNTR) and characterize the heterogeneity and function of this genetic element. Analysis of human populations around the world uncovered the existence of alleles ranging from 1 to 5 copies of the repeat, with 2-, 3- and 5-copy alleles being the most common but displaying considerable geographical differences in frequency. The repeated sequence overlaps a C/EBP-ATF transcriptional regulatory element and is highly conserved, but not repeated, in various mammalian species, including great apes. The repeat is however evident in Neanderthal and Denisovan genomes. Reporter plasmid experiments in human cell culture reveal that an increased copy number of the TRIB3 promoter 33-bp repeat results in increased transcriptional activity. In line with this, analysis of whole genome sequencing and RNA-Seq data from human cohorts demonstrates that the copy number of TRIB3 promoter 33-bp repeats is positively correlated with TRIB3 mRNA expression level in many tissues throughout the body. Moreover, the copy number of the TRIB3 33-bp repeat appears to be linked to known TRIB3 eQTL SNPs as well as TRIB3 SNPs reported in genetic association studies. Taken together, the results indicate that the promoter 33-bp VNTR constitutes a causal variant for TRIB3 expression variation between individuals and could underlie the results of SNP-based genetic studies.}, }
@article {pmid32574964, year = {2020}, author = {Mathov, Y and Batyrev, D and Meshorer, E and Carmel, L}, title = {Harnessing epigenetics to study human evolution.}, journal = {Current opinion in genetics &amp; development}, volume = {62}, number = {}, pages = {23-29}, doi = {10.1016/j.gde.2020.05.023}, pmid = {32574964}, issn = {1879-0380}, mesh = {*DNA Methylation ; *Epigenesis, Genetic ; *Evolution, Molecular ; *Genetic Variation ; *Genome, Human ; Humans ; }, abstract = {Recent advances in ancient DNA extraction and high-throughput sequencing technologies enabled the high-quality sequencing of archaic genomes, including the Neanderthal and the Denisovan. While comparisons with modern humans revealed both archaic-specific and human-specific sequence changes, in the absence of gene expression information, understanding the functional implications of such genetic variations remains a major challenge. To study gene regulation in archaic humans, epigenetic research comes to our aid. DNA methylation, which is highly correlated with transcription, can be directly measured in modern samples, as well as reconstructed in ancient samples. This puts DNA methylation as a natural basis for comparative epigenetics between modern humans, archaic humans and nonhuman primates.}, }
@article {pmid32571487, year = {2020}, author = {Kim, J and Perkins, GB and Coates, PT}, title = {Evolutionary immunology: how your ancestry can affect your kidney transplant.}, journal = {Kidney international}, volume = {98}, number = {1}, pages = {45-47}, doi = {10.1016/j.kint.2020.01.020}, pmid = {32571487}, issn = {1523-1755}, mesh = {Alleles ; Animals ; Biological Evolution ; Humans ; *Kidney Transplantation ; Mice ; Phosphorylation ; Tumor Necrosis Factor alpha-Induced Protein 3 ; }, }
@article {pmid32556248, year = {2020}, author = {Khan, N and de Manuel, M and Peyregne, S and Do, R and Prufer, K and Marques-Bonet, T and Varki, N and Gagneux, P and Varki, A}, title = {Multiple Genomic Events Altering Hominin SIGLEC Biology and Innate Immunity Predated the Common Ancestor of Humans and Archaic Hominins.}, journal = {Genome biology and evolution}, volume = {12}, number = {7}, pages = {1040-1050}, pmid = {32556248}, issn = {1759-6653}, support = {R01 GM032373/GM/NIGMS NIH HHS/United States ; U01 MH106874/MH/NIMH NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Animals ; *Evolution, Molecular ; Gene Expression ; Genome ; Hominidae/*genetics/immunology ; Humans ; Immunity, Innate/genetics ; Multigene Family ; Mutation ; Polymorphism, Genetic ; Selection, Genetic ; Sialic Acid Binding Ig-like Lectin 3/*genetics ; }, abstract = {Human-specific pseudogenization of the CMAH gene eliminated the mammalian sialic acid (Sia) Neu5Gc (generating an excess of its precursor Neu5Ac), thus changing ubiquitous cell surface "self-associated molecular patterns" that modulate innate immunity via engagement of CD33-related-Siglec receptors. The Alu-fusion-mediated loss-of-function of CMAH fixed ∼2-3 Ma, possibly contributing to the origins of the genus Homo. The mutation likely altered human self-associated molecular patterns, triggering multiple events, including emergence of human-adapted pathogens with strong preference for Neu5Ac recognition and/or presenting Neu5Ac-containing molecular mimics of human glycans, which can suppress immune responses via CD33-related-Siglec engagement. Human-specific alterations reported in some gene-encoding Sia-sensing proteins suggested a "hotspot" in hominin evolution. The availability of more hominid genomes including those of two extinct hominins now allows full reanalysis and evolutionary timing. Functional changes occur in 8/13 members of the human genomic cluster encoding CD33-related Siglecs, all predating the human common ancestor. Comparisons with great ape genomes indicate that these changes are unique to hominins. We found no evidence for strong selection after the Human-Neanderthal/Denisovan common ancestor, and these extinct hominin genomes include almost all major changes found in humans, indicating that these changes in hominin sialobiology predate the Neanderthal-human divergence ∼0.6 Ma. Multiple changes in this genomic cluster may also explain human-specific expression of CD33rSiglecs in unexpected locations such as amnion, placental trophoblast, pancreatic islets, ovarian fibroblasts, microglia, Natural Killer(NK) cells, and epithelia. Taken together, our data suggest that innate immune interactions with pathogens markedly altered hominin Siglec biology between 0.6 and 2 Ma, potentially affecting human evolution.}, }
@article {pmid32546518, year = {2020}, author = {Mafessoni, F and Grote, S and de Filippo, C and Slon, V and Kolobova, KA and Viola, B and Markin, SV and Chintalapati, M and Peyrégne, S and Skov, L and Skoglund, P and Krivoshapkin, AI and Derevianko, AP and Meyer, M and Kelso, J and Peter, B and Prüfer, K and Pääbo, S}, title = {A high-coverage Neandertal genome from Chagyrskaya Cave.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {26}, pages = {15132-15136}, pmid = {32546518}, issn = {1091-6490}, mesh = {Animals ; Biological Evolution ; Female ; Fossils ; Gene Expression Regulation ; Genetic Variation ; *Genome ; Humans ; Inbreeding ; Neanderthals/*genetics ; Population Density ; Russia ; }, abstract = {We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to Neandertals in western Eurasia [Prüfer et al., Science 358, 655-658 (2017); Hajdinjak et al., Nature 555, 652-656 (2018)] than to Neandertals who lived earlier in Denisova Cave [Prüfer et al., Nature 505, 43-49 (2014)], which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with the fact that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains, and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more amino-acid-changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.}, }
@article {pmid32531199, year = {2020}, author = {Almarri, MA and Bergström, A and Prado-Martinez, J and Yang, F and Fu, B and Dunham, AS and Chen, Y and Hurles, ME and Tyler-Smith, C and Xue, Y}, title = {Population Structure, Stratification, and Introgression of Human Structural Variation.}, journal = {Cell}, volume = {182}, number = {1}, pages = {189-199.e15}, pmid = {32531199}, issn = {1097-4172}, support = {FC001595/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; FC001595/CRUK_/Cancer Research UK/United Kingdom ; FC001595/WT_/Wellcome Trust/United Kingdom ; FC001595/ARC_/Arthritis Research UK/United Kingdom ; }, mesh = {Alleles ; Databases, Genetic ; Gene Dosage ; Gene Duplication ; Gene Frequency/genetics ; Genetic Variation ; *Genetics, Population ; Genome, Human ; *Genomic Structural Variation ; Humans ; }, abstract = {Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Some reach high frequency and are private to continental groups or even individual populations, including regionally restricted runaway duplications and putatively introgressed variants from archaic hominins. By de novo assembly of 25 genomes using linked-read sequencing, we discover 1,643 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. Our results illustrate the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.}, }
@article {pmid32494067, year = {2020}, author = {Skov, L and Coll Macià, M and Sveinbjörnsson, G and Mafessoni, F and Lucotte, EA and Einarsdóttir, MS and Jonsson, H and Halldorsson, B and Gudbjartsson, DF and Helgason, A and Schierup, MH and Stefansson, K}, title = {The nature of Neanderthal introgression revealed by 27,566 Icelandic genomes.}, journal = {Nature}, volume = {582}, number = {7810}, pages = {78-83}, pmid = {32494067}, issn = {1476-4687}, mesh = {Animals ; Female ; Genetic Association Studies ; Genetic Introgression/*genetics ; Genome, Human/*genetics ; *Genomics ; Haploidy ; Humans ; Iceland ; Male ; *Mutation ; Neanderthals/*genetics ; Phenotype ; Phylogeny ; }, abstract = {Human evolutionary history is rich with the interbreeding of divergent populations. Most humans outside of Africa trace about 2% of their genomes to admixture from Neanderthals, which occurred 50-60 thousand years ago[1]. Here we examine the effect of this event using 14.4 million putative archaic chromosome fragments that were detected in fully phased whole-genome sequences from 27,566 Icelanders, corresponding to a range of 56,388-112,709 unique archaic fragments that cover 38.0-48.2% of the callable genome. On the basis of the similarity with known archaic genomes, we assign 84.5% of fragments to an Altai or Vindija Neanderthal origin and 3.3% to Denisovan origin; 12.2% of fragments are of unknown origin. We find that Icelanders have more Denisovan-like fragments than expected through incomplete lineage sorting. This is best explained by Denisovan gene flow, either into ancestors of the introgressing Neanderthals or directly into humans. A within-individual, paired comparison of archaic fragments with syntenic non-archaic fragments revealed that, although the overall rate of mutation was similar in humans and Neanderthals during the 500 thousand years that their lineages were separate, there were differences in the relative frequencies of mutation types-perhaps due to different generation intervals for males and females. Finally, we assessed 271 phenotypes, report 5 associations driven by variants in archaic fragments and show that the majority of previously reported associations are better explained by non-archaic variants.}, }
@article {pmid32330268, year = {2020}, author = {Lodewijk, GA and Fernandes, DP and Vretzakis, I and Savage, JE and Jacobs, FMJ}, title = {Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels.}, journal = {Molecular biology and evolution}, volume = {37}, number = {9}, pages = {2531-2548}, pmid = {32330268}, issn = {1537-1719}, mesh = {Animals ; *Biological Evolution ; Genome, Human ; Genomic Structural Variation ; Humans ; Multigene Family ; Neanderthals/*genetics ; Receptor, Notch2/*genetics/metabolism ; }, abstract = {Ever since the availability of genomes from Neanderthals, Denisovans, and ancient humans, the field of evolutionary genomics has been searching for protein-coding variants that may hold clues to how our species evolved over the last ∼600,000 years. In this study, we identify such variants in the human-specific NOTCH2NL gene family, which were recently identified as possible contributors to the evolutionary expansion of the human brain. We find evidence for the existence of unique protein-coding NOTCH2NL variants in Neanderthals and Denisovans which could affect their ability to activate Notch signaling. Furthermore, in the Neanderthal and Denisovan genomes, we find unusual NOTCH2NL configurations, not found in any of the modern human genomes analyzed. Finally, genetic analysis of archaic and modern humans reveals ongoing adaptive evolution of modern human NOTCH2NL genes, identifying three structural variants acting complementary to drive our genome to produce a lower dosage of NOTCH2NL protein. Because copy-number variations of the 1q21.1 locus, encompassing NOTCH2NL genes, are associated with severe neurological disorders, this seemingly contradicting drive toward low levels of NOTCH2NL protein indicates that the optimal dosage of NOTCH2NL may have not yet been settled in the human population.}, }
@article {pmid32193295, year = {2020}, author = {Bergström, A and McCarthy, SA and Hui, R and Almarri, MA and Ayub, Q and Danecek, P and Chen, Y and Felkel, S and Hallast, P and Kamm, J and Blanché, H and Deleuze, JF and Cann, H and Mallick, S and Reich, D and Sandhu, MS and Skoglund, P and Scally, A and Xue, Y and Durbin, R and Tyler-Smith, C}, title = {Insights into human genetic variation and population history from 929 diverse genomes.}, journal = {Science (New York, N.Y.)}, volume = {367}, number = {6484}, pages = {}, pmid = {32193295}, issn = {1095-9203}, support = {207492/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; /ERC_/European Research Council/International ; /HHMI/Howard Hughes Medical Institute/United States ; 206194/WT_/Wellcome Trust/United Kingdom ; 098051/WT_/Wellcome Trust/United Kingdom ; FC001595/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; FC001595/MRC_/Medical Research Council/United Kingdom ; 207492/WT_/Wellcome Trust/United Kingdom ; FC001595/ARC_/Arthritis Research UK/United Kingdom ; FC001595/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Africa ; Americas ; Animals ; Asia ; DNA Copy Number Variations ; *Genetic Variation ; *Genetics, Population ; *Genome, Human ; Haplotypes ; Hominidae/genetics ; Humans ; INDEL Mutation ; Neanderthals/genetics ; Oceania ; Phylogeny ; Polymorphism, Single Nucleotide ; Population Density ; Racial Groups/genetics ; *Whole Genome Sequencing ; }, abstract = {Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.}, }
@article {pmid32128408, year = {2020}, author = {Rogers, AR and Harris, NS and Achenbach, AA}, title = {Neanderthal-Denisovan ancestors interbred with a distantly related hominin.}, journal = {Science advances}, volume = {6}, number = {8}, pages = {eaay5483}, pmid = {32128408}, issn = {2375-2548}, mesh = {Animals ; Confidence Intervals ; *Consanguinity ; Gene Flow ; Genetics, Population ; Hominidae/*genetics ; Models, Genetic ; Neanderthals/*genetics ; Phylogeny ; }, abstract = {Previous research has shown that modern Eurasians interbred with their Neanderthal and Denisovan predecessors. We show here that hundreds of thousands of years earlier, the ancestors of Neanderthals and Denisovans interbred with their own Eurasian predecessors-members of a "superarchaic" population that separated from other humans about 2 million years ago. The superarchaic population was large, with an effective size between 20 and 50 thousand individuals. We confirm previous findings that (i) Denisovans also interbred with superarchaics, (ii) Neanderthals and Denisovans separated early in the middle Pleistocene, (iii) their ancestors endured a bottleneck of population size, and (iv) the Neanderthal population was large at first but then declined in size. We provide qualified support for the view that (v) Neanderthals interbred with the ancestors of modern humans.}, }
@article {pmid32032517, year = {2020}, author = {Gokhman, D and Mishol, N and de Manuel, M and de Juan, D and Shuqrun, J and Meshorer, E and Marques-Bonet, T and Rak, Y and Carmel, L}, title = {Reconstructing Denisovan Anatomy Using DNA Methylation Maps.}, journal = {Cell}, volume = {180}, number = {3}, pages = {601}, doi = {10.1016/j.cell.2020.01.020}, pmid = {32032517}, issn = {1097-4172}, }
@article {pmid34692055, year = {2020}, author = {,  and He, Y and Lou, H and Cui, C and Deng, L and Gao, Y and Zheng, W and Guo, Y and Wang, X and Ning, Z and Li, J and Li, B and Bai, C and ,  and ,  and ,  and ,  and ,  and Liu, S and Wu, T and Xu, S and Qi, X and Su, B}, title = {De novo assembly of a Tibetan genome and identification of novel structural variants associated with high-altitude adaptation.}, journal = {National science review}, volume = {7}, number = {2}, pages = {391-402}, pmid = {34692055}, issn = {2053-714X}, abstract = {Structural variants (SVs) may play important roles in human adaptation to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17 900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high-quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%-1.53%) compared to other East Asian genomes (0.70%-0.98%), reflecting a unique genomic composition of Tibetans. One such archaic hominid shared sequence-a 662-bp intronic insertion in the SCUBE2 gene-is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.}, }
@article {pmid31935281, year = {2020}, author = {Gouy, A and Excoffier, L}, title = {Polygenic Patterns of Adaptive Introgression in Modern Humans Are Mainly Shaped by Response to Pathogens.}, journal = {Molecular biology and evolution}, volume = {37}, number = {5}, pages = {1420-1433}, doi = {10.1093/molbev/msz306}, pmid = {31935281}, issn = {1537-1719}, mesh = {Adaptation, Biological/*genetics ; *Genetic Introgression ; Host-Pathogen Interactions/*genetics ; Humans ; Melanesia ; *Multifactorial Inheritance ; *Selection, Genetic ; }, abstract = {Anatomically modern humans carry many introgressed variants from other hominins in their genomes. Some of them affect their phenotype and can thus be negatively or positively selected. Several individual genes have been proposed to be the subject of adaptive introgression, but the possibility of polygenic adaptive introgression has not been extensively investigated yet. In this study, we analyze archaic introgression maps with refined functional enrichment methods to find signals of polygenic adaptation of introgressed variants. We first apply a method to detect sets of connected genes (subnetworks) within biological pathways that present higher-than-expected levels of archaic introgression. We then introduce and apply a new statistical test to distinguish between epistatic and independent selection in gene sets of present-day humans. We identify several known targets of adaptive introgression, and we show that they belong to larger networks of introgressed genes. After correction for genetic linkage, we find that signals of polygenic adaptation are mostly explained by independent and potentially sequential selection episodes. However, we also find some gene sets where introgressed variants present significant signals of epistatic selection. Our results confirm that archaic introgression has facilitated local adaptation, especially in immunity related and metabolic functions and highlight its involvement in a coordinated response to pathogens out of Africa.}, }
@article {pmid31878873, year = {2019}, author = {Bücking, R and Cox, MP and Hudjashov, G and Saag, L and Sudoyo, H and Stoneking, M}, title = {Archaic mitochondrial DNA inserts in modern day nuclear genomes.}, journal = {BMC genomics}, volume = {20}, number = {1}, pages = {1017}, pmid = {31878873}, issn = {1471-2164}, mesh = {Animals ; Cell Nucleus/*genetics ; DNA, Mitochondrial/*genetics ; Evolution, Molecular ; Genomics/*methods ; Hominidae/genetics ; Neanderthals/genetics ; Phylogeny ; }, abstract = {BACKGROUND: Traces of interbreeding of Neanderthals and Denisovans with modern humans in the form of archaic DNA have been detected in the genomes of present-day human populations outside sub-Saharan Africa. Up to now, only nuclear archaic DNA has been detected in modern humans; we therefore attempted to identify archaic mitochondrial DNA (mtDNA) residing in modern human nuclear genomes as nuclear inserts of mitochondrial DNA (NUMTs).<br><br>RESULTS: We analysed 221 high-coverage genomes from Oceania and Indonesia using an approach which identifies reads that map both to the nuclear and mitochondrial DNA. We then classified reads according to the source of the mtDNA, and found one NUMT of Denisovan mtDNA origin, present in 15 analysed genomes; analysis of the flanking region suggests that this insertion is more likely to have happened in a Denisovan individual and introgressed into modern humans with the Denisovan nuclear DNA, rather than in a descendant of a Denisovan female and a modern human male.<br><br>CONCLUSIONS: Here we present our pipeline for detecting introgressed NUMTs in next generation sequencing data that can be used on genomes sequenced in the future. Further discovery of such archaic NUMTs in modern humans can be used to detect interbreeding between archaic and modern humans and can reveal new insights into the nature of such interbreeding events.}, }
@article {pmid31848254, year = {2020}, author = {Scott, GR and Irish, JD and Martinón-Torres, M}, title = {A more comprehensive view of the Denisovan 3-rooted lower second molar from Xiahe.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {1}, pages = {37-38}, pmid = {31848254}, issn = {1091-6490}, mesh = {Asian People ; *Fossils ; Humans ; Molar/anatomy &amp; histology ; *Tooth ; }, }
@article {pmid31809748, year = {2019}, author = {Wall, JD and Ratan, A and Stawiski, E and , }, title = {Identification of African-Specific Admixture between Modern and Archaic Humans.}, journal = {American journal of human genetics}, volume = {105}, number = {6}, pages = {1254-1261}, pmid = {31809748}, issn = {1537-6605}, support = {P30 CA044579/CA/NCI NIH HHS/United States ; R01 GM115433/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Black People/*genetics ; *Fossils ; Gene Pool ; *Genetics, Population ; *Genome, Human ; Hominidae/*genetics ; Humans ; Neanderthals/*genetics ; }, abstract = {Recent work has demonstrated that two archaic human groups (Neanderthals and Denisovans) interbred with modern humans and contributed to the contemporary human gene pool. These findings relied on the availability of high-coverage genomes from both Neanderthals and Denisovans. Here we search for evidence of archaic admixture from a worldwide panel of 1,667 individuals using an approach that does not require the presence of an archaic human reference genome. We find no evidence for archaic admixture in the Andaman Islands, as previously claimed, or on the island of Flores, where Homo floresiensis fossils have been found. However, we do find evidence for at least one archaic admixture event in sub-Saharan Africa, with the strongest signal in Khoesan and Pygmy individuals from Southern and Central Africa. The locations of these putative archaic admixture tracts are weighted against functional regions of the genome, consistent with the long-term effects of purifying selection against introgressed genetic material.}, }
@article {pmid31702050, year = {2020}, author = {Gokcumen, O}, title = {Archaic hominin introgression into modern human genomes.}, journal = {American journal of physical anthropology}, volume = {171 Suppl 70}, number = {}, pages = {60-73}, doi = {10.1002/ajpa.23951}, pmid = {31702050}, issn = {1096-8644}, support = {1714867//United States National Science Foundation/International ; }, mesh = {Animals ; DNA/genetics ; *Gene Flow ; *Genetic Introgression ; *Genome, Human ; Hominidae/*genetics ; Humans ; Neanderthals/genetics ; }, abstract = {Ancient genomes from multiple Neanderthal and the Denisovan individuals, along with DNA sequence data from diverse contemporary human populations strongly support the prevalence of gene flow among different hominins. Recent studies now provide evidence for multiple gene flow events that leave genetic signatures in extant and ancient human populations. These events include older gene flow from an unknown hominin in Africa predating out-of-Africa migrations, and in the last 50,000-100,000 years, multiple gene flow events from Neanderthals into ancestral Eurasian human populations, and at least three distinct introgression events from a lineage close to Denisovans into ancestors of extant Southeast Asian and Oceanic populations. Some of these introgression events may have happened as late as 20,000 years before present and reshaped the way in which we think about human evolution. In this review, I aim to answer anthropologically relevant questions with regard to recent research on ancient hominin introgression in the human lineage. How have genomic data from archaic hominins changed our view of human evolution? Is there any doubt about whether introgression from ancient hominins to the ancestors of present-day humans occurred? What is the current view of human evolutionary history from the genomics perspective? What is the impact of introgression on human phenotypes?}, }
@article {pmid31591491, year = {2019}, author = {Colbran, LL and Gamazon, ER and Zhou, D and Evans, P and Cox, NJ and Capra, JA}, title = {Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences.}, journal = {Nature ecology &amp; evolution}, volume = {3}, number = {11}, pages = {1598-1606}, pmid = {31591491}, issn = {2397-334X}, support = {T32 GM080178/GM/NIGMS NIH HHS/United States ; R01 GM115836/GM/NIGMS NIH HHS/United States ; R01 MH101820/MH/NIMH NIH HHS/United States ; R01 MH113362/MH/NIMH NIH HHS/United States ; R35 HG010718/HG/NHGRI NIH HHS/United States ; R01 MH090937/MH/NIMH NIH HHS/United States ; R35 GM127087/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Female ; Genome, Human ; Haplotypes ; *Hominidae ; Humans ; *Neanderthals ; Phenotype ; }, abstract = {Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes' regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone.}, }
@article {pmid31560950, year = {2019}, author = {Mata, X and Renaud, G and Mollereau, C}, title = {The repertoire of family A-peptide GPCRs in archaic hominins.}, journal = {Peptides}, volume = {122}, number = {}, pages = {170154}, doi = {10.1016/j.peptides.2019.170154}, pmid = {31560950}, issn = {1873-5169}, mesh = {Animals ; Diabetic Nephropathies/*genetics/pathology ; *Evolution, Molecular ; Genome, Human/genetics ; Haplotypes/genetics ; Hominidae/genetics ; Humans ; Neanderthals/genetics ; Obesity/*genetics/pathology ; Peptides/genetics ; Platelet Aggregation/genetics ; Receptors, G-Protein-Coupled/*genetics ; Risk Factors ; }, abstract = {Given the importance of G-protein coupled receptors in the regulation of many physiological functions, deciphering the relationships between genotype and phenotype in past and present hominin GPCRs is of main interest to understand the evolutionary process that contributed to the present-day variability in human traits and health. Here, we carefully examined the publicly available genomic and protein sequence databases of the archaic hominins (Neanderthal and Denisova) to draw up the catalog of coding variations in GPCRs for peptide ligands, in comparison with living humans. We then searched in the literature the functional changes, phenotypes and risk of disease possibly associated with the detected variants. Our survey suggests that Neanderthal and Denisovan hominins were likely prone to lower risk of obesity, to enhanced platelet aggregation in response to thrombin, to better response to infection, to less anxiety and aggressiveness and to favorable sociability. While some archaic variants were likely advantageous in the past, they might be responsible for maladaptive disorders today in the context of modern life and/or specific regional distribution. For example, an archaic haplotype in the neuromedin receptor 2 is susceptible to confer risk of diabetic nephropathy in type 1 diabetes in present-day Europeans. Paying attention to the pharmacological properties of some of the archaic variants described in this study may be helpful to understand the variability of therapeutic efficacy between individuals or ethnic groups.}, }
@article {pmid31558742, year = {2019}, author = {Morley, MW and Goldberg, P and Uliyanov, VA and Kozlikin, MB and Shunkov, MV and Derevianko, AP and Jacobs, Z and Roberts, RG}, title = {Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {13785}, pmid = {31558742}, issn = {2045-2322}, mesh = {Animals ; Archaeology ; *Caves ; Cold Climate ; DNA, Ancient/isolation &amp; purification ; *Fossils ; History, Ancient ; *Hominidae/genetics ; Humans ; Neanderthals/genetics ; Paleontology ; Siberia ; }, abstract = {Denisova Cave in southern Siberia uniquely contains evidence of occupation by a recently discovered group of archaic hominins, the Denisovans, starting from the middle of the Middle Pleistocene. Artefacts, ancient DNA and a range of animal and plant remains have been recovered from the sedimentary deposits, along with a few fragmentary fossils of Denisovans, Neanderthals and a first-generation Neanderthal-Denisovan offspring. The deposits also contain microscopic traces of hominin and animal activities that can provide insights into the use of the cave over the last 300,000 years. Here we report the results of a micromorphological study of intact sediment blocks collected from the Pleistocene deposits in the Main and East Chambers of Denisova Cave. The presence of charcoal attests to the use of fire by hominins, but other evidence of their activities preserved in the microstratigraphic record are few. The ubiquitous occurrence of coprolites, which we attribute primarily to hyenas, indicates that the site was visited for much of its depositional history by cave-dwelling carnivores. Microscopic traces of post-depositional diagenesis, bioturbation and incipient cryoturbation are observed in only a few regions of the deposit examined here. Micromorphology can help identify areas of sedimentary deposit that are most conducive to ancient DNA preservation and could be usefully integrated with DNA analyses of sediments at archaeological sites to illuminate features of their human and environmental history that are invisible to the naked eye.}, }
@article {pmid31539495, year = {2019}, author = {Gokhman, D and Mishol, N and de Manuel, M and de Juan, D and Shuqrun, J and Meshorer, E and Marques-Bonet, T and Rak, Y and Carmel, L}, title = {Reconstructing Denisovan Anatomy Using DNA Methylation Maps.}, journal = {Cell}, volume = {179}, number = {1}, pages = {180-192.e10}, doi = {10.1016/j.cell.2019.08.035}, pmid = {31539495}, issn = {1097-4172}, mesh = {Animals ; Base Sequence ; DNA Methylation/*genetics ; Databases, Genetic ; Extinction, Biological ; Fossils ; Genome, Human/genetics ; Humans ; Neanderthals/*anatomy &amp; histology/*genetics ; Pan troglodytes/*anatomy &amp; histology/*genetics ; *Phenotype ; Polymorphism, Single Nucleotide/genetics ; Skeleton ; Skull ; }, abstract = {Denisovans are an extinct group of humans whose morphology remains unknown. Here, we present a method for reconstructing skeletal morphology using DNA methylation patterns. Our method is based on linking unidirectional methylation changes to loss-of-function phenotypes. We tested performance by reconstructing Neanderthal and chimpanzee skeletal morphologies and obtained >85% precision in identifying divergent traits. We then applied this method to the Denisovan and offer a putative morphological profile. We suggest that Denisovans likely shared with Neanderthals traits such as an elongated face and a wide pelvis. We also identify Denisovan-derived changes, such as an increased dental arch and lateral cranial expansion. Our predictions match the only morphologically informative Denisovan bone to date, as well as the Xuchang skull, which was suggested by some to be a Denisovan. We conclude that DNA methylation can be used to reconstruct anatomical features, including some that do not survive in the fossil record.}, }
@article {pmid31534238, year = {2019}, author = {Zammit, NW and Siggs, OM and Gray, PE and Horikawa, K and Langley, DB and Walters, SN and Daley, SR and Loetsch, C and Warren, J and Yap, JY and Cultrone, D and Russell, A and Malle, EK and Villanueva, JE and Cowley, MJ and Gayevskiy, V and Dinger, ME and Brink, R and Zahra, D and Chaudhri, G and Karupiah, G and Whittle, B and Roots, C and Bertram, E and Yamada, M and Jeelall, Y and Enders, A and Clifton, BE and Mabbitt, PD and Jackson, CJ and Watson, SR and Jenne, CN and Lanier, LL and Wiltshire, T and Spitzer, MH and Nolan, GP and Schmitz, F and Aderem, A and Porebski, BT and Buckle, AM and Abbott, DW and Ziegler, JB and Craig, ME and Benitez-Aguirre, P and Teo, J and Tangye, SG and King, C and Wong, M and Cox, MP and Phung, W and Tang, J and Sandoval, W and Wertz, IE and Christ, D and Goodnow, CC and Grey, ST}, title = {Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.}, journal = {Nature immunology}, volume = {20}, number = {10}, pages = {1299-1310}, pmid = {31534238}, issn = {1529-2916}, support = {R01 AI052127/AI/NIAID NIH HHS/United States ; U54 AI054523/AI/NIAID NIH HHS/United States ; }, mesh = {Alleles ; Animals ; Extinction, Biological ; Humans ; Immunity ; Inflammation ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation, Missense/genetics ; Phosphorylation ; Poxviridae/*physiology ; Poxviridae Infections/*immunology ; Protein Domains/*genetics ; Tumor Necrosis Factor alpha-Induced Protein 3/*genetics ; }, abstract = {Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.}, }
@article {pmid31517046, year = {2019}, author = {Bennett, EA and Crevecoeur, I and Viola, B and Derevianko, AP and Shunkov, MV and Grange, T and Maureille, B and Geigl, EM}, title = {Morphology of the Denisovan phalanx closer to modern humans than to Neanderthals.}, journal = {Science advances}, volume = {5}, number = {9}, pages = {eaaw3950}, pmid = {31517046}, issn = {2375-2548}, mesh = {Animals ; Finger Phalanges/*anatomy &amp; histology ; *Genome, Human ; Humans ; Molar/*anatomy &amp; histology ; *Neanderthals/anatomy &amp; histology/genetics ; Species Specificity ; }, abstract = {A fully sequenced high-quality genome has revealed in 2010 the existence of a human population in Asia, the Denisovans, related to and contemporaneous with Neanderthals. Only five skeletal remains are known from Denisovans, mostly molars; the proximal fragment of a fifth finger phalanx used to generate the genome, however, was too incomplete to yield useful morphological information. Here, we demonstrate through ancient DNA analysis that a distal fragment of a fifth finger phalanx from the Denisova Cave is the larger, missing part of this phalanx. Our morphometric analysis shows that its dimensions and shape are within the variability of Homo sapiens and distinct from the Neanderthal fifth finger phalanges. Thus, unlike Denisovan molars, which display archaic characteristics not found in modern humans, the only morphologically informative Denisovan postcranial bone identified to date is suggested here to be plesiomorphic and shared between Denisovans and modern humans.}, }
@article {pmid31506618, year = {2019}, author = {Callaway, E}, title = {Lost Denisovan bone reveals surprisingly human-like finger.}, journal = {Nature}, volume = {573}, number = {7773}, pages = {175-176}, pmid = {31506618}, issn = {1476-4687}, mesh = {Animals ; Archaeology ; Fingers ; *Hominidae ; Humans ; *Neanderthals ; }, }
@article {pmid33951887, year = {2019}, author = {Caldararo, N}, title = {Probability, Populations, Phylogenetics, and Hominin Speciation.}, journal = {Human biology}, volume = {90}, number = {2}, pages = {129-155}, doi = {10.13110/humanbiology.90.2.04}, pmid = {33951887}, issn = {1534-6617}, abstract = {A number of recent articles have appeared on the hominin Denisova fossil remains. Many of them focus on attempts to produce DNA sequences from the extracted samples. Often these project mitochondrial DNA (mtDNA) sequences from the fossils of a number of Neandertals and the Denisovans in an attempt to understand the evolution of Middle Pleistocene human ancestors. These articles introduce a number of problems in the interpretation of speciation in hominins. One concerns the degradation of the ancient DNA and its interpretation as authentic genetic information. Another problem concerns the ideas of "species" versus "population" and the use of these ideas in building evolutionary diagrams to indicate ancestry and extinction. A third issue concerns the theory of haplotypes in the mtDNA. Given the severe constraints on mutations in the mtDNA genome to maintain functionality and the purifying processes to reduce such mutations in the ovaries, putative geographic and historical variations seem contradictory. Local diversity and variations in supposed "macrohaplotypes" are explained as back migrations or back mutations, which dilutes the robust nature of the theory. A central issue involves what human variation means, how much population variation there has been in the past, and whether this variation distinguishes hominid speciation or is simply a process of anagenesis. This brings up the question of how much can be interpreted from the analysis of DNA. Some businesses today claim to be able to use DNA analysis to discover past ethnic identities, and a new niche in restaurants is producing "DNA" menus. Perhaps some caution is in order.}, }
@article {pmid31386798, year = {2020}, author = {Mikaeeli, S and Susan-Resiga, D and Girard, E and Ben Djoudi Ouadda, A and Day, R and Prost, S and Seidah, NG}, title = {Functional analysis of natural PCSK9 mutants in modern and archaic humans.}, journal = {The FEBS journal}, volume = {287}, number = {3}, pages = {515-528}, doi = {10.1111/febs.15036}, pmid = {31386798}, issn = {1742-4658}, support = {148363//CIHR/Canada ; }, mesh = {Animals ; Binding Sites ; DNA Methylation ; Humans ; *Loss of Function Mutation ; Neanderthals/*genetics ; Proprotein Convertase 9/chemistry/*genetics/metabolism ; Protein Binding ; Receptors, LDL/metabolism ; }, abstract = {PCSK9 is the last member of the proprotein convertases (PCs) family and its gene is mutated in ~ 2% to 3% of individuals with familial hypercholesterolemia (FH). This protein enhances the degradation of the low-density lipoprotein receptor (LDLR) and hence increases the levels of circulating LDL-cholesterol (LDLc). Studies of the underlying mechanism(s) regulating the activity of different mutations in the PCSK9 gene are ongoing as they enhance our understanding of the biology and clinical relevance of PCSK9 and its partners. In an attempt to unravel the regulation of PCSK9 transcription and possibly identify mutation 'hot spot' regions with alterations in CpG methylation, we present for the first time the complete methylome profile of the PCSK9 gene in modern and archaic humanoids. Our data showed that the genomes of modern humans and archaic PCSK9 exhibit a similar methylation pattern. Next, we defined the mechanistic consequences of three PCSK9 natural mutations (PCSK9-R96L, -R105W, and -P174S) and one archaic Denisovan mutation (PCSK9-H449L) using various complementary cellular and in vitro binding assays. Our results showed that the PCSK9-H449L is a loss-of-function (LOF) mutation, likely due to its lower binding affinity to the LDLR. Similarly, PCSK9-R96L and -R105W are LOF mutations, even though they have been identified in FH patients. The PCSK9-R105W mutation leads to a significantly lower autocatalytic processing of proPCSK9. PCSK9-P174S resulted in a LOF in both extracellular and intracellular pathways. In conclusion, our extensive analyses revealed that all studied mutations result in PCSK9 LOF, via various mechanisms, leading to lower levels of LDLc.}, }
@article {pmid31285349, year = {2019}, author = {Bailey, SE and Hublin, JJ and Antón, SC}, title = {Rare dental trait provides morphological evidence of archaic introgression in Asian fossil record.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, number = {30}, pages = {14806-14807}, pmid = {31285349}, issn = {1091-6490}, mesh = {Animals ; Asian People/genetics ; *Evolution, Molecular ; Fossils/*anatomy &amp; histology ; Hominidae/*anatomy &amp; histology/genetics ; Humans ; Mandible/anatomy &amp; histology ; Molar/*anatomy &amp; histology ; }, abstract = {The recently described Denisovan hemimandible from Xiahe, China [F. Chen et al., (2019) Nature 569, 409-412], possesses an unusual dental feature: a 3-rooted lower second molar. A survey of the clinical and bioarchaeological literature demonstrates that the 3-rooted lower molar is rare (less than 3.5% occurrence) in non-Asian Homo sapiens In contrast, its presence in Asian-derived populations can exceed 40% in China and the New World. It has long been thought that the prevalence of 3-rooted lower molars in Asia is a relatively late acquisition occurring well after the origin and dispersal of H. sapiens However, the presence of a 3-rooted lower second molar in this 160,000-y-old fossil hominin suggests greater antiquity for the trait. Importantly, it also provides morphological evidence of a strong link between archaic and recent Asian H. sapiens populations. This link provides compelling evidence that modern Asian lineages acquired the 3-rooted lower molar via introgression from Denisovans.}, }
@article {pmid31278514, year = {2019}, author = {Brzozowska, MM and Havula, E and Allen, RB and Cox, MP}, title = {Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians.}, journal = {Reviews in endocrine &amp; metabolic disorders}, volume = {20}, number = {3}, pages = {321-332}, pmid = {31278514}, issn = {1573-2606}, mesh = {Australia ; Diabetes Mellitus, Type 2/*genetics/*pathology ; Genome-Wide Association Study ; Humans ; Indigenous Peoples ; Obesity/genetics/pathology ; }, abstract = {Indigenous Australians are particularly affected by type 2 diabetes mellitus (T2D) due to both their genetic susceptibility and a range of environmental and lifestyle risk factors. Recent genetic studies link predisposition to some diseases, including T2D, to alleles acquired from archaic hominins, such as Neanderthals and Denisovans, which persist in the genomes of modern humans today. Indo-Pacific human populations, including Indigenous Australians, remain extremely underrepresented in genomic research with a paucity of data examining the impact of Denisovan or Neanderthal lineages on human phenotypes in Oceania. The few genetic studies undertaken emphasize the uniqueness and antiquity of Indigenous Australian genomes, with possibly the largest proportion of Denisovan ancestry of any population in the world. In this review, we focus on the potential contributions of ancient genes/pathways to modern human phenotypes, while also highlighting the evolutionary roles of genetic adaptation to dietary and environmental changes associated with an adopted Western lifestyle. We discuss the role of genetic and epigenetic factors in the pathogenesis of T2D in understudied Indigenous Australians, including the potential impact of archaic gene lineages on this disease. Finally, we propose that greater understanding of the underlying genetic predisposition may contribute to the clinical efficacy of diabetes management in Indigenous Australians. We suggest that improved identification of T2D risk variants in Oceania is needed. Such studies promise to clarify how genetic and phenotypic differences vary between populations and, crucially, provide novel targets for personalised medical therapies in currently marginalized groups.}, }
@article {pmid31164119, year = {2019}, author = {Shebanits, K and Günther, T and Johansson, ACV and Maqbool, K and Feuk, L and Jakobsson, M and Larhammar, D}, title = {Copy number determination of the gene for the human pancreatic polypeptide receptor NPY4R using read depth analysis and droplet digital PCR.}, journal = {BMC biotechnology}, volume = {19}, number = {1}, pages = {31}, pmid = {31164119}, issn = {1472-6750}, mesh = {DNA Copy Number Variations/*genetics ; *Gene Dosage ; Genome, Human/genetics ; Genomics/methods ; Humans ; Polymerase Chain Reaction/*methods ; Receptors, Neuropeptide Y/*genetics ; Reproducibility of Results ; Sequence Analysis, DNA/*methods ; }, abstract = {BACKGROUND: Copy number variation (CNV) plays an important role in human genetic diversity and has been associated with multiple complex disorders. Here we investigate a CNV on chromosome 10q11.22 that spans NPY4R, the gene for the appetite-regulating pancreatic polypeptide receptor Y4. This genomic region has been challenging to map due to multiple repeated elements and its precise organization has not yet been resolved. Previous studies using microarrays were interpreted to show that the most common copy number was 2 per genome.<br><br>RESULTS: We have investigated 18 individuals from the 1000 Genomes project using the well-established method of read depth analysis and the new droplet digital PCR (ddPCR) method. We find that the most common copy number for NPY4R is 4. The estimated number of copies ranged from three to seven based on read depth analyses with Control-FREEC and CNVnator, and from four to seven based on ddPCR. We suggest that the difference between our results and those published previously can be explained by methodological differences such as reference gene choice, data normalization and method reliability. Three high-quality archaic human genomes (two Neanderthal and one Denisova) display four copies of the NPY4R gene indicating that a duplication occurred prior to the human-Neanderthal/Denisova split.<br><br>CONCLUSIONS: We conclude that ddPCR is a sensitive and reliable method for CNV determination, that it can be used for read depth calibration in CNV studies based on already available whole-genome sequencing data, and that further investigation of NPY4R copy number variation and its consequences are necessary due to the role of Y4 receptor in food intake regulation.}, }
@article {pmid31163991, year = {2019}, author = {Santander, C and Montinaro, F and Capelli, C}, title = {Searching for archaic contribution in Africa.}, journal = {Annals of human biology}, volume = {46}, number = {2}, pages = {129-139}, doi = {10.1080/03014460.2019.1624823}, pmid = {31163991}, issn = {1464-5033}, mesh = {Africa ; Animals ; Black People/*genetics ; DNA, Ancient/*analysis ; Genome, Human ; Hominidae/*genetics ; Humans ; *Hybridization, Genetic ; }, abstract = {Context: Africa's role in the narrative of human evolution is indisputably emphasised in the emergence of Homo sapiens. However, once humans dispersed beyond Africa, the history of those who stayed remains vastly under-studied, lacking the proper attention the birthplace of both modern and archaic humans deserves. The sequencing of Neanderthal and Denisovan genomes has elucidated evidence of admixture between archaic and modern humans outside of Africa, but has not aided efforts in answering whether archaic admixture happened within Africa. Objectives: This article reviews the state of research for archaic introgression in African populations and discusses recent insights into this topic. Methods: Gathering published sources and recently released preprints, this review reports on the different methods developed for detecting archaic introgression. Particularly it discusses how relevant these are when implemented on African populations and what findings these studies have shown so far. Results: Methods for detecting archaic introgression have been predominantly developed and implemented on non-African populations. Recent preprints present new methods considering African populations. While a number of studies using these methods suggest archaic introgression in Africa, without an African archaic genome to validate these results, such findings remain as putative archaic introgression. Conclusion: In light of the caveats with implementing current archaic introgression detection methods in Africa, we recommend future studies to concentrate on unravelling the complicated demographic history of Africa through means of ancient DNA where possible and through more focused efforts to sequence modern DNA from more representative populations across the African continent.}, }
@article {pmid31043746, year = {2019}, author = {Chen, F and Welker, F and Shen, CC and Bailey, SE and Bergmann, I and Davis, S and Xia, H and Wang, H and Fischer, R and Freidline, SE and Yu, TL and Skinner, MM and Stelzer, S and Dong, G and Fu, Q and Dong, G and Wang, J and Zhang, D and Hublin, JJ}, title = {A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau.}, journal = {Nature}, volume = {569}, number = {7756}, pages = {409-412}, pmid = {31043746}, issn = {1476-4687}, mesh = {Altitude ; Animals ; Caves ; *Fossils ; Hominidae/*anatomy &amp; histology/classification ; Human Migration ; Humans ; Mandible/*anatomy &amp; histology ; Phylogeny ; Tibet ; Tooth/anatomy &amp; histology ; }, abstract = {Denisovans are members of a hominin group who are currently only known directly from fragmentary fossils, the genomes of which have been studied from a single site, Denisova Cave[1-3] in Siberia. They are also known indirectly from their genetic legacy through gene flow into several low-altitude East Asian populations[4,5] and high-altitude modern Tibetans[6]. The lack of morphologically informative Denisovan fossils hinders our ability to connect geographically and temporally dispersed fossil hominins from Asia and to understand in a coherent manner their relation to recent Asian populations. This includes understanding the genetic adaptation of humans to the high-altitude Tibetan Plateau[7,8], which was inherited from the Denisovans. Here we report a Denisovan mandible, identified by ancient protein analysis[9,10], found on the Tibetan Plateau in Baishiya Karst Cave, Xiahe, Gansu, China. We determine the mandible to be at least 160 thousand years old through U-series dating of an adhering carbonate matrix. The Xiahe specimen provides direct evidence of the Denisovans outside the Altai Mountains and its analysis unique insights into Denisovan mandibular and dental morphology. Our results indicate that archaic hominins occupied the Tibetan Plateau in the Middle Pleistocene epoch and successfully adapted to high-altitude hypoxic environments long before the regional arrival of modern Homo sapiens.}, }
@article {pmid31043736, year = {2019}, author = {Warren, M}, title = {Biggest Denisovan fossil yet spills ancient human's secrets.}, journal = {Nature}, volume = {569}, number = {7754}, pages = {16-17}, pmid = {31043736}, issn = {1476-4687}, }
@article {pmid30981557, year = {2019}, author = {Jacobs, GS and Hudjashov, G and Saag, L and Kusuma, P and Darusallam, CC and Lawson, DJ and Mondal, M and Pagani, L and Ricaut, FX and Stoneking, M and Metspalu, M and Sudoyo, H and Lansing, JS and Cox, MP}, title = {Multiple Deeply Divergent Denisovan Ancestries in Papuans.}, journal = {Cell}, volume = {177}, number = {4}, pages = {1010-1021.e32}, doi = {10.1016/j.cell.2019.02.035}, pmid = {30981557}, issn = {1097-4172}, mesh = {Animals ; Asian People/genetics ; Biological Evolution ; Gene Flow ; Genetic Introgression/*genetics ; Genetic Variation/genetics ; Genome, Human/genetics ; Haplotypes/*genetics ; Hominidae/*genetics ; Humans ; Indonesia ; Neanderthals/genetics ; Oceania ; }, abstract = {Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.}, }
@article {pmid30942856, year = {2019}, author = {Harris, DN and Ruczinski, I and Yanek, LR and Becker, LC and Becker, DM and Guio, H and Cui, T and Chilton, FH and Mathias, RA and O'Connor, TD}, title = {Evolution of Hominin Polyunsaturated Fatty Acid Metabolism: From Africa to the New World.}, journal = {Genome biology and evolution}, volume = {11}, number = {5}, pages = {1417-1430}, pmid = {30942856}, issn = {1759-6653}, support = {R01 AT008621/AT/NCCIH NIH HHS/United States ; R01 HL087698/HL/NHLBI NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; U01 HL072518/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Evolution, Molecular ; Fatty Acid Desaturases/*genetics/metabolism ; Fatty Acids, Unsaturated/*metabolism ; Hominidae/*genetics/metabolism ; Humans ; Indians, North American/genetics ; Selection, Genetic ; Siberia ; }, abstract = {The metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (>20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. The rate-limiting steps of this process are catalyzed by fatty acid desaturase (FADS) 1 and 2. Therefore, understanding the evolutionary history of the FADS genes is essential to our understanding of hominin evolution. The FADS genes have two haplogroups, ancestral and derived, with the derived haplogroup being associated with more efficient LC-PUFA biosynthesis than the ancestral haplogroup. In addition, there is a complex global distribution of these haplogroups that is suggestive of Neanderthal introgression. We confirm that Native American ancestry is nearly fixed for the ancestral haplogroup, and replicate a positive selection signal in Native Americans. This positive selection potentially continued after the founding of the Americas, although simulations suggest that the timing is dependent on the allele frequency of the ancestral Beringian population. We also find that the Neanderthal FADS haplotype is more closely related to the derived haplogroup and the Denisovan clusters closer to the ancestral haplogroup. Furthermore, the derived haplogroup has a time to the most recent common ancestor of 688,474 years before present. These results support an ancient polymorphism, as opposed to Neanderthal introgression, forming in the FADS region during the Pleistocene with possibly differential selection pressures on both haplogroups. The near fixation of the ancestral haplogroup in Native American ancestry calls for future studies to explore the potential health risk of associated low LC-PUFA levels in these populations.}, }
@article {pmid30889271, year = {2019}, author = {Vyas, DN and Mulligan, CJ}, title = {Analyses of Neanderthal introgression suggest that Levantine and southern Arabian populations have a shared population history.}, journal = {American journal of physical anthropology}, volume = {169}, number = {2}, pages = {227-239}, doi = {10.1002/ajpa.23818}, pmid = {30889271}, issn = {1096-8644}, support = {BCS-1258965//National Science Foundation/International ; }, mesh = {Animals ; Arabia ; Gene Flow/genetics ; Gene Frequency/genetics ; *Genetics, Population ; History, Ancient ; Human Migration/*history ; Humans ; Middle East ; Neanderthals/*genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {OBJECTIVES: Modern humans are thought to have interbred with Neanderthals in the Near East soon after modern humans dispersed out of Africa. This introgression event likely took place in either the Levant or southern Arabia depending on the dispersal route out of Africa that was followed. In this study, we compare Neanderthal introgression in contemporary Levantine and southern Arabian populations to investigate Neanderthal introgression and to study Near Eastern population history.<br><br>MATERIALS AND METHODS: We analyzed genotyping data on >400,000 autosomal SNPs from seven Levantine and five southern Arabian populations and compared these data to those from populations from around the world including Neanderthal and Denisovan genomes. We used f4 and D statistics to estimate and compare levels of Neanderthal introgression between Levantine, southern Arabian, and comparative global populations. We also identified 1,581 putative Neanderthal-introgressed SNPs within our dataset and analyzed their allele frequencies as a means to compare introgression patterns in Levantine and southern Arabian genomes.<br><br>RESULTS: We find that Levantine and southern Arabian populations have similar levels of Neanderthal introgression to each other but lower levels than other non-Africans. Furthermore, we find that introgressed SNPs have very similar allele frequencies in the Levant and southern Arabia, which indicates that Neanderthal introgression is similarly distributed in Levantine and southern Arabian genomes.<br><br>DISCUSSION: We infer that the ancestors of contemporary Levantine and southern Arabian populations received Neanderthal introgression prior to separating from each other and that there has been extensive gene flow between these populations.}, }
@article {pmid30773169, year = {2019}, author = {Buttura, RV and Ramalho, J and Lima, THA and Donadi, EA and Veiga-Castelli, LC and Mendes-Junior, CT and Castelli, EC}, title = {HLA-F displays highly divergent and frequent haplotype lineages associated with different mRNA expression levels.}, journal = {Human immunology}, volume = {80}, number = {2}, pages = {112-119}, doi = {10.1016/j.humimm.2018.10.016}, pmid = {30773169}, issn = {1879-1166}, mesh = {Animals ; Brazil ; Gene Expression Regulation ; Gene Frequency ; Genetics, Population ; Haplotypes ; High-Throughput Nucleotide Sequencing ; Histocompatibility Antigens Class I/*genetics ; Humans ; Linkage Disequilibrium ; Neanderthals/genetics ; Polymorphism, Genetic ; Promoter Regions, Genetic/*genetics ; RNA, Messenger/*genetics ; }, abstract = {HLA-F is one of the most conserved loci among the HLA gene family. The exact function of HLA-F is still under investigation. HLA-F might present tolerogenic features, participate in the stabilization of HLA molecules in open conformation, and also participate in the recycling of HLA molecules. Here we evaluate the variability and haplotype structure of the HLA-F distal promoter segment (from -1893 to -943) and how this segment is correlated with the coding region. Variability at the promoter segment was surveyed in 196 Brazilian samples using second-generation sequencing. The HLA-F promoter region presents two major haplotype lineages. Most of the variable sites are in perfect linkage and associated with a single promoter haplotype, here named F[∗]distal-C. This haplotype is associated with F[∗]01:01:02 alleles, while alleles from the F[∗]01:01:01 or F[∗]01:03 groups present closely related promoter sequences. F[∗]distal-C is quite frequent in Brazil and in worldwide populations, with frequencies ranging from 8.41% at the Iberian Population in Spain to 34.34% in Vietnam. F[∗]distal-C is also present in Neanderthal and Denisovan samples. In silico analyses demonstrated that F[∗]distal-C presents a different transcription factor binding profile compared with other HLA-F promoters. Moreover, individuals carrying this haplotype present higher HLA-F mRNA expression levels. Functional studies are required to define the exact mechanism underlying this higher HLA-F mRNA expression level associated with F[∗]distal-C and F[∗]01:01:02 alleles.}, }
@article {pmid30772945, year = {2019}, author = {James, WPT and Johnson, RJ and Speakman, JR and Wallace, DC and Frühbeck, G and Iversen, PO and Stover, PJ}, title = {Nutrition and its role in human evolution.}, journal = {Journal of internal medicine}, volume = {285}, number = {5}, pages = {533-549}, doi = {10.1111/joim.12878}, pmid = {30772945}, issn = {1365-2796}, mesh = {Animals ; *Biological Evolution ; DNA, Mitochondrial/genetics ; Emigration and Immigration ; Hominidae/genetics/*physiology ; Humans ; Mutation ; *Nutritional Physiological Phenomena ; }, abstract = {Our understanding of human evolution has improved rapidly over recent decades, facilitated by large-scale cataloguing of genomic variability amongst both modern and archaic humans. It seems clear that the evolution of the ancestors of chimpanzees and hominins separated 7-9 million years ago with some migration out of Africa by the earlier hominins; Homo sapiens slowly emerged as climate change resulted in drier, less forested African conditions. The African populations expanded and evolved in many different conditions with slow mutation and selection rates in the human genome, but with much more rapid mutation occurring in mitochondrial DNA. We now have evidence stretching back 300 000 years of humans in their current form, but there are clearly four very different large African language groups that correlate with population DNA differences. Then, about 50 000-100 000 years ago a small subset of modern humans also migrated out of Africa resulting in a persistent signature of more limited genetic diversity amongst non-African populations. Hybridization with archaic hominins occurred around this time such that all non-African modern humans possess some Neanderthal ancestry and Melanesian populations additionally possess some Denisovan ancestry. Human populations both within and outside Africa also adapted to diverse aspects of their local environment including altitude, climate, UV exposure, diet and pathogens, in some cases leaving clear signatures of patterns of genetic variation. Notable examples include haemoglobin changes conferring resistance to malaria, other immune changes and the skin adaptations favouring the synthesis of vitamin D. As humans migrated across Eurasia, further major mitochondrial changes occurred with some interbreeding with ancient hominins and the development of alcohol intolerance. More recently, an ability to retain lactase persistence into adulthood has evolved rapidly under the environmental stimulus of pastoralism with the ability to husband lactating ruminants. Increased amylase copy numbers seem to relate to the availability of starchy foods, whereas the capacity to desaturase and elongate monounsaturated fatty acids in different societies seems to be influenced by whether there is a lack of supply of readily available dietary sources of long-chain polyunsaturated fatty acids. The process of human evolution includes genetic drift and adaptation to local environments, in part through changes in mitochondrial and nuclear DNA. These genetic changes may underlie susceptibilities to some modern human pathologies including folate-responsive neural tube defects, diabetes, other age-related pathologies and mental health disorders.}, }
@article {pmid30700881, year = {2019}, author = {Dennell, R}, title = {Dating of hominin discoveries at Denisova.}, journal = {Nature}, volume = {565}, number = {7741}, pages = {571-572}, doi = {10.1038/d41586-019-00264-0}, pmid = {30700881}, issn = {1476-4687}, mesh = {Animals ; Archaeology ; Caves ; *Fossils ; *Hominidae ; }, }
@article {pmid30700871, year = {2019}, author = {Douka, K and Slon, V and Jacobs, Z and Ramsey, CB and Shunkov, MV and Derevianko, AP and Mafessoni, F and Kozlikin, MB and Li, B and Grün, R and Comeskey, D and Devièse, T and Brown, S and Viola, B and Kinsley, L and Buckley, M and Meyer, M and Roberts, RG and Pääbo, S and Kelso, J and Higham, T}, title = {Age estimates for hominin fossils and the onset of the Upper Palaeolithic at Denisova Cave.}, journal = {Nature}, volume = {565}, number = {7741}, pages = {640-644}, doi = {10.1038/s41586-018-0870-z}, pmid = {30700871}, issn = {1476-4687}, mesh = {Animals ; Bayes Theorem ; *Caves ; DNA, Mitochondrial/genetics ; Deer ; Femur/chemistry ; *Fossils ; Geologic Sediments/chemistry ; History, Ancient ; *Hominidae/genetics ; Humans ; Neanderthals/genetics ; Oxygen Isotopes ; *Radiometric Dating ; Siberia ; Time Factors ; Tooth/chemistry ; }, abstract = {Denisova Cave in the Siberian Altai (Russia) is a key site for understanding the complex relationships between hominin groups that inhabited Eurasia in the Middle and Late Pleistocene epoch. DNA sequenced from human remains found at this site has revealed the presence of a hitherto unknown hominin group, the Denisovans[1,2], and high-coverage genomes from both Neanderthal and Denisovan fossils provide evidence for admixture between these two populations[3]. Determining the age of these fossils is important if we are to understand the nature of hominin interaction, and aspects of their cultural and subsistence adaptations. Here we present 50 radiocarbon determinations from the late Middle and Upper Palaeolithic layers of the site. We also report three direct dates for hominin fragments and obtain a mitochondrial DNA sequence for one of them. We apply a Bayesian age modelling approach that combines chronometric (radiocarbon, uranium series and optical ages), stratigraphic and genetic data to calculate probabilistically the age of the human fossils at the site. Our modelled estimate for the age of the oldest Denisovan fossil suggests that this group was present at the site as early as 195,000 years ago (at 95.4% probability). All Neanderthal fossils-as well as Denisova 11, the daughter of a Neanderthal and a Denisovan[4]-date to between 80,000 and 140,000 years ago. The youngest Denisovan dates to 52,000-76,000 years ago. Direct radiocarbon dating of Upper Palaeolithic tooth pendants and bone points yielded the earliest evidence for the production of these artefacts in northern Eurasia, between 43,000 and 49,000 calibrated years before present (taken as AD 1950). On the basis of current archaeological evidence, it may be assumed that these artefacts are associated with the Denisovan population. It is not currently possible to determine whether anatomically modern humans were involved in their production, as modern-human fossil and genetic evidence of such antiquity has not yet been identified in the Altai region.}, }
@article {pmid30700870, year = {2019}, author = {Jacobs, Z and Li, B and Shunkov, MV and Kozlikin, MB and Bolikhovskaya, NS and Agadjanian, AK and Uliyanov, VA and Vasiliev, SK and O'Gorman, K and Derevianko, AP and Roberts, RG}, title = {Timing of archaic hominin occupation of Denisova Cave in southern Siberia.}, journal = {Nature}, volume = {565}, number = {7741}, pages = {594-599}, doi = {10.1038/s41586-018-0843-2}, pmid = {30700870}, issn = {1476-4687}, mesh = {Animals ; *Caves ; Geologic Sediments/chemistry ; History, Ancient ; *Hominidae ; Siberia ; Time Factors ; }, abstract = {The Altai region of Siberia was inhabited for parts of the Pleistocene by at least two groups of archaic hominins-Denisovans and Neanderthals. Denisova Cave, uniquely, contains stratified deposits that preserve skeletal and genetic evidence of both hominins, artefacts made from stone and other materials, and a range of animal and plant remains. The previous site chronology is based largely on radiocarbon ages for fragments of bone and charcoal that are up to 50,000 years old; older ages of equivocal reliability have been estimated from thermoluminescence and palaeomagnetic analyses of sediments, and genetic analyses of hominin DNA. Here we describe the stratigraphic sequences in Denisova Cave, establish a chronology for the Pleistocene deposits and associated remains from optical dating of the cave sediments, and reconstruct the environmental context of hominin occupation of the site from around 300,000 to 20,000 years ago.}, }
@article {pmid30672457, year = {2019}, author = {Henry, JP}, title = {[Genetics and origin of Homo sapiens].}, journal = {Medecine sciences : M/S}, volume = {35}, number = {1}, pages = {39-45}, doi = {10.1051/medsci/2018311}, pmid = {30672457}, issn = {1958-5381}, mesh = {Africa ; Animals ; Asia ; Biological Evolution ; DNA/analysis/chemistry ; Europe ; *Evolution, Molecular ; *Genome, Human ; Hominidae/*genetics ; Human Genome Project ; Humans ; Neanderthals/genetics ; Phylogeny ; Polymorphism, Single Nucleotide ; Selection, Genetic ; Sequence Homology ; }, abstract = {Usually, paleoanthropology studies remains and artefacts. However, more recently, genetics offer new avenues. Information on humanisation mechanisms has been obtained from comparison with primate or archaic Homo DNA sequences. Likewise, the 1 000 Genomes Project has characterized the geographic spectrum of human genetic variation offering a basis for a genomic study of Homo sapiens phylogeny. From these studies, a model, Out of Africa, was derived. His origin is Africa, where he lived 200 000 years ago. A small fraction of the population left Africa between 50 and 100 000 years ago that have populated the rest of the world, to Europe, coastal Asia to Australia and mainland Asia to Behring Land Bridge and America. The model is supported by the decrease of genetic diversity with the distance to Eastern Africa (serial founder effect). In Europe and Asia, Homo sapiens met archaic Homo neanderthalis and H denisova. The presence of 1-3% neanderthalis sequences in modern Homo ADN indicates admixtures between these groups. Some archaic sequences are on positive selection pressure, thus suggesting that the extinct hominins might have facilitated the adaptation of H sapiens to new environments.}, }
@article {pmid30651539, year = {2019}, author = {Mondal, M and Bertranpetit, J and Lao, O}, title = {Approximate Bayesian computation with deep learning supports a third archaic introgression in Asia and Oceania.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {246}, pmid = {30651539}, issn = {2041-1723}, abstract = {Since anatomically modern humans dispersed Out of Africa, the evolutionary history of Eurasian populations has been marked by introgressions from presently extinct hominins. Some of these introgressions have been identified using sequenced ancient genomes (Neanderthal and Denisova). Other introgressions have been proposed for still unidentified groups using the genetic diversity present in current human populations. We built a demographic model based on deep learning in an Approximate Bayesian Computation framework to infer the evolutionary history of Eurasian populations including past introgression events in Out of Africa populations fitting the current genetic evidence. In addition to the reported Neanderthal and Denisovan introgressions, our results support a third introgression in all Asian and Oceanian populations from an archaic population. This population is either related to the Neanderthal-Denisova clade or diverged early from the Denisova lineage. We propose the use of deep learning methods for clarifying situations with high complexity in evolutionary genomics.}, }
@article {pmid30566634, year = {2019}, author = {Reher, D and Key, FM and Andrés, AM and Kelso, J}, title = {Immune Gene Diversity in Archaic and Present-day Humans.}, journal = {Genome biology and evolution}, volume = {11}, number = {1}, pages = {232-241}, pmid = {30566634}, issn = {1759-6653}, mesh = {Animals ; Genetic Variation ; Humans ; Immunity, Innate/*genetics ; *Major Histocompatibility Complex ; Neanderthals/*genetics/immunology ; }, abstract = {Genome-wide analyses of two Neandertals and a Denisovan have shown that these archaic humans had lower genetic heterozygosity than present-day people. A similar reduction in genetic diversity of protein-coding genes (gene diversity) was found in exome sequences of three Neandertals. Reduced gene diversity, particularly in genes involved in immunity, may have important functional consequences. In fact, it has been suggested that reduced diversity in immune genes may have contributed to Neandertal extinction. We therefore explored gene diversity in different human groups, and at different time points on the Neandertal lineage, with a particular focus on the diversity of genes involved in innate immunity and genes of the Major Histocompatibility Complex (MHC).We find that the two Neandertals and a Denisovan have similar gene diversity, all significantly lower than any present-day human. This is true across gene categories, with no gene set showing an excess decrease in diversity compared with the genome-wide average. Innate immune-related genes show a similar reduction in diversity to other genes, both in present-day and archaic humans. There is also no observable decrease in gene diversity over time in Neandertals, suggesting that there may have been no ongoing reduction in gene diversity in later Neandertals, although this needs confirmation with a larger sample size. In both archaic and present-day humans, genes with the highest levels of diversity are enriched for MHC-related functions. In fact, in archaic humans the MHC genes show evidence of having retained more diversity than genes involved only in the innate immune system.}, }
@article {pmid30278065, year = {2018}, author = {Hoover, KC}, title = {Intragenus (Homo) variation in a chemokine receptor gene (CCR5).}, journal = {PloS one}, volume = {13}, number = {10}, pages = {e0204989}, pmid = {30278065}, issn = {1932-6203}, mesh = {Animals ; Gene Expression Regulation ; *Genetic Variation ; Hominidae/*genetics ; Humans ; Receptors, CCR5/*genetics ; Species Specificity ; }, abstract = {Humans have a comparatively higher rate of more polymorphisms in regulatory regions of the primate CCR5 gene, an immune system gene with both general and specific functions. This has been interpreted as allowing flexibility and diversity of gene expression in response to varying disease loads. A broad expression repertoire is useful to humans-the only globally distributed primate-due to our unique adaptive pattern that increased pathogen exposure and disease loads (e.g., sedentism, subsistence practices). The main objective of the study was to determine if the previously observed human pattern of increased variation extended to other members of our genus, Homo. The data for this study are mined from the published genomes of extinct hominins (four Neandertals and two Denisovans), an ancient human (Ust'-Ishim), and modern humans (1000 Genomes). An average of 15 polymorphisms per individual were found in human populations (with a total of 262 polymorphisms). There were 94 polymorphisms identified across extinct Homo (an average of 13 per individual) with 41 previously observed in modern humans and 53 novel polymorphisms (32 in Denisova and 21 in Neandertal). Neither the frequency nor distribution of polymorphisms across gene regions exhibit significant differences within the genus Homo. Thus, humans are not unique with regards to the increased frequency of regulatory polymorphisms and the evolution of variation patterns across CCR5 gene appears to have originated within the genus. A broader evolutionary perspective on regulatory flexibility may be that it provided an advantage during the transition to confrontational foraging (and later hunting) that altered human-environment interaction as well as during migration to Eurasia and encounters with novel pathogens.}, }
@article {pmid30226838, year = {2018}, author = {Skov, L and Hui, R and Shchur, V and Hobolth, A and Scally, A and Schierup, MH and Durbin, R}, title = {Detecting archaic introgression using an unadmixed outgroup.}, journal = {PLoS genetics}, volume = {14}, number = {9}, pages = {e1007641}, pmid = {30226838}, issn = {1553-7404}, support = {207492/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; WT207492/WT_/Wellcome Trust/United Kingdom ; WT206194/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Asian People/genetics ; Black People/genetics ; Fossils ; Genome, Human/*genetics ; Hominidae/*genetics ; Humans ; Hybridization, Genetic/*genetics ; Native Hawaiian or Other Pacific Islander/genetics ; Neanderthals/*genetics ; Phylogeny ; White People/genetics ; }, abstract = {Human populations outside of Africa have experienced at least two bouts of introgression from archaic humans, from Neanderthals and Denisovans. In Papuans there is prior evidence of both these introgressions. Here we present a new approach to detect segments of individual genomes of archaic origin without using an archaic reference genome. The approach is based on a hidden Markov model that identifies genomic regions with a high density of single nucleotide variants (SNVs) not seen in unadmixed populations. We show using simulations that this provides a powerful approach to identifying segments of archaic introgression with a low rate of false detection, given data from a suitable outgroup population is available, without the archaic introgression but containing a majority of the variation that arose since initial separation from the archaic lineage. Furthermore our approach is able to infer admixture proportions and the times both of admixture and of initial divergence between the human and archaic populations. We apply the model to detect archaic introgression in 89 Papuans and show how the identified segments can be assigned to likely Neanderthal or Denisovan origin. We report more Denisovan admixture than previous studies and find a shift in size distribution of fragments of Neanderthal and Denisovan origin that is compatible with a difference in admixture time. Furthermore, we identify small amounts of Denisova ancestry in South East Asians and South Asians.}, }
@article {pmid30209350, year = {2018}, author = {Clyde, D}, title = {The girl with Neanderthal and Denisovan parents.}, journal = {Nature reviews. Genetics}, volume = {19}, number = {11}, pages = {668-669}, doi = {10.1038/s41576-018-0054-6}, pmid = {30209350}, issn = {1471-0064}, mesh = {Female ; Male ; Fathers ; Genome ; Mothers ; *Neanderthals/genetics ; Parents ; Animals ; }, }
@article {pmid30135579, year = {2018}, author = {Slon, V and Mafessoni, F and Vernot, B and de Filippo, C and Grote, S and Viola, B and Hajdinjak, M and Peyrégne, S and Nagel, S and Brown, S and Douka, K and Higham, T and Kozlikin, MB and Shunkov, MV and Derevianko, AP and Kelso, J and Meyer, M and Prüfer, K and Pääbo, S}, title = {The genome of the offspring of a Neanderthal mother and a Denisovan father.}, journal = {Nature}, volume = {561}, number = {7721}, pages = {113-116}, pmid = {30135579}, issn = {1476-4687}, support = {324139/ERC_/European Research Council/International ; 694707/ERC_/European Research Council/International ; 715069/ERC_/European Research Council/International ; }, mesh = {Alleles ; Animals ; Fathers ; Female ; Gene Flow/genetics ; Genome ; Genomics ; History, Ancient ; Hominidae/*genetics ; Humans ; Hybridization, Genetic/*genetics ; Male ; Mothers ; Neanderthals/*genetics ; Time Factors ; }, abstract = {Neanderthals and Denisovans are extinct groups of hominins that separated from each other more than 390,000 years ago[1,2]. Here we present the genome of 'Denisova 11', a bone fragment from Denisova Cave (Russia)[3] and show that it comes from an individual who had a Neanderthal mother and a Denisovan father. The father, whose genome bears traces of Neanderthal ancestry, came from a population related to a later Denisovan found in the cave[4-6]. The mother came from a population more closely related to Neanderthals who lived later in Europe[2,7] than to an earlier Neanderthal found in Denisova Cave[8], suggesting that migrations of Neanderthals between eastern and western Eurasia occurred sometime after 120,000 years ago. The finding of a first-generation Neanderthal-Denisovan offspring among the small number of archaic specimens sequenced to date suggests that mixing between Late Pleistocene hominin groups was common when they met.}, }
@article {pmid30135540, year = {2018}, author = {Warren, M}, title = {Mum's a Neanderthal, Dad's a Denisovan: First discovery of an ancient-human hybrid.}, journal = {Nature}, volume = {560}, number = {7719}, pages = {417-418}, doi = {10.1038/d41586-018-06004-0}, pmid = {30135540}, issn = {1476-4687}, }
@article {pmid30022013, year = {2018}, author = {Dolgova, O and Lao, O}, title = {Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes.}, journal = {Genes}, volume = {9}, number = {7}, pages = {}, pmid = {30022013}, issn = {2073-4425}, abstract = {The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Current non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease.}, }
@article {pmid29914355, year = {2018}, author = {Cserhati, MF and Mooter, ME and Peterson, L and Wicks, B and Xiao, P and Pauley, M and Guda, C}, title = {Motifome comparison between modern human, Neanderthal and Denisovan.}, journal = {BMC genomics}, volume = {19}, number = {1}, pages = {472}, pmid = {29914355}, issn = {1471-2164}, support = {P20 GM103427/GM/NIGMS NIH HHS/United States ; P30 CA036727/CA/NCI NIH HHS/United States ; 2P20GM103427//Nebraska INBRE/ ; 5P30CA036727//CCSG award/ ; }, mesh = {Animals ; Endogenous Retroviruses/genetics ; *Fossils ; *Genome ; Humans ; Neanderthals/*genetics ; Nucleotide Motifs/*genetics ; Phenotype ; Promoter Regions, Genetic ; Trans-Activators ; }, abstract = {BACKGROUND: The availability of the genomes of two archaic humans, Neanderthal and Denisovan, and that of modern humans provides researchers an opportunity to investigate genetic differences between these three subspecies on a genome-wide scale. Here we describe an algorithm that predicts statistically significant motifs based on the difference between a given motif's actual and expected distributions. The algorithm was previously applied to plants but was modified for this work.<br><br>RESULTS: The result of applying the algorithm to the human, Neanderthal, and Denisovan genomes is a catalog of potential regulatory motifs in these three human subspecies. We examined the distributions of these motifs in genetic elements including human retroviruses, human accelerated regions, and human accelerated conserved noncoding sequences regions. Differences in these distributions could be the origin of differences in phenotype between the three subspecies. Twenty significant motifs common to all three genomes were found; thirty-three were found in endogenous retroviruses in Neanderthal and Denisovan. Ten of these motifs mapped to the 22&#xa0;bp core of MiR-1304. The core of this genetic element regulates the ENAM and AMTN genes, which take part in odontogenesis and whose 3' UTRs contained significant motifs. The introns of 20 genes were found to contain a large number of significant motifs, which were also overrepresented in 49 human accelerated regions. These genes include NAV2, SorCS2, TRAPPC9, GRID1, PRDM16, CAMTA1, and ASIC which are all involved in neuroregulation. Further analysis of these genes using the GO database indicates that many are associated with neurodevelopment. Also, varying numbers of significant motifs were found to occur in regions of the Neanderthal and Denisovan genomes that are missing from the human genome, suggesting further functional differences between modern and archaic humans.<br><br>CONCLUSION: Although Neanderthal and Denisovan are now extinct, detailed examination of elements from their genomes can shed light on possible phenotypic and cognitive differences between these two archaic human subspecies and modern humans. Genetic similarities and differences between these three subspecies and other fossil hominids would also be of interest.}, }
@article {pmid29747567, year = {2018}, author = {Banerjee, N and Polushina, T and Bettella, F and Giddaluru, S and Steen, VM and Andreassen, OA and Le Hellard, S}, title = {Recently evolved human-specific methylated regions are enriched in schizophrenia signals.}, journal = {BMC evolutionary biology}, volume = {18}, number = {1}, pages = {63}, pmid = {29747567}, issn = {1471-2148}, support = {#2 T23273//Norges Forskningsr&#xe5;d/International ; SKGJ-MED-008//KG Jebsen Foundation/International ; }, mesh = {Adult ; Bipolar Disorder/genetics ; Body Height/genetics ; Body Mass Index ; DNA Methylation/*genetics ; *Evolution, Molecular ; Female ; Genetic Markers ; Genome-Wide Association Study ; Genotype ; Humans ; Major Histocompatibility Complex/genetics ; Male ; Molecular Sequence Annotation ; Multifactorial Inheritance ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Schizophrenia/*genetics ; }, abstract = {BACKGROUND: One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants.<br><br>RESULTS: Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n&#x2009;=&#x2009;10,000) and bootstrapping (n&#x2009;=&#x2009;5000) in INRICH (p&#x2009;<&#x2009;0.01). Some enrichment of association with height was observed at the gene level.<br><br>CONCLUSIONS: Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.}, }
@article {pmid29739306, year = {2018}, author = {Akkuratov, EE and Gelfand, MS and Khrameeva, EE}, title = {Neanderthal and Denisovan ancestry in Papuans: A functional study.}, journal = {Journal of bioinformatics and computational biology}, volume = {16}, number = {2}, pages = {1840011}, doi = {10.1142/S0219720018400115}, pmid = {29739306}, issn = {1757-6334}, mesh = {Alleles ; Animals ; Black People/genetics ; Bone Remodeling/genetics ; Cluster Analysis ; Genetics, Population ; *Genome, Human ; Hominidae/*genetics ; Humans ; Multigene Family ; Neanderthals/genetics ; Papua New Guinea ; Polymorphism, Single Nucleotide ; Transcription Factors/genetics ; }, abstract = {Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.}, }
@article {pmid29658973, year = {2018}, author = {Viscardi, LH and Paixão-Côrtes, VR and Comas, D and Salzano, FM and Rovaris, D and Bau, CD and Amorim, CEG and Bortolini, MC}, title = {Searching for ancient balanced polymorphisms shared between Neanderthals and Modern Humans.}, journal = {Genetics and molecular biology}, volume = {41}, number = {1}, pages = {67-81}, pmid = {29658973}, issn = {1415-4757}, abstract = {Hominin evolution is characterized by adaptive solutions often rooted in behavioral and cognitive changes. If balancing selection had an important and long-lasting impact on the evolution of these traits, it can be hypothesized that genes associated with them should carry an excess of shared polymorphisms (trans- SNPs) across recent Homo species. In this study, we investigate the role of balancing selection in human evolution using available exomes from modern (Homo sapiens) and archaic humans (H. neanderthalensis and Denisovan) for an excess of trans-SNP in two gene sets: one associated with the immune system (IMMS) and another one with behavioral system (BEHS). We identified a significant excess of trans-SNPs in IMMS (N=547), of which six of these located within genes previously associated with schizophrenia. No excess of trans-SNPs was found in BEHS, but five genes in this system harbor potential signals for balancing selection and are associated with psychiatric or neurodevelopmental disorders. Our approach evidenced recent Homo trans-SNPs that have been previously implicated in psychiatric diseases such as schizophrenia, suggesting that a genetic repertoire common to the immune and behavioral systems could have been maintained by balancing selection starting before the split between archaic and modern humans.}, }
@article {pmid29608725, year = {2018}, author = {Zehra, R and Abbasi, AA}, title = {Homo sapiens-Specific Binding Site Variants within Brain Exclusive Enhancers Are Subject to Accelerated Divergence across Human Population.}, journal = {Genome biology and evolution}, volume = {10}, number = {3}, pages = {956-966}, pmid = {29608725}, issn = {1759-6653}, mesh = {Animals ; Binding Sites/genetics ; Brain/metabolism ; Enhancer Elements, Genetic/*genetics ; *Evolution, Molecular ; Humans ; Primates/*genetics ; Species Specificity ; Transcription Factors/genetics ; }, abstract = {Empirical assessments of human accelerated noncoding DNA frgaments have delineated presence of many cis-regulatory elements. Enhancers make up an important category of such accelerated cis-regulatory elements that efficiently control the spatiotemporal expression of many developmental genes. Establishing plausible reasons for accelerated enhancer sequence divergence in Homo sapiens has been termed significant in various previously published studies. This acceleration by including closely related primates and archaic human data has the potential to open up evolutionary avenues for deducing present-day brain structure. This study relied on empirically confirmed brain exclusive enhancers to avoid any misjudgments about their regulatory status and categorized among them a subset of enhancers with an exceptionally accelerated rate of lineage specific divergence in humans. In this assorted set, 13 distinct transcription factor binding sites were located that possessed unique existence in humans. Three of 13 such sites belonging to transcription factors SOX2, RUNX1/3, and FOS/JUND possessed single nucleotide variants that made them unique to H. sapiens upon comparisons with Neandertal and Denisovan orthologous sequences. These variants modifying the binding sites in modern human lineage were further substantiated as single nucleotide polymorphisms via exploiting 1000 Genomes Project Phase3 data. Long range haplotype based tests laid out evidence of positive selection to be governing in African population on two of the modern human motif modifying alleles with strongest results for SOX2 binding site. In sum, our study acknowledges acceleration in noncoding regulatory landscape of the genome and highlights functional parts within it to have undergone accelerated divergence in present-day human population.}, }
@article {pmid29570998, year = {2018}, author = {Vernot, B and Pääbo, S}, title = {The Predecessors Within . .}, journal = {Cell}, volume = {173}, number = {1}, pages = {6-7}, doi = {10.1016/j.cell.2018.03.023}, pmid = {29570998}, issn = {1097-4172}, mesh = {Asia ; *Family ; Humans ; }, abstract = {By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations.}, }
@article {pmid29551270, year = {2018}, author = {Browning, SR and Browning, BL and Zhou, Y and Tucci, S and Akey, JM}, title = {Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture.}, journal = {Cell}, volume = {173}, number = {1}, pages = {53-61.e9}, pmid = {29551270}, issn = {1097-4172}, support = {R01 GM110068/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Asian People/genetics ; *Genome, Human ; Humans ; Neanderthals/genetics ; Selection, Genetic ; Exome Sequencing ; }, abstract = {Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. VIDEO ABSTRACT.}, }
@article {pmid29477182, year = {2018}, author = {Warren, KA and Ritzman, TB and Humphreys, RA and Percival, CJ and Hallgrímsson, B and Ackermann, RR}, title = {Craniomandibular form and body size variation of first generation mouse hybrids: A model for hominin hybridization.}, journal = {Journal of human evolution}, volume = {116}, number = {}, pages = {57-74}, pmid = {29477182}, issn = {1095-8606}, support = {R01 DE019638/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; Biological Evolution ; Body Size/genetics ; Fossils/anatomy &amp; histology ; Hominidae/*anatomy &amp; histology/genetics/*physiology ; *Hybridization, Genetic ; Mandible/anatomy &amp; histology ; Mice/*anatomy &amp; histology/genetics/*physiology ; *Models, Animal ; Phenotype ; Skull/anatomy &amp; histology ; }, abstract = {Hybridization occurs in a number of mammalian lineages, including among primate taxa. Analyses of ancient genomes have shown that hybridization between our lineage and other archaic hominins in Eurasia occurred numerous times in the past. However, we still have limited empirical data on what a hybrid skeleton looks like, or how to spot patterns of hybridization among fossils for which there are no genetic data. Here we use experimental mouse models to supplement previous studies of primates. We characterize size and shape variation in the cranium and mandible of three wild-derived inbred mouse strains and their first generation (F1) hybrids. The three parent taxa in our analysis represent lineages that diverged over approximately the same period as the human/Neanderthal/Denisovan lineages and their hybrids are variably successful in the wild. Comparisons of body size, as quantified by long bone measurements, are also presented to determine whether the identified phenotypic effects of hybridization are localized to the cranium or represent overall body size changes. The results indicate that hybrid cranial and mandibular sizes, as well as limb length, exceed that of the parent taxa in all cases. All three F1 hybrid crosses display similar patterns of size and form variation. These results are generally consistent with earlier studies on primates and other mammals, suggesting that the effects of hybridization may be similar across very different scenarios of hybridization, including different levels of hybrid fitness. This paper serves to supplement previous studies aimed at identifying F1 hybrids in the fossil record and to introduce further research that will explore hybrid morphologies using mice as a proxy for better understanding hybridization in the hominin fossil record.}, }
@article {pmid29445326, year = {2018}, author = {Leacock, S and Syed, P and James, VM and Bode, A and Kawakami, K and Keramidas, A and Suster, M and Lynch, JW and Harvey, RJ}, title = {Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses.}, journal = {Frontiers in molecular neuroscience}, volume = {11}, number = {}, pages = {23}, pmid = {29445326}, issn = {1662-5099}, support = {MR/J004049/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Inhibitory glycine receptors (GlyRs) are pentameric ligand-gated anion channels with major roles in startle disease/hyperekplexia (GlyR α1), cortical neuronal migration/autism spectrum disorder (GlyR α2), and inflammatory pain sensitization/rhythmic breathing (GlyR α3). However, the role of the GlyR α4 subunit has remained enigmatic, because the corresponding human gene (GLRA4) is thought to be a pseudogene due to an in-frame stop codon at position 390 within the fourth membrane-spanning domain (M4). Despite this, a recent genetic study has implicated GLRA4 in intellectual disability, behavioral problems and craniofacial anomalies. Analyzing data from sequenced genomes, we found that GlyR α4 subunit genes are predicted to be intact and functional in the majority of vertebrate species-with the exception of humans. Cloning of human GlyR α4 cDNAs excluded alternative splicing and RNA editing as mechanisms for restoring a full-length GlyR α4 subunit. Moreover, artificial restoration of the missing conserved arginine (R390) in the human cDNA was not sufficient to restore GlyR α4 function. Further bioinformatic and mutagenesis analysis revealed an additional damaging substitution at K59 that ablates human GlyR α4 function, which is not present in other vertebrate GlyR α4 sequences. The substitutions K59 and X390 were also present in the genome of an ancient Denisovan individual, indicating that GLRA4 has been a pseudogene for at least 30,000-50,000 years. In artificial synapses, we found that both mouse and gorilla α4β GlyRs mediate synaptic currents with unusually slow decay kinetics. Lastly, to gain insights into the biological role of GlyR α4 function, we studied the duplicated genes glra4a and glra4b in zebrafish. While glra4b expression is restricted to the retina, using a novel tol2-GAL4FF gene trap line (SAIGFF16B), we found that the zebrafish GlyR α4a subunit gene (glra4a) is strongly expressed in spinal cord and hindbrain commissural neurones. Using gene knockdown and a dominant-negative GlyR α4a[R278Q] mutant, we found that GlyR α4a contributes to touch-evoked escape behaviors in zebrafish. Thus, although GlyR α4 is unlikely to be involved in human startle responses or disease states, this subtype may contribute to escape behaviors in other organisms.}, }
@article {pmid29428968, year = {2018}, author = {Jiang, L and Peng, J and Huang, M and Liu, J and Wang, L and Ma, Q and Zhao, H and Yang, X and Ji, A and Li, C}, title = {Differentiation analysis for estimating individual ancestry from the Tibetan Plateau by an archaic altitude adaptation EPAS1 haplotype among East Asian populations.}, journal = {International journal of legal medicine}, volume = {132}, number = {6}, pages = {1527-1535}, pmid = {29428968}, issn = {1437-1596}, support = {2017YFC0803501//National Key Research and Development Program of China/ ; 2016JB039//basic research project/ ; 2017JB027//basic research project/ ; }, mesh = {Adaptation, Physiological ; Altitude ; Asian People/*genetics ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; China ; Genotype ; *Haplotypes ; Humans ; *Polymorphism, Single Nucleotide ; Tibet/ethnology ; }, abstract = {Tibetans have adapted to the extreme environment of high altitude for hundreds of generations. A highly differentiated 5-SNP (Single Nucleotide Polymorphism) haplotype motif (AGGAA) on a hypoxic pathway gene, EPAS1, is observed in Tibetans and lowlanders. To evaluate the potential usage of the 5-SNP haplotype in ancestry inference for Tibetan or Tibetan-related populations, we analyzed this haplotype in 1053 individuals of 12 Chinese populations residing on the Tibetan Plateau, peripheral regions of Tibet, and plain regions. These data were integrated with the genotypes from the 1000 Genome populations and populations in a previously reported paper for population structure analyses. We found that populations representing highland and lowland groups have different dominant ancestry components. The core Denisovan haplotype (AGGAA) was observed at a frequency of 72.32% in the Tibetan Plateau, with a frequency range from 9.48 to 21.05% in the peripheral regions and < 2.5% in the plains area. From the individual perspective, 87.57% of the individuals from the Tibetan Plateau carried the archaic haplotype, while < 5% of the Chinese Han people carried the haplotype. Our findings indicate that the 5-SNP haplotype has a special distribution pattern in populations of Tibet and peripheral regions and could be integrated into AISNP (Ancestry Informative Single Nucleotide Polymorphism) panels to enhance ancestry resolution.}, }
@article {pmid29383489, year = {2018}, author = {Yew, CW and Lu, D and Deng, L and Wong, LP and Ong, RT and Lu, Y and Wang, X and Yunus, Y and Aghakhanian, F and Mokhtar, SS and Hoque, MZ and Voo, CL and Abdul Rahman, T and Bhak, J and Phipps, ME and Xu, S and Teo, YY and Kumar, SV and Hoh, BP}, title = {Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.}, journal = {Human genetics}, volume = {137}, number = {2}, pages = {161-173}, pmid = {29383489}, issn = {1432-1203}, support = {100-RM/BIOTEK 16/6/2 B (1/2011)//Kementerian Sains, Teknologi dan Inovasi (MY)/ ; [100-RMI/GOV 16/6/2 (19/2011]//Kementerian Sains, Teknologi dan Inovasi (MY)/ ; 100-RM/BIOTEK 16/6/2 B (1/2011)//Kementerian Sains, Teknologi dan Inovasi (MY)/ ; 100-RM/BIOTEK 16/6/2 B (1/2011)//Kementerian Sains, Teknologi dan Inovasi (MY)/ ; FRGS/1/2015/ST03/UCSI/01/1//Ministry of Higher Education, Malaysia (MY)/ ; NRF-RF-2010-05//National Foundation for Cancer Research (US)/ ; NRF-RF-2010-05//National Foundation for Cancer Research (US)/ ; NRF-RF-2010-05//National Research Foundation Singapore (SG)/ ; 91331204//National Natural Science Foundation of China (CN)/ ; 31525014//National Natural Science Foundation of China (CN)/ ; 91731303//National Natural Science Foundation of China (CN)/ ; 31771388//National Natural Science Foundation of China (CN)/ ; 31501011//National Natural Science Foundation of China (CN)/ ; 31711530221//National Institutes of Natural Sciences (JP)/ ; 10040231//Industry Strategic Development Program/ ; (1.150014.01)//Ulsan National Institute of Science and Technology (KR)/ ; }, mesh = {Asia, Southeastern ; Borneo ; DNA, Mitochondrial/*genetics ; Gene Flow/genetics ; Genetic Variation/*genetics ; *Genetics, Population ; Genome, Human/*genetics ; Genomics ; Human Migration ; Humans ; Malaysia ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.}, }
@article {pmid29175608, year = {2018}, author = {Walter Costa, MB and Höner Zu Siederdissen, C and Tulpan, D and Stadler, PF and Nowick, K}, title = {Temporal ordering of substitutions in RNA evolution: Uncovering the structural evolution of the Human Accelerated Region 1.}, journal = {Journal of theoretical biology}, volume = {438}, number = {}, pages = {143-150}, doi = {10.1016/j.jtbi.2017.11.015}, pmid = {29175608}, issn = {1095-8541}, mesh = {*Evolution, Molecular ; Humans ; Models, Biological ; Mutation/genetics ; Nucleic Acid Conformation ; Probability ; RNA, Untranslated/*chemistry/*genetics ; Time Factors ; }, abstract = {The Human Accelerated Region 1 (HAR1) is the most rapidly evolving region in the human genome. It is part of two overlapping long non-coding RNAs, has a length of only 118 nucleotides and features 18 human specific changes compared to an ancestral sequence that is extremely well conserved across non-human primates. The human HAR1 forms a stable secondary structure that is strikingly different from the one in chimpanzee as well as other closely related species, again emphasizing its human-specific evolutionary history. This suggests that positive selection has acted to stabilize human-specific features in the ensemble of HAR1 secondary structures. To investigate the evolutionary history of the human HAR1 structure, we developed a computational model that evaluates the relative likelihood of evolutionary trajectories as a probabilistic version of a Hamiltonian path problem. The model predicts that the most likely last step in turning the ancestral primate HAR1 into the human HAR1 was exactly the substitution that distinguishes the modern human HAR1 sequence from that of Denisovan, an archaic human, providing independent support for our model. The MutationOrder software is available for download and can be applied to other instances of RNA structure evolution.}, }
@article {pmid28950836, year = {2017}, author = {Xu, D and Jaber, Y and Pavlidis, P and Gokcumen, O}, title = {VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences.}, journal = {BMC bioinformatics}, volume = {18}, number = {1}, pages = {426}, pmid = {28950836}, issn = {1471-2105}, mesh = {Algorithms ; Animals ; Base Sequence ; *Genetic Loci ; *Genome, Human ; Humans ; INDEL Mutation/genetics ; *Phylogeny ; Primates ; Sequence Alignment/*methods ; Sequence Analysis, DNA ; *Software ; User-Computer Interface ; }, abstract = {BACKGROUND: Constructing alignments and phylogenies for a given locus from large genome sequencing studies with relevant outgroups allow novel evolutionary and anthropological insights. However, no user-friendly tool has been developed to integrate thousands of recently available and anthropologically relevant genome sequences to construct complete sequence alignments and phylogenies.<br><br>RESULTS: Here, we provide VCFtoTree, a user friendly tool with a graphical user interface that directly accesses online databases to download, parse and analyze genome variation data for regions of interest. Our pipeline combines popular sequence datasets and tree building algorithms with custom data parsing to generate accurate alignments and phylogenies using all the individuals from the 1000 Genomes Project, Neanderthal and Denisovan genomes, as well as reference genomes of Chimpanzee and Rhesus Macaque. It can also be applied to other phased human genomes, as well as genomes from other species. The output of our pipeline includes an alignment in FASTA format and a tree file in newick format.<br><br>CONCLUSION: VCFtoTree fulfills the increasing demand for constructing alignments and phylogenies for a given loci from thousands of available genomes. Our software provides a user friendly interface for a wider audience without prerequisite knowledge in programming. VCFtoTree can be accessed from https://github.com/duoduoo/VCFtoTree_3.0.0 .}, }
@article {pmid28902892, year = {2017}, author = {Zanolli, C and Hourset, M and Esclassan, R and Mollereau, C}, title = {Neanderthal and Denisova tooth protein variants in present-day humans.}, journal = {PloS one}, volume = {12}, number = {9}, pages = {e0183802}, pmid = {28902892}, issn = {1932-6203}, mesh = {Animals ; Dental Enamel/anatomy &amp; histology/metabolism ; Dental Enamel Proteins/*genetics/metabolism ; Fossils ; Gene Frequency ; Genome, Human ; Geography ; *Hominidae/genetics/metabolism ; Humans ; *Neanderthals/genetics/metabolism ; Organ Size ; Phylogeny ; *Polymorphism, Genetic ; Selection, Genetic ; Sequence Homology, Amino Acid ; Tooth/anatomy &amp; histology/chemistry/*metabolism ; }, abstract = {Environment parameters, diet and genetic factors interact to shape tooth morphostructure. In the human lineage, archaic and modern hominins show differences in dental traits, including enamel thickness, but variability also exists among living populations. Several polymorphisms, in particular in the non-collagenous extracellular matrix proteins of the tooth hard tissues, like enamelin, are involved in dental structure variation and defects and may be associated with dental disorders or susceptibility to caries. To gain insights into the relationships between tooth protein polymorphisms and dental structural morphology and defects, we searched for non-synonymous polymorphisms in tooth proteins from Neanderthal and Denisova hominins. The objective was to identify archaic-specific missense variants that may explain the dental morphostructural variability between extinct and modern humans, and to explore their putative impact on present-day dental phenotypes. Thirteen non-collagenous extracellular matrix proteins specific to hard dental tissues have been selected, searched in the publicly available sequence databases of Neanderthal and Denisova individuals and compared with modern human genome data. A total of 16 non-synonymous polymorphisms were identified in 6 proteins (ameloblastin, amelotin, cementum protein 1, dentin matrix acidic phosphoprotein 1, enamelin and matrix Gla protein). Most of them are encoded by dentin and enamel genes located on chromosome 4, previously reported to show signs of archaic introgression within Africa. Among the variants shared with modern humans, two are ancestral (common with apes) and one is the derived enamelin major variant, T648I (rs7671281), associated with a thinner enamel and specific to the Homo lineage. All the others are specific to Neanderthals and Denisova, and are found at a very low frequency in modern Africans or East and South Asians, suggesting that they may be related to particular dental traits or disease susceptibility in these populations. This modern regional distribution of archaic dental polymorphisms may reflect persistence of archaic variants in some populations and may contribute in part to the geographic dental variations described in modern humans.}, }
@article {pmid28855259, year = {2017}, author = {Gardner, EJ and Lam, VK and Harris, DN and Chuang, NT and Scott, EC and Pittard, WS and Mills, RE and ,  and Devine, SE}, title = {The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology.}, journal = {Genome research}, volume = {27}, number = {11}, pages = {1916-1929}, pmid = {28855259}, issn = {1549-5469}, support = {R01 HG002898/HG/NHGRI NIH HHS/United States ; R01 HG006849/HG/NHGRI NIH HHS/United States ; R01 GM059290/GM/NIGMS NIH HHS/United States ; R01 CA166661/CA/NCI NIH HHS/United States ; F31 HG009223/HG/NHGRI NIH HHS/United States ; T32 DK067872/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Computational Biology/*methods ; *DNA Transposable Elements ; Databases, Genetic ; Evolution, Molecular ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Neanderthals/*genetics ; Pan troglodytes/*genetics ; Polymorphism, Single Nucleotide ; Software ; Whole Genome Sequencing/methods ; }, abstract = {Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.}, }
@article {pmid28854687, year = {2017}, author = {Jinam, TA and Phipps, ME and Aghakhanian, F and Majumder, PP and Datar, F and Stoneking, M and Sawai, H and Nishida, N and Tokunaga, K and Kawamura, S and Omoto, K and Saitou, N}, title = {Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture.}, journal = {Genome biology and evolution}, volume = {9}, number = {8}, pages = {2013-2022}, pmid = {28854687}, issn = {1759-6653}, mesh = {Asian People/genetics ; *Genetics, Population ; *Genome, Human ; Genome-Wide Association Study ; Humans ; Malaysia ; Philippines ; *Phylogeny ; *Polymorphism, Single Nucleotide ; }, abstract = {Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the "First Sundaland People." To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People.}, }
@article {pmid28854627, year = {2017}, author = {Sharbrough, J and Havird, JC and Noe, GR and Warren, JM and Sloan, DB}, title = {The Mitonuclear Dimension of Neanderthal and Denisovan Ancestry in Modern Human Genomes.}, journal = {Genome biology and evolution}, volume = {9}, number = {6}, pages = {1567-1581}, pmid = {28854627}, issn = {1759-6653}, mesh = {Alleles ; Animals ; Cell Nucleus/chemistry/*genetics ; DNA, Mitochondrial/chemistry/*genetics ; *Evolution, Molecular ; Gene Flow ; *Genome, Human ; Hominidae/classification/*genetics ; Humans ; Neanderthals/classification/*genetics ; Nucleic Acid Conformation ; Polymorphism, Genetic ; Reproductive Isolation ; }, abstract = {Some human populations interbred with Neanderthals and Denisovans, resulting in substantial contributions to modern-human genomes. Therefore, it is now possible to use genomic data to investigate mechanisms that shaped historical gene flow between humans and our closest hominin relatives. More generally, in eukaryotes, mitonuclear interactions have been argued to play a disproportionate role in generating reproductive isolation. There is no evidence of mtDNA introgression into modern human populations, which means that all introgressed nuclear alleles from archaic hominins must function on a modern-human mitochondrial background. Therefore, mitonuclear interactions are also potentially relevant to hominin evolution. We performed a detailed accounting of mtDNA divergence among hominin lineages and used population-genomic data to test the hypothesis that mitonuclear incompatibilities have preferentially restricted the introgression of nuclear genes with mitochondrial functions. We found a small but significant underrepresentation of introgressed Neanderthal alleles at such nuclear loci. Structural analyses of mitochondrial enzyme complexes revealed that these effects are unlikely to be mediated by physically interacting sites in mitochondrial and nuclear gene products. We did not detect any underrepresentation of introgressed Denisovan alleles at mitochondrial-targeted loci, but this may reflect reduced power because locus-specific estimates of Denisovan introgression are more conservative. Overall, we conclude that genes involved in mitochondrial function may have been subject to distinct selection pressures during the history of introgression from archaic hominins but that mitonuclear incompatibilities have had, at most, a small role in shaping genome-wide introgression patterns, perhaps because of limited functional divergence in mtDNA and interacting nuclear genes.}, }
@article {pmid28784789, year = {2017}, author = {Rogers, AR and Bohlender, RJ and Huff, CD}, title = {Early history of Neanderthals and Denisovans.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {114}, number = {37}, pages = {9859-9863}, pmid = {28784789}, issn = {1091-6490}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R25 CA057730/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Biological Evolution ; *Evolution, Molecular ; Fossils ; Gene Flow/*genetics ; Genome, Human/genetics ; Hominidae/*classification/*genetics ; Humans ; Neanderthals/classification/*genetics ; *Pedigree ; Phylogeny ; }, abstract = {Extensive DNA sequence data have made it possible to reconstruct human evolutionary history in unprecedented detail. We introduce a method to study the past several hundred thousand years. Our results show that (i) the Neanderthal-Denisovan lineage declined to a small size just after separating from the modern lineage, (ii) Neanderthals and Denisovans separated soon thereafter, and (iii) the subsequent Neanderthal population was large and deeply subdivided. They also (iv) support previous estimates of gene flow from Neanderthals into modern Eurasians. These results suggest an archaic human diaspora early in the Middle Pleistocene.}, }
@article {pmid28695206, year = {2017}, author = {Slon, V and Viola, B and Renaud, G and Gansauge, MT and Benazzi, S and Sawyer, S and Hublin, JJ and Shunkov, MV and Derevianko, AP and Kelso, J and Prüfer, K and Meyer, M and Pääbo, S}, title = {A fourth Denisovan individual.}, journal = {Science advances}, volume = {3}, number = {7}, pages = {e1700186}, pmid = {28695206}, issn = {2375-2548}, support = {694707/ERC_/European Research Council/International ; }, abstract = {The presence of Neandertals in Europe and Western Eurasia before the arrival of anatomically modern humans is well supported by archaeological and paleontological data. In contrast, fossil evidence for Denisovans, a sister group of Neandertals recently identified on the basis of DNA sequences, is limited to three specimens, all of which originate from Denisova Cave in the Altai Mountains (Siberia, Russia). We report the retrieval of DNA from a deciduous lower second molar (Denisova 2), discovered in a deep stratigraphic layer in Denisova Cave, and show that this tooth comes from a female Denisovan individual. On the basis of the number of "missing substitutions" in the mitochondrial DNA determined from the specimen, we find that Denisova 2 is substantially older than two of the other Denisovans, reinforcing the view that Denisovans were likely to have been present in the vicinity of Denisova Cave over an extended time period. We show that the level of nuclear DNA sequence diversity found among Denisovans is within the lower range of that of present-day human populations.}, }
@article {pmid28464262, year = {2017}, author = {Reales, G and Rovaris, DL and Jacovas, VC and Hünemeier, T and Sandoval, JR and Salazar-Granara, A and Demarchi, DA and Tarazona-Santos, E and Felkl, AB and Serafini, MA and Salzano, FM and Bisso-Machado, R and Comas, D and Paixão-Côrtes, VR and Bortolini, MC}, title = {A tale of agriculturalists and hunter-gatherers: Exploring the thrifty genotype hypothesis in native South Americans.}, journal = {American journal of physical anthropology}, volume = {163}, number = {3}, pages = {591-601}, doi = {10.1002/ajpa.23233}, pmid = {28464262}, issn = {1096-8644}, mesh = {Agriculture/*history ; Anthropology, Physical ; Apolipoproteins E/genetics ; CD36 Antigens/genetics ; Genotype ; History, Ancient ; Humans ; Indians, South American/*genetics/*history ; Polymorphism, Single Nucleotide/*genetics ; RNA-Binding Proteins/genetics ; }, abstract = {OBJECTIVES: To determine genetic differences between agriculturalist and hunter-gatherer southern Native American populations for selected metabolism-related markers and to test whether Neel's thrifty genotype hypothesis (TGH) could explain the genetic patterns observed in these populations.<br><br>MATERIALS AND METHODS: 375 Native South American individuals from 17 populations were genotyped using six markers (APOE rs429358 and rs7412; APOA2 rs5082; CD36 rs3211883; TCF7L2 rs11196205; and IGF2BP2 rs11705701). Additionally, APOE genotypes from 39 individuals were obtained from the literature. AMOVA, main effects, and gene-gene interaction tests were performed.<br><br>RESULTS: We observed differences in allele distribution patterns between agriculturalists and hunter-gatherers for some markers. For instance, between-groups component of genetic variance (FCT) for APOE rs429358 showed strong differences in allelic distributions between hunter-gatherers and agriculturalists (p&#x2009;=&#x2009;0.00196). Gene-gene interaction analysis indicated that the APOE E4/CD36 TT and APOE E4/IGF2BP2 A carrier combinations occur at a higher frequency in hunter-gatherers, but this combination is not replicated in archaic (Neanderthal and Denisovan) and ancient (Anzick, Saqqaq, Ust-Ishim, Mal'ta) hunter-gatherer individuals.<br><br>DISCUSSION: A complex scenario explains the observed frequencies of the tested markers in hunter-gatherers. Different factors, such as pleotropic alleles, rainforest selective pressures, and population dynamics, may be collectively shaping the observed genetic patterns. We conclude that although TGH seems a plausible hypothesis to explain part of the data, other factors may be important in our tested populations.}, }
@article {pmid28450384, year = {2017}, author = {Slon, V and Hopfe, C and Weiß, CL and Mafessoni, F and de la Rasilla, M and Lalueza-Fox, C and Rosas, A and Soressi, M and Knul, MV and Miller, R and Stewart, JR and Derevianko, AP and Jacobs, Z and Li, B and Roberts, RG and Shunkov, MV and de Lumley, H and Perrenoud, C and Gušić, I and Kućan, &#x17d; and Rudan, P and Aximu-Petri, A and Essel, E and Nagel, S and Nickel, B and Schmidt, A and Prüfer, K and Kelso, J and Burbano, HA and Pääbo, S and Meyer, M}, title = {Neandertal and Denisovan DNA from Pleistocene sediments.}, journal = {Science (New York, N.Y.)}, volume = {356}, number = {6338}, pages = {605-608}, doi = {10.1126/science.aam9695}, pmid = {28450384}, issn = {1095-9203}, mesh = {Animals ; Caves ; DNA, Ancient/analysis/*isolation &amp; purification ; DNA, Mitochondrial/analysis/*isolation &amp; purification ; Europe ; Fossils ; Geologic Sediments/chemistry ; Hominidae/*classification/*genetics ; Sequence Analysis, DNA ; }, abstract = {Although a rich record of Pleistocene human-associated archaeological assemblages exists, the scarcity of hominin fossils often impedes the understanding of which hominins occupied a site. Using targeted enrichment of mitochondrial DNA, we show that cave sediments represent a rich source of ancient mammalian DNA that often includes traces of hominin DNA, even at sites and in layers where no hominin remains have been discovered. By automation-assisted screening of numerous sediment samples, we detected Neandertal DNA in eight archaeological layers from four caves in Eurasia. In Denisova Cave, we retrieved Denisovan DNA in a Middle Pleistocene layer near the bottom of the stratigraphy. Our work opens the possibility of detecting the presence of hominin groups at sites and in areas where no skeletal remains are found.}, }
@article {pmid28448578, year = {2017}, author = {Hu, H and Petousi, N and Glusman, G and Yu, Y and Bohlender, R and Tashi, T and Downie, JM and Roach, JC and Cole, AM and Lorenzo, FR and Rogers, AR and Brunkow, ME and Cavalleri, G and Hood, L and Alpatty, SM and Prchal, JT and Jorde, LB and Robbins, PA and Simonson, TS and Huff, CD}, title = {Evolutionary history of Tibetans inferred from whole-genome sequencing.}, journal = {PLoS genetics}, volume = {13}, number = {4}, pages = {e1006675}, pmid = {28448578}, issn = {1553-7404}, support = {R35 GM118335/GM/NIGMS NIH HHS/United States ; 089457/Z/09/Z/WT_/Wellcome Trust/United Kingdom ; R01 GM104390/GM/NIGMS NIH HHS/United States ; P50 GM076547/GM/NIGMS NIH HHS/United States ; R01 GM059290/GM/NIGMS NIH HHS/United States ; I01 CX001372/CX/CSRD VA/United States ; R00 HL118215/HL/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P30 CA016672/CA/NCI NIH HHS/United States ; R25 CA057730/CA/NCI NIH HHS/United States ; }, mesh = {Adaptation, Physiological/*genetics ; Altitude ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; Cytochrome P-450 Enzyme System/genetics ; Female ; *Genome, Human ; Haplotypes ; High-Throughput Nucleotide Sequencing ; Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Male ; Molecular Sequence Annotation ; Proteins/genetics ; Receptors, Calcitriol/genetics ; Selection, Genetic/*genetics ; Tibet ; }, abstract = {The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.}, }
@article {pmid28444387, year = {2017}, author = {Jégou, B and Sankararaman, S and Rolland, AD and Reich, D and Chalmel, F}, title = {Meiotic Genes Are Enriched in Regions of Reduced Archaic Ancestry.}, journal = {Molecular biology and evolution}, volume = {34}, number = {8}, pages = {1974-1980}, pmid = {28444387}, issn = {1537-1719}, support = {R00 GM111744/GM/NIGMS NIH HHS/United States ; R01 GM100233/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Alleles ; Animals ; Databases, Genetic ; Evolution, Molecular ; Gene Expression Regulation, Developmental/genetics ; Genome, Human/genetics ; Genomics ; Hominidae/*genetics ; Humans ; Male ; Meiosis/*genetics ; Neanderthals/*genetics ; Selection, Genetic ; Testis ; }, abstract = {About 1-6% of the genetic ancestry of modern humans today originates from admixture with archaic humans. It has recently been shown that autosomal genomic regions with a reduced proportion of Neanderthal and Denisovan ancestries (NA and DA) are significantly enriched in genes that are more expressed in testis than in other tissues. To determine whether a cellular segregation pattern would exist, we combined maps of archaic introgression with a cross-analysis of three transcriptomic datasets deciphering the transcriptional landscape of human gonadal cell types. We reveal that the regions deficient in both NA and DA contain a significant enrichment of genes transcribed in meiotic germ cells. The interbreeding of anatomically modern humans with archaic humans may have introduced archaic-derived alleles that contributed to genetic incompatibilities affecting meiosis that were subsequently purged by natural selection.}, }
@article {pmid28434540, year = {2017}, author = {Ao, H and Liu, CR and Roberts, AP and Zhang, P and Xu, X}, title = {An updated age for the Xujiayao hominin from the Nihewan Basin, North China: Implications for Middle Pleistocene human evolution in East Asia.}, journal = {Journal of human evolution}, volume = {106}, number = {}, pages = {54-65}, doi = {10.1016/j.jhevol.2017.01.014}, pmid = {28434540}, issn = {1095-8606}, mesh = {Animals ; China ; *Electron Spin Resonance Spectroscopy ; *Fossils ; *Hominidae ; Humans ; Molar ; Neanderthals ; Time Factors ; }, abstract = {The Xujiayao site in the Nihewan Basin (North China) is one of the most important Paleolithic sites in East Asia. Twenty Homo fossils, which were previously assigned to an archaic Homo sapiens group, have been excavated along with more than 30,000 lithic artifacts and ∼5000 mammalian fossil specimens. Dating of the Xujiayao hominin has been pursued since its excavation in the 1970s, but its age has remained controversial because of limitations of the dating techniques that have been applied to available materials. Here, we report new ages for the Xujiayao hominin based on combined electron spin resonance (ESR) dating of quartz in the sediments and high-resolution magnetostratigraphy of the fluvio-lacustrine sequence. The magnetostratigraphy suggests that the upper Matuyama and Brunhes polarity chrons are recorded at Xujiayao. The ESR dating results indicate a pooled average age of 260-370 ka for the Homo-bearing layer, which is consistent with its position within the middle Brunhes normal polarity chron indicated by magnetostratigraphy. This age estimate makes the Xujiayao hominin among the oldest mid-Pleistocene hominins with derived Neanderthal traits in East Asia. This age is consistent with the time when early Denisovans, a sister group of Neanderthals, appeared and colonized eastern Eurasia. Our updated age and the Neanderthal-like traits of the Xujiayao Homo fossils, particularly the Denisovan-like molar teeth, make it possible that the Xujiayao hominin could represent an early Denisovan.}, }
@article {pmid28233034, year = {2017}, author = {Tashi, T and Scott Reading, N and Wuren, T and Zhang, X and Moore, LG and Hu, H and Tang, F and Shestakova, A and Lorenzo, F and Burjanivova, T and Koul, P and Guchhait, P and Wittwer, CT and Julian, CG and Shah, B and Huff, CD and Gordeuk, VR and Prchal, JT and Ge, R}, title = {Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {95}, number = {6}, pages = {665-670}, pmid = {28233034}, issn = {1432-1440}, support = {K12 HD057022/HD/NICHD NIH HHS/United States ; R01 HL138181/HL/NHLBI NIH HHS/United States ; P01 CA108671/CA/NCI NIH HHS/United States ; }, mesh = {Acclimatization/*genetics ; Adult ; Altitude ; Asian People/*genetics ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; Erythropoietin/blood ; Female ; Ferritins/blood ; Gene-Environment Interaction ; Haplotypes ; Hemoglobins/*analysis ; Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases/*genetics ; Male ; Polymorphism, Single Nucleotide ; Tibet ; }, abstract = {UNLABELLED: Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans.<br><br>KEY MESSAGE: Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.}, }
@article {pmid33473722, year = {2017}, author = {Druzhkova, AS and Makunin, AI and Vorobieva, NV and Vasiliev, SK and Ovodov, ND and Shunkov, MV and Trifonov, VA and Graphodatsky, AS}, title = {Complete mitochondrial genome of an extinct Equus (Sussemionus) ovodovi specimen from Denisova cave (Altai, Russia).}, journal = {Mitochondrial DNA. Part B, Resources}, volume = {2}, number = {1}, pages = {79-81}, pmid = {33473722}, issn = {2380-2359}, abstract = {Sussemionus is an extinct subgenus of Equus first characterized and delineated in 2010. The almost complete mitochondrial genome is available only for a single specimen of Sussemionus - a 40,000 years old E. ovodovi from Proskuryakova cave (Khakassia, Russia). Our studies of ancient horses from Denisova cave (Altai, Russia) revealed mitochondrial DNA of this species in a 32,000 years old sample. Using alignments to multiple mitochondrial genomes of non-caballine equids, we recovered 100% complete mitochondrial genome of E. ovodovi for the first time. Phylogenetic analysis demonstrates close relationship between this individual and the one previously described in Khakassia.}, }
@article {pmid28158547, year = {2016}, author = {Povysil, G and Hochreiter, S}, title = {IBD Sharing between Africans, Neandertals, and Denisovans.}, journal = {Genome biology and evolution}, volume = {8}, number = {12}, pages = {3406-3416}, pmid = {28158547}, issn = {1759-6653}, mesh = {Africa ; Animals ; Asian People/genetics ; Black People/genetics ; Breeding ; DNA/genetics ; *Evolution, Molecular ; *Gene Flow ; Genome ; Hominidae/*genetics ; Humans ; Neanderthals/genetics ; White People/genetics ; }, abstract = {Interbreeding between ancestors of humans and other hominins outside of Africa has been studied intensively, while their common history within Africa still lacks proper attention. However, shedding light on human evolution in this time period about which little is known, is essential for understanding subsequent events outside of Africa. We investigate the genetic relationships of humans, Neandertals, and Denisovans by identifying very short DNA segments in the 1000 Genomes Phase 3 data that these hominins share identical by descent (IBD). By focusing on low frequency and rare variants, we identify very short IBD segments with high confidence. These segments reveal events from a very distant past because shorter IBD segments are presumably older than longer ones. We extracted two types of very old IBD segments that are not only shared among humans, but also with Neandertals and/or Denisovans. The first type contains longer segments that are found primarily in Asians and Europeans where more segments are found in South Asians than in East Asians for both Neandertal and Denisovan. These longer segments indicate complex admixture events outside of Africa. The second type consists of shorter segments that are shared mainly by Africans and therefore may indicate events involving ancestors of humans and other ancient hominins within Africa. Our results from the autosomes are further supported by an analysis of chromosome X, on which segments that are shared by Africans and match the Neandertal and/or Denisovan genome were even more prominent. Our results indicate that interbreeding with other hominins was a common feature of human evolution starting already long before ancestors of modern humans left Africa.}, }
@article {pmid28007980, year = {2017}, author = {Racimo, F and Gokhman, D and Fumagalli, M and Ko, A and Hansen, T and Moltke, I and Albrechtsen, A and Carmel, L and Huerta-Sánchez, E and Nielsen, R}, title = {Archaic Adaptive Introgression in TBX15/WARS2.}, journal = {Molecular biology and evolution}, volume = {34}, number = {3}, pages = {509-524}, pmid = {28007980}, issn = {1537-1719}, support = {R01 HG003229/HG/NHGRI NIH HHS/United States ; }, mesh = {Adaptation, Biological/*genetics ; Adipose Tissue/physiology ; Alleles ; Animals ; DNA Methylation ; DNA, Ancient ; Greenland ; Haplotypes ; Humans ; Inuit/*genetics ; Models, Genetic ; Neanderthals ; Polymorphism, Single Nucleotide ; Selection, Genetic ; Sequence Analysis, DNA/methods ; T-Box Domain Proteins/*genetics ; }, abstract = {A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.}, }
@article {pmid27919236, year = {2016}, author = {Pajic, P and Lin, YL and Xu, D and Gokcumen, O}, title = {The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence.}, journal = {BMC evolutionary biology}, volume = {16}, number = {1}, pages = {265}, pmid = {27919236}, issn = {1471-2148}, mesh = {Alleles ; Cornified Envelope Proline-Rich Proteins/*genetics ; *Evolution, Molecular ; *Gene Deletion ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Polymorphism, Single Nucleotide ; Psoriasis/*genetics ; Sequence Deletion ; }, abstract = {BACKGROUND: A common, 32kb deletion of LCE3B and LCE3C genes is strongly associated with psoriasis. We recently found that this deletion is ancient, predating Human-Denisovan divergence. However, it was not clear why negative selection has not removed this deletion from the population.<br><br>RESULTS: Here, we show that the haplotype block that harbors the deletion (i) retains high allele frequency among extant and ancient human populations; (ii) harbors unusually high nucleotide variation (&#x3c0;, P&#x2009;<&#x2009;4.1&#x2009;&#xd7;&#x2009;10[-3]); (iii) contains an excess of intermediate frequency variants (Tajima's D, P&#x2009;<&#x2009;3.9&#x2009;&#xd7;&#x2009;10[-3]); and (iv) has an unusually long time to coalescence to the most recent common ancestor (TSel, 0.1 quantile).<br><br>CONCLUSIONS: Our results are most parsimonious with the scenario where the LCE3BC deletion has evolved under balancing selection in humans. More broadly, this is consistent with the hypothesis that a balance between autoimmunity and natural vaccination through increased exposure to pathogens maintains this deletion in humans.}, }
@article {pmid27916748, year = {2017}, author = {Noe, F and Polster, J and Geithe, C and Kotthoff, M and Schieberle, P and Krautwurst, D}, title = {OR2M3: A Highly Specific and Narrowly Tuned Human Odorant Receptor for the Sensitive Detection of Onion Key Food Odorant 3-Mercapto-2-methylpentan-1-ol.}, journal = {Chemical senses}, volume = {42}, number = {3}, pages = {195-210}, doi = {10.1093/chemse/bjw118}, pmid = {27916748}, issn = {1464-3553}, mesh = {Cells, Cultured ; Humans ; Molecular Structure ; Odorants/*analysis ; Onions/*chemistry ; Pentanols/*analysis/chemistry ; Receptors, Odorant/*metabolism ; *Smell ; Sulfhydryl Compounds/*analysis/chemistry ; }, abstract = {The detection of key food odorants appears to be an important capability of odorant receptors. Here, thiols occupy an outstanding position among the 230 known key food odorants because of their very low odor thresholds. Members of the homologous series of 3-mercapto-2-methylalkan-1-ols have been described as onion key food odorants or food constituents and are detected at logarithmically different thresholds. 3-Mercapto-2-methylpentan-1-ol being the only key food odorant within this series also has the lowest odor threshold. Most odorants typically activate combinations of odorant receptors, which may be narrowly or broadly tuned. Consequently, a specific receptor activation pattern will define an odor quality. In contrast, here we show that just 1 of the 391 human odorant receptors, OR2M3, responded exclusively to 3-mercapto-2-methylpentan-1-ol of the 190 key food odorants tested, with a half maximal effective concentration at submicromolar concentration. Moreover, neither the Denisovan OR2M3 nor the closest OR2M3 homologs from five species did respond to this compound. This outstanding specificity of extremely narrowly tuned human OR2M3 can explain both odor qualities and odor threshold trend within a homologous series of 3-mercapto-2-methylalkan-1-ols and suggests a modern human-specific, food-related function of OR2M3 in detecting a single onion key food odorant.}, }
@article {pmid27839976, year = {2016}, author = {Gittelman, RM and Schraiber, JG and Vernot, B and Mikacenic, C and Wurfel, MM and Akey, JM}, title = {Archaic Hominin Admixture Facilitated Adaptation to Out-of-Africa Environments.}, journal = {Current biology : CB}, volume = {26}, number = {24}, pages = {3375-3382}, pmid = {27839976}, issn = {1879-0445}, support = {R01 GM110068/GM/NIGMS NIH HHS/United States ; }, mesh = {Adaptation, Physiological/*genetics ; Animals ; *Biological Evolution ; DNA/*genetics ; Demography ; Gene Expression Regulation ; Genetic Variation ; *Genome, Human/genetics ; Haplotypes ; Humans ; Neanderthals ; Pigmentation ; }, abstract = {As modern humans dispersed from Africa throughout the world, they encountered and interbred with archaic hominins, including Neanderthals and Denisovans [1, 2]. Although genome-scale maps of introgressed sequences have been constructed [3-6], considerable gaps in knowledge remain about the functional, phenotypic, and evolutionary significance of archaic hominin DNA that persists in present-day individuals. Here, we describe a comprehensive set of analyses that identified 126 high-frequency archaic haplotypes as putative targets of adaptive introgression in geographically diverse populations. These loci are enriched for immune-related genes (such as OAS1/2/3, TLR1/6/10, and TNFAIP3) and also encompass genes (including OCA2 and BNC2) that influence skin pigmentation phenotypes. Furthermore, we leveraged existing and novel large-scale gene expression datasets to show many positively selected archaic haplotypes act as expression quantitative trait loci (eQTLs), suggesting that modulation of transcript abundance was a common mechanism facilitating adaptive introgression. Our results demonstrate that hybridization between modern and archaic hominins provided an important reservoir of advantageous alleles that enabled adaptation to out-of-Africa environments.}, }
@article {pmid27756828, year = {2017}, author = {Racimo, F and Marnetto, D and Huerta-Sánchez, E}, title = {Signatures of Archaic Adaptive Introgression in Present-Day Human Populations.}, journal = {Molecular biology and evolution}, volume = {34}, number = {2}, pages = {296-317}, pmid = {27756828}, issn = {1537-1719}, support = {R01 HG003229/HG/NHGRI NIH HHS/United States ; }, mesh = {Adaptation, Biological/*genetics ; Alleles ; Animals ; Biological Evolution ; Computer Simulation ; DNA, Ancient/*analysis ; Databases, Nucleic Acid ; Evolution, Molecular ; Gene Frequency ; Genetics, Population ; Haplotypes ; Humans ; Neanderthals ; Phylogeny ; Selection, Genetic ; Sequence Analysis, DNA/*methods ; }, abstract = {Comparisons of DNA from archaic and modern humans show that these groups interbred, and in some cases received an evolutionary advantage from doing so. This process-adaptive introgression-may lead to a faster rate of adaptation than is predicted from models with mutation and selection alone. Within the last couple of years, a series of studies have identified regions of the genome that are likely examples of adaptive introgression. In many cases, once a region was ascertained as being introgressed, commonly used statistics based on both haplotype as well as allele frequency information were employed to test for positive selection. Introgression by itself, however, changes both the haplotype structure and the distribution of allele frequencies, thus confounding traditional tests for detecting positive selection. Therefore, patterns generated by introgression alone may lead to false inferences of positive selection. Here we explore models involving both introgression and positive selection to investigate the behavior of various statistics under adaptive introgression. In particular, we find that the number and allelic frequencies of sites that are uniquely shared between archaic humans and specific present-day populations are particularly useful for detecting adaptive introgression. We then examine the 1000 Genomes dataset to characterize the landscape of uniquely shared archaic alleles in human populations. Finally, we identify regions that were likely subject to adaptive introgression and discuss some of the most promising candidate genes located in these regions.}, }
@article {pmid27708712, year = {2016}, author = {Stankiewicz, P}, title = {One pedigree we all may have come from - did Adam and Eve have the chromosome 2 fusion?.}, journal = {Molecular cytogenetics}, volume = {9}, number = {}, pages = {72}, pmid = {27708712}, issn = {1755-8166}, abstract = {BACKGROUND: In contrast to Great Apes, who have 48 chromosomes, modern humans and likely Neandertals and Denisovans have and had, respectively, 46 chromosomes. The reduction in chromosome number was caused by the head-to-head fusion of two ancestral chromosomes to form human chromosome 2 (HSA2) and may have contributed to the reproductive barrier with Great Apes.<br><br>RESULTS: Next generation sequencing and molecular clock analyses estimated that this fusion arose prior to our last common ancestor with Neandertal and Denisovan hominins&#x2009;~&#x2009;0.74 - 4.5 million years ago.<br><br>HYPOTHESES: I propose that, unlike recurrent Robertsonian translocations in humans, the HSA2 fusion was a single nonrecurrent event that spread through a small polygamous clan population bottleneck. Its heterozygous to homozygous conversion, fixation, and accumulation in the succeeding populations was likely facilitated by an evolutionary advantage through the genomic loss rather than deregulation of expression of the gene(s) flanking the HSA2 fusion site at 2q13.<br><br>CONCLUSIONS: The origin of HSA2 might have been a critical evolutionary event influencing higher cognitive functions in various early subspecies of hominins. Next generation sequencing of Homo heidelbergensis and Homo erectus genomes and complete reconstruction of DNA sequence of the orthologous subtelomeric chromosomes in Great Apes should enable more precise timing of HSA2 formation and better understanding of its evolutionary consequences.}, }
@article {pmid27695917, year = {2017}, author = {Yasukochi, Y and Ohashi, J}, title = {Elucidating the origin of HLA-B*73 allelic lineage: Did modern humans benefit by archaic introgression?.}, journal = {Immunogenetics}, volume = {69}, number = {1}, pages = {63-67}, pmid = {27695917}, issn = {1432-1211}, mesh = {Alleles ; Animals ; Asian People/genetics ; Black People/genetics ; Europe ; *Evolution, Molecular ; *Genome, Human ; HLA-B Antigens/*genetics ; Haplotypes/*genetics ; Hominidae/classification/*genetics ; Humans ; Neanderthals/genetics ; Pan troglodytes/genetics ; Phylogeny ; }, abstract = {A previous study reported that some of the human leukocyte antigen (HLA) alleles and haplotypes in present-day humans were acquired by admixture with archaic humans; specifically, an exceptionally diverged HLA-B*73 allele was proposed to be transmitted from Denisovans, although the DNA sequence of HLA-B*73 has not been detected in the Denisovan genome. Here, we argue against the hypothesis that HLA-B*73 introgressed from Denisovans into early modern humans. A phylogenetic analysis revealed that HLA-B*73:01 formed a monophyletic group with a chimpanzee MHC-B allele, strongly suggesting that the HLA-B*73 allelic lineage has been maintained in humans as well as in chimpanzees since the divergence of humans and chimpanzees. The global distribution of HLA-B*73 allele showed that the population frequency of HLA-B*73 in west Asia (0.24 %)-a possible site of admixture with Denisovans-is lower than that in Europe (0.72 %) and in south Asia (0.69 %). Furthermore, HLA-B*73 is not observed in Melanesia even though the Melanesian genome contains the highest proportion of Denisovan ancestry in present-day human populations. Single nucleotide polymorphisms in HLA-A*11-HLA-C*12:02 or HLA-A*11-C*15 haplotypes, one of which was assumed to be transmitted together with HLA-B*73 from Denisovans by the study of Abi-Rached and colleagues, were not differentiated from those in other HLA-A-C haplotypes in modern humans. These results do not support the introgression hypothesis. Thus, we conclude that it is highly likely that HLA-B*73 allelic lineage has been maintained in the direct ancestors of modern humans.}, }
@article {pmid27662059, year = {2016}, author = {Wall, JD and Yoshihara Caldeira Brandt, D}, title = {Archaic admixture in human history.}, journal = {Current opinion in genetics &amp; development}, volume = {41}, number = {}, pages = {93-97}, doi = {10.1016/j.gde.2016.07.002}, pmid = {27662059}, issn = {1879-0380}, mesh = {Africa ; Animals ; DNA, Ancient/*analysis ; Genetics, Population/*history ; History, Ancient ; Hominidae/*genetics ; Humans ; Neanderthals/*genetics ; }, abstract = {Modern humans evolved in Southern or Eastern Africa, and spread from there across the rest of the world. As they expanded across Africa and Eurasia, they encountered other hominin groups. The extent to which modern and 'archaic' human groups interbred is an area of active research, and while we know that modern humans interbred with Neanderthals and Denisovans, there is not yet agreement on how many admixture events there were or on how much Neanderthal or Denisovan DNA can be found in contemporary genomes. Here we review what is known about archaic admixture in human history, with a focus on what has been discovered in the past 2 years.}, }
@article {pmid27655273, year = {2016}, author = {Aarts, JM and Alink, GM and Scherjon, F and MacDonald, K and Smith, AC and Nijveen, H and Roebroeks, W}, title = {Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans.}, journal = {PloS one}, volume = {11}, number = {9}, pages = {e0161102}, pmid = {27655273}, issn = {1932-6203}, abstract = {Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions.}, }
@article {pmid27569548, year = {2016}, author = {Lu, D and Lou, H and Yuan, K and Wang, X and Wang, Y and Zhang, C and Lu, Y and Yang, X and Deng, L and Zhou, Y and Feng, Q and Hu, Y and Ding, Q and Yang, Y and Li, S and Jin, L and Guan, Y and Su, B and Kang, L and Xu, S}, title = {Ancestral Origins and Genetic History of Tibetan Highlanders.}, journal = {American journal of human genetics}, volume = {99}, number = {3}, pages = {580-594}, pmid = {27569548}, issn = {1537-6605}, support = {K99 AA021802/AA/NIAAA NIH HHS/United States ; R00 AA021802/AA/NIAAA NIH HHS/United States ; }, mesh = {Altitude ; Animals ; Asian People/*genetics ; China/ethnology ; Ethnicity/genetics ; Gene Flow/*genetics ; Gene Pool ; Genetics, Population ; Genome, Human/*genetics ; Haplotypes/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Models, Genetic ; Neanderthals/genetics ; Oceania/ethnology ; *Phylogeny ; Selection, Genetic ; Tibet ; }, abstract = {The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000-38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders' genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.}, }
@article {pmid27517578, year = {2016}, author = {Caldararo, N}, title = {Denisovans, Melanesians, Europeans, and Neandertals: The Confusion of DNA Assumptions and the Biological Species Concept.}, journal = {Journal of molecular evolution}, volume = {83}, number = {1-2}, pages = {78-87}, pmid = {27517578}, issn = {1432-1432}, mesh = {Animals ; Biological Evolution ; DNA/genetics ; DNA, Ancient/*analysis ; Fossils ; Hominidae/genetics ; Humans ; Neanderthals/*genetics ; Sequence Alignment/methods ; Sequence Analysis, DNA/methods ; }, abstract = {A number of recent articles have appeared on the Denisova fossil remains and attempts to produce DNA sequences from them. One of these recently appeared in Science by Vernot et al. (Science 352:235-239, 2016). We would like to advance an alternative interpretation of the data presented. One concerns the problem of contamination/degradation of the determined DNA sequenced. Just as the publication of the first Neandertal sequence included an interpretation that argued that Neandertals had not contributed any genes to modern humans, the Denisovan interpretation has considerable influence on ideas regarding human evolution. The new papers, however, confuse established ideas concerning the nature of species, as well as the use of terms like premodern, Archaic Homo, and Homo heidelbergensis. Examination of these problems presents a solution by means of reinterpreting the results. Given the claims for gene transfer among a number of Mid Pleistocene hominids, it may be time to reexamine the idea of anagenesis in hominid evolution.}, }
@article {pmid27486223, year = {2016}, author = {Hubbard, TD and Murray, IA and Bisson, WH and Sullivan, AP and Sebastian, A and Perry, GH and Jablonski, NG and Perdew, GH}, title = {Divergent Ah Receptor Ligand Selectivity during Hominin Evolution.}, journal = {Molecular biology and evolution}, volume = {33}, number = {10}, pages = {2648-2658}, pmid = {27486223}, issn = {1537-1719}, support = {R01 ES004869/ES/NIEHS NIH HHS/United States ; R01 ES019964/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Benzo(a)pyrene ; Biological Evolution ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1B1/genetics ; DNA/metabolism ; Evolution, Molecular ; Hominidae/*genetics ; Humans ; Ligands ; Neanderthals/*genetics ; Polycyclic Aromatic Hydrocarbons/metabolism ; Receptors, Aryl Hydrocarbon/*genetics ; }, abstract = {We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking.}, }
@article {pmid27463216, year = {2016}, author = {Taylor, JS and Reimchen, TE}, title = {Opsin gene repertoires in northern archaic hominids.}, journal = {Genome}, volume = {59}, number = {8}, pages = {541-549}, doi = {10.1139/gen-2015-0164}, pmid = {27463216}, issn = {1480-3321}, mesh = {Animals ; Anthropology, Physical ; Base Sequence ; Evolution, Molecular ; Genome, Human ; Hominidae/*genetics ; Humans ; Methyl-CpG-Binding Protein 2/genetics ; Neanderthals/genetics ; Opsins/*genetics ; Phylogeny ; Vision, Ocular/genetics ; }, abstract = {The Neanderthals' northern distribution, hunting techniques, and orbit breadths suggest that they were more active in dim light than modern humans. We surveyed visual opsin genes from four Neanderthals and two other archaic hominids to see if they provided additional support for this hypothesis. This analysis was motivated by the observation that alleles responsible for anomalous trichromacy in humans are more common in northern latitudes, by data suggesting that these variants might enhance vision in mesopic conditions, and by the observation that dim light active species often have fewer opsin genes than diurnal relatives. We also looked for evidence of convergent amino acid substitutions in Neanderthal opsins and orthologs from crepuscular or nocturnal species. The Altai Neanderthal, the Denisovan, and the Ust'-Ishim early modern human had opsin genes that encoded proteins identical to orthologs in the human reference genome. Opsins from the Vindija Cave Neanderthals (three females) had many nonsynonymous substitutions, including several predicted to influence colour vision (e.g., stop codons). However, the functional implications of these observations were difficult to assess, given that "control" loci, where no substitutions were expected, differed from humans to the same extent. This left unresolved the test for colour vision deficiencies in Vindija Cave Neanderthals.}, }
@article {pmid27429943, year = {2016}, author = {Ko, KH}, title = {Hominin interbreeding and the evolution of human variation.}, journal = {Journal of biological research (Thessalonike, Greece)}, volume = {23}, number = {}, pages = {17}, pmid = {27429943}, issn = {1790-045X}, abstract = {Mitochondrial Eve confirms the "out of Africa" theory, but the evidence also supports interbreeding between Homo sapiens and other hominins: Neanderthals, Denisovans, and Homo heidelbergensis. This article explains how interbreeding between early H. sapiens and archaic hominins occurred. The availability of edible insects in East Asia aided the spread of the unaggressive, highly cooperative Neanderthals, who interbred with H. sapiens in Asia, resulting in a higher admixture of Neanderthal DNA in East Asian populations. Geographical variation in degree of interbreeding between H. sapiens and Neanderthals likely contributed to neurological and behavioral differences in modern humans. Similarly, people with Denisovan genetic admixture were better able to dwell in mountainous regions, allowing their genetic legacy to cross the Himalayas and persist in Southeast Asian and Oceanian H. sapiens. In the Sub-Saharan region, unaffected by Denisovan or Neanderthal interbreeding, H. sapiens interbred with H. heidelbergensis, because high humidity militated against fire-making and allowed the survival of these non-fire-making hominins.}, }
@article {pmid27423248, year = {2017}, author = {Miga, KH}, title = {Chromosome-Specific Centromere Sequences Provide an Estimate of the Ancestral Chromosome 2 Fusion Event in Hominin Genomes.}, journal = {The Journal of heredity}, volume = {108}, number = {1}, pages = {45-52}, doi = {10.1093/jhered/esw039}, pmid = {27423248}, issn = {1465-7333}, mesh = {Animals ; *Centromere ; Chromosomes, Human, Pair 2 ; *Chromosomes, Mammalian ; DNA, Satellite ; *Evolution, Molecular ; *Genome ; Genomics/methods ; Hominidae/*genetics ; Humans ; Pan troglodytes/genetics ; }, abstract = {Human chromosome 2 is a product of a telomere fusion of two ancestral chromosomes and loss/degeneration of one of the two original centromeres. Genomic signatures of this event are limited to inverted telomeric repeats at the precise site of chromosomal fusion and to the small amount of relic centromeric sequences that remain on 2q21.2. Unlike the site of fusion, which is enriched for sequences that are shared elsewhere in the human genome, the region of the nonfunctioning and degenerate ancestral centromere appears to share limited similarity with other sites in the human genome, thereby providing an opportunity to study this genomic arrangement in short, fragmented ancient DNA genomic datasets. Here, chromosome-assigned satellite DNAs are used to study shared centromere sequence organization in Denisovan and Neandertal genomes. By doing so, one is able to provide evidence for the presence of both active and degenerate centromeric satellite profiles on chromosome 2 in these archaic genomes, supporting the hypothesis that the chromosomal fusion event took place prior to our last common ancestor with Denisovan and Neandertal hominins and presenting a genomic reference for predicting karyotype in ancient genomic datasets.}, }
@article {pmid27274045, year = {2016}, author = {Slatkin, M and Racimo, F}, title = {Ancient DNA and human history.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {113}, number = {23}, pages = {6380-6387}, pmid = {27274045}, issn = {1091-6490}, support = {R01 GM040282/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; DNA Contamination ; *DNA, Ancient ; Fossils ; Genome ; Hominidae/*genetics ; Humans ; }, abstract = {We review studies of genomic data obtained by sequencing hominin fossils with particular emphasis on the unique information that ancient DNA (aDNA) can provide about the demographic history of humans and our closest relatives. We concentrate on nuclear genomic sequences that have been published in the past few years. In many cases, particularly in the Arctic, the Americas, and Europe, aDNA has revealed historical demographic patterns in a way that could not be resolved by analyzing present-day genomes alone. Ancient DNA from archaic hominins has revealed a rich history of admixture between early modern humans, Neanderthals, and Denisovans, and has allowed us to disentangle complex selective processes. Information from aDNA studies is nowhere near saturation, and we believe that future aDNA sequences will continue to change our understanding of hominin history.}, }
@article {pmid27063929, year = {2016}, author = {Houldcroft, CJ and Underdown, SJ}, title = {Neanderthal genomics suggests a pleistocene time frame for the first epidemiologic transition.}, journal = {American journal of physical anthropology}, volume = {160}, number = {3}, pages = {379-388}, doi = {10.1002/ajpa.22985}, pmid = {27063929}, issn = {1096-8644}, mesh = {Animals ; Anthropology, Physical ; Communicable Diseases/*genetics/history/*immunology/microbiology ; Evolution, Molecular ; Fossils ; Genome/*genetics/*immunology ; Genomics ; History, Ancient ; Humans ; Neanderthals/*genetics/*immunology ; }, abstract = {High quality Altai Neanderthal and Denisovan genomes are revealing which regions of archaic hominin DNA have persisted in the modern human genome. A number of these regions are associated with response to infection and immunity, with a suggestion that derived Neanderthal alleles found in modern Europeans and East Asians may be associated with autoimmunity. As such Neanderthal genomes are an independent line of evidence of which infectious diseases Neanderthals were genetically adapted to. Sympathetically, human genome adaptive introgression is an independent line of evidence of which infectious diseases were important for AMH coming in to Eurasia and interacting with Neanderthals. The Neanderthals and Denisovans present interesting cases of hominin hunter-gatherers adapted to a Eurasian rather than African infectious disease package. Independent sources of DNA-based evidence allow a re-evaluation of the first epidemiologic transition and how infectious disease affected Pleistocene hominins. By combining skeletal, archaeological and genetic evidence from modern humans and extinct Eurasian hominins, we question whether the first epidemiologic transition in Eurasia featured a new package of infectious diseases or a change in the impact of existing pathogens. Coupled with pathogen genomics, this approach supports the view that many infectious diseases are pre-Neolithic, and the list continues to expand. The transfer of pathogens between hominin populations, including the expansion of pathogens from Africa, may also have played a role in the extinction of the Neanderthals and offers an important mechanism to understand hominin-hominin interactions well back beyond the current limits for aDNA extraction from fossils alone. Am J Phys Anthropol 160:379-388, 2016. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27032491, year = {2016}, author = {Sankararaman, S and Mallick, S and Patterson, N and Reich, D}, title = {The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans.}, journal = {Current biology : CB}, volume = {26}, number = {9}, pages = {1241-1247}, pmid = {27032491}, issn = {1879-0445}, support = {/HHMI/Howard Hughes Medical Institute/United States ; K99 GM111744/GM/NIGMS NIH HHS/United States ; R00 GM111744/GM/NIGMS NIH HHS/United States ; R01 GM100233/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Demography ; Genome, Human ; Humans ; Models, Genetic ; Neanderthals/*genetics ; Racial Groups/*genetics ; Time Factors ; }, abstract = {Some present-day humans derive up to ∼5% [1] of their ancestry from archaic Denisovans, an even larger proportion than the ∼2% from Neanderthals [2]. We developed methods that can disambiguate the locations of segments of Denisovan and Neanderthal ancestry in present-day humans and applied them to 257 high-coverage genomes from 120 diverse populations, among which were 20 individual Oceanians with high Denisovan ancestry [3]. In Oceanians, the average size of Denisovan fragments is larger than Neanderthal fragments, implying a more recent average date of Denisovan admixture in the history of these populations (p = 0.00004). We document more Denisovan ancestry in South Asia than is expected based on existing models of history, reflecting a previously undocumented mixture related to archaic humans (p = 0.0013). Denisovan ancestry, just like Neanderthal ancestry, has been deleterious on a modern human genetic background, as reflected by its depletion near genes. Finally, the reduction of both archaic ancestries is especially pronounced on chromosome X and near genes more highly expressed in testes than other tissues (p = 1.2 × 10(-7) to 3.2 × 10(-7) for Denisovan and 2.2 × 10(-3) to 2.9 × 10(-3) for Neanderthal ancestry even after controlling for differences in level of selective constraint across gene classes). This suggests that reduced male fertility may be a general feature of mixtures of human populations diverged by >500,000 years.}, }
@article {pmid27020421, year = {2016}, author = {Brown, S and Higham, T and Slon, V and Pääbo, S and Meyer, M and Douka, K and Brock, F and Comeskey, D and Procopio, N and Shunkov, M and Derevianko, A and Buckley, M}, title = {Identification of a new hominin bone from Denisova Cave, Siberia using collagen fingerprinting and mitochondrial DNA analysis.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {23559}, pmid = {27020421}, issn = {2045-2322}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols ; Bone and Bones/*metabolism ; Collagen/analysis/*metabolism ; Cyclophosphamide ; DNA, Mitochondrial/chemistry/classification/*genetics ; Doxorubicin ; Evolution, Molecular ; *Fossils ; Hominidae ; Humans ; Phylogeny ; Podophyllotoxin ; Radiometric Dating ; Sequence Analysis, DNA ; Siberia ; Tandem Mass Spectrometry ; Time Factors ; Vincristine ; }, abstract = {DNA sequencing has revolutionised our understanding of archaic humans during the Middle and Upper Palaeolithic. Unfortunately, while many Palaeolithic sites contain large numbers of bones, the majority of these lack the diagnostic features necessary for traditional morphological identification. As a result the recovery of Pleistocene-age human remains is extremely rare. To circumvent this problem we have applied a method of collagen fingerprinting to more than 2000 fragmented bones from the site of Denisova Cave, Russia, in order to facilitate the discovery of human remains. As a result of our analysis a single hominin bone (Denisova 11) was identified, supported through in-depth peptide sequencing analysis, and found to carry mitochondrial DNA of the Neandertal type. Subsequent radiocarbon dating revealed the bone to be >50,000 years old. Here we demonstrate the huge potential collagen fingerprinting has for identifying hominin remains in highly fragmentary archaeological assemblages, improving the resources available for wider studies into human evolution.}, }
@article {pmid26995655, year = {2016}, author = {Árnason, &#xda;}, title = {The Out of Africa hypothesis and the ancestry of recent humans: Cherchez la femme (et l'homme).}, journal = {Gene}, volume = {585}, number = {1}, pages = {9-12}, doi = {10.1016/j.gene.2016.03.018}, pmid = {26995655}, issn = {1879-0038}, mesh = {Africa ; Animals ; Asia ; *Biological Evolution ; China ; DNA, Mitochondrial/genetics ; Europe ; *Evolution, Molecular ; Female ; *Fossils ; Gene Flow ; Humans ; Male ; Neanderthals/*genetics ; Phylogeny ; }, abstract = {The Out of Africa hypothesis (OOAH) has been a mainstay in the discussion of human evolution since its presentation in the 1980's. However, recent advances in palaeontology and molecular genetics have made it possible to examine the hypothesis in a manner that was inconceivable at the time of its proposal. The palaeontological progress relates to early Homo finds in the Caucasus, Denisova finds in the Altai Mountains and Neanderthal finds in a wide range of localities from the Altai Mountains, the Caucasus, the Levant, Asia Minor, southern and Central Europe and the Iberian Peninsula. The Eurasian location of these finds and recognition of the principle of Last common ancestor (LCA) lend no support to OOAH. The same conclusion is drawn from genomic findings, which (a) have revealed the presence of Denisovan and Neanderthal nuclear DNA, primarily in the genomes of recent Eurasians and (b) have shown genomic introgression from early modern humans into Neanderthals in the Altai Mountains. Similarly, archaeological finds in Sulawesi and the discovery of ≈100,000years old human teeth in southern China constitute strong independent challenges to OOAH. The genomic and palaeogenomic results and the new palaeontological and archaeological discoveries suggest (a) that the ancestors of modern humans had their origin in a Eurasian (largely Asian) biogeographic region which may also have extended into NE Africa, and (b) that the founders of basal African lineages became separated, geographically and genetically, in the westernmost part of this region and spread from there to different parts of the African continent.}, }
@article {pmid26989198, year = {2016}, author = {Vernot, B and Tucci, S and Kelso, J and Schraiber, JG and Wolf, AB and Gittelman, RM and Dannemann, M and Grote, S and McCoy, RC and Norton, H and Scheinfeldt, LB and Merriwether, DA and Koki, G and Friedlaender, JS and Wakefield, J and Pääbo, S and Akey, JM}, title = {Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.}, journal = {Science (New York, N.Y.)}, volume = {352}, number = {6282}, pages = {235-239}, pmid = {26989198}, issn = {1095-9203}, support = {R01 GM110068/GM/NIGMS NIH HHS/United States ; 5R01GM110068/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; DNA/*genetics ; Genetic Variation ; Genome, Human/*genetics ; Humans ; Melanesia ; Native Hawaiian or Other Pacific Islander/*genetics ; Neanderthals/*genetics ; Sequence Analysis, DNA ; }, abstract = {Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.}, }
@article {pmid26976447, year = {2016}, author = {Meyer, M and Arsuaga, JL and de Filippo, C and Nagel, S and Aximu-Petri, A and Nickel, B and Martínez, I and Gracia, A and Bermúdez de Castro, JM and Carbonell, E and Viola, B and Kelso, J and Prüfer, K and Pääbo, S}, title = {Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins.}, journal = {Nature}, volume = {531}, number = {7595}, pages = {504-507}, pmid = {26976447}, issn = {1476-4687}, mesh = {Alleles ; Animals ; DNA, Mitochondrial/genetics ; Fossils ; Genome, Mitochondrial/genetics ; Hominidae/classification/*genetics ; Male ; Neanderthals/classification/genetics ; *Phylogeny ; Sequence Alignment ; Spain ; }, abstract = {A unique assemblage of 28 hominin individuals, found in Sima de los Huesos in the Sierra de Atapuerca in Spain, has recently been dated to approximately 430,000 years ago. An interesting question is how these Middle Pleistocene hominins were related to those who lived in the Late Pleistocene epoch, in particular to Neanderthals in western Eurasia and to Denisovans, a sister group of Neanderthals so far known only from southern Siberia. While the Sima de los Huesos hominins share some derived morphological features with Neanderthals, the mitochondrial genome retrieved from one individual from Sima de los Huesos is more closely related to the mitochondrial DNA of Denisovans than to that of Neanderthals. However, since the mitochondrial DNA does not reveal the full picture of relationships among populations, we have investigated DNA preservation in several individuals found at Sima de los Huesos. Here we recover nuclear DNA sequences from two specimens, which show that the Sima de los Huesos hominins were related to Neanderthals rather than to Denisovans, indicating that the population divergence between Neanderthals and Denisovans predates 430,000 years ago. A mitochondrial DNA recovered from one of the specimens shares the previously described relationship to Denisovan mitochondrial DNAs, suggesting, among other possibilities, that the mitochondrial DNA gene pool of Neanderthals turned over later in their history.}, }
@article {pmid26966016, year = {2016}, author = {Ghirotto, S and Tassi, F and Barbujani, G and Pattini, L and Hayward, C and Vollenweider, P and Bochud, M and Rampoldi, L and Devuyst, O}, title = {The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {27}, number = {10}, pages = {2983-2996}, pmid = {26966016}, issn = {1533-3450}, support = {295733/ERC_/European Research Council/International ; GGP14263/TI_/Telethon/Italy ; MC_PC_U127561128/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *Evolution, Molecular ; Genetic Loci ; Genetic Markers ; Genetic Variation ; Humans ; Urinary Tract Infections/genetics ; Uromodulin/*genetics ; }, abstract = {Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs.}, }
@article {pmid26898827, year = {2016}, author = {Gokhman, D and Meshorer, E and Carmel, L}, title = {Epigenetics: It's Getting Old. Past Meets Future in Paleoepigenetics.}, journal = {Trends in ecology &amp; evolution}, volume = {31}, number = {4}, pages = {290-300}, doi = {10.1016/j.tree.2016.01.010}, pmid = {26898827}, issn = {1872-8383}, mesh = {Animals ; DNA/genetics ; DNA Methylation ; *Epigenesis, Genetic ; Hominidae/*genetics ; }, abstract = {Recent years have witnessed the rise of ancient DNA (aDNA) technology, allowing comparative genomics to be carried out at unprecedented time resolution. While it is relatively straightforward to use aDNA to identify recent genomic changes, it is much less clear how to utilize it to study changes in epigenetic regulation. Here we review recent works demonstrating that highly degraded aDNA still contains sufficient information to allow reconstruction of epigenetic signals, including DNA methylation and nucleosome positioning maps. We discuss challenges arising from the tissue specificity of epigenetics, and show how some of them might in fact turn into advantages. Finally, we introduce a method to infer methylation states in tissues that do not tend to be preserved over time.}, }
@article {pmid26886800, year = {2016}, author = {Kuhlwilm, M and Gronau, I and Hubisz, MJ and de Filippo, C and Prado-Martinez, J and Kircher, M and Fu, Q and Burbano, HA and Lalueza-Fox, C and de la Rasilla, M and Rosas, A and Rudan, P and Brajkovic, D and Kucan, &#x17d; and Gušic, I and Marques-Bonet, T and Andrés, AM and Viola, B and Pääbo, S and Meyer, M and Siepel, A and Castellano, S}, title = {Ancient gene flow from early modern humans into Eastern Neanderthals.}, journal = {Nature}, volume = {530}, number = {7591}, pages = {429-433}, pmid = {26886800}, issn = {1476-4687}, support = {R01 GM102192/GM/NIGMS NIH HHS/United States ; GM102192/GM/NIGMS NIH HHS/United States ; U01 MH106874/MH/NIMH NIH HHS/United States ; }, mesh = {Altitude ; Animals ; Bayes Theorem ; Chromosomes, Human, Pair 21/genetics ; Croatia/ethnology ; Gene Flow/*genetics ; Genome, Human/genetics ; Genomics ; Haplotypes/genetics ; Heterozygote ; Humans ; Hybridization, Genetic/genetics ; Neanderthals/*genetics ; Phylogeny ; Population Density ; Siberia ; Spain/ethnology ; Time Factors ; }, abstract = {It has been shown that Neanderthals contributed genetically to modern humans outside Africa 47,000-65,000 years ago. Here we analyse the genomes of a Neanderthal and a Denisovan from the Altai Mountains in Siberia together with the sequences of chromosome 21 of two Neanderthals from Spain and Croatia. We find that a population that diverged early from other modern humans in Africa contributed genetically to the ancestors of Neanderthals from the Altai Mountains roughly 100,000 years ago. By contrast, we do not detect such a genetic contribution in the Denisovan or the two European Neanderthals. We conclude that in addition to later interbreeding events, the ancestors of Neanderthals from the Altai Mountains and early modern humans met and interbred, possibly in the Near East, many thousands of years earlier than previously thought.}, }
@article {pmid26883865, year = {2016}, author = {Hackinger, S and Kraaijenbrink, T and Xue, Y and Mezzavilla, M and Asan,  and van Driem, G and Jobling, MA and de Knijff, P and Tyler-Smith, C and Ayub, Q}, title = {Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas.}, journal = {Human genetics}, volume = {135}, number = {4}, pages = {393-402}, pmid = {26883865}, issn = {1432-1203}, support = {/WT_/Wellcome Trust/United Kingdom ; 087576/WT_/Wellcome Trust/United Kingdom ; 098051/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Altitude ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; *Haplotypes ; Humans ; Polymorphism, Single Nucleotide ; }, abstract = {High-altitude adaptation in Tibetans is influenced by introgression of a 32.7-kb haplotype from the Denisovans, an extinct branch of archaic humans, lying within the endothelial PAS domain protein 1 (EPAS1), and has also been reported in Sherpa. We genotyped 19 variants in this genomic region in 1507 Eurasian individuals, including 1188 from Bhutan and Nepal residing at altitudes between 86 and 4550 m above sea level. Derived alleles for five SNPs characterizing the core Denisovan haplotype (AGGAA) were present at high frequency not only in Tibetans and Sherpa, but also among many populations from the Himalayas, showing a significant correlation with altitude (Spearman's correlation coefficient = 0.75, p value 3.9 × 10(-11)). Seven East- and South-Asian 1000 Genomes Project individuals shared the Denisovan haplotype extending beyond the 32-kb region, enabling us to refine the haplotype structure and identify a candidate regulatory variant (rs370299814) that might be interacting in an additive manner with the derived G allele of rs150877473, the variant previously associated with high-altitude adaptation in Tibetans. Denisovan-derived alleles were also observed at frequencies of 3-14% in the 1000 Genomes Project African samples. The closest African haplotype is, however, separated from the Asian high-altitude haplotype by 22 mutations whereas only three mutations, including rs150877473, separate the Asians from the Denisovan, consistent with distant shared ancestry for African and Asian haplotypes and Denisovan adaptive introgression.}, }
@article {pmid31265485, year = {2016}, author = {Dannemann, M and Andrés, AM and Kelso, J}, title = {Erratum: Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.}, journal = {American journal of human genetics}, volume = {98}, number = {2}, pages = {399}, doi = {10.1016/j.ajhg.2016.01.012}, pmid = {31265485}, issn = {1537-6605}, abstract = {[This corrects the article DOI: 10.1016/j.ajhg.2015.11.015.].}, }
@article {pmid26748514, year = {2016}, author = {Dannemann, M and Andrés, AM and Kelso, J}, title = {Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.}, journal = {American journal of human genetics}, volume = {98}, number = {1}, pages = {22-33}, pmid = {26748514}, issn = {1537-6605}, mesh = {Adaptation, Physiological/*genetics ; Animals ; Cell Line ; *Haplotypes ; Humans ; Neanderthals/*genetics ; Polymorphism, Single Nucleotide ; Toll-Like Receptors/*genetics ; }, abstract = {Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with increased [corrected] microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans.}, }
@article {pmid26719974, year = {2015}, author = {Arciero, E and Biagini, SA and Chen, Y and Xue, Y and Luiselli, D and Tyler-Smith, C and Pagani, L and Ayub, Q}, title = {Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians.}, journal = {PloS one}, volume = {10}, number = {12}, pages = {e0146072}, pmid = {26719974}, issn = {1932-6203}, support = {/WT_/Wellcome Trust/United Kingdom ; 098051/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Asian People/*genetics ; Bone and Bones/*metabolism ; Core Binding Factor Alpha 1 Subunit/genetics ; DNA-Binding Proteins/genetics ; Gene Frequency/genetics ; Haplotypes/genetics ; Humans ; Low Density Lipoprotein Receptor-Related Protein-5/genetics ; Osteoporosis/genetics ; Polymorphism, Single Nucleotide/genetics ; Selection, Genetic/genetics ; Trans-Activators ; Vitamin D/*genetics ; }, abstract = {Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20-60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.}, }
@article {pmid26693966, year = {2015}, author = {Gunbin, KV and Afonnikov, DA and Kolchanov, NA and Derevianko, AP and Rogaev, EI}, title = {The evolution of Homo sapiens denisova and Homo sapiens neanderthalensis miRNA targeting genes in the prenatal and postnatal brain.}, journal = {BMC genomics}, volume = {16 Suppl 13}, number = {Suppl 13}, pages = {S4}, pmid = {26693966}, issn = {1471-2164}, mesh = {Animals ; Brain/*embryology/growth &amp; development/metabolism ; *Evolution, Molecular ; *Gene Expression Regulation ; Hominidae/*genetics ; Humans ; Infant, Newborn ; MicroRNAs/*genetics ; Pan troglodytes ; RNA, Messenger/*genetics ; }, abstract = {BACKGROUND: As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.<br><br>RESULTS: A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.<br><br>CONCLUSIONS: Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.}, }
@article {pmid26630009, year = {2015}, author = {Sawyer, S and Renaud, G and Viola, B and Hublin, JJ and Gansauge, MT and Shunkov, MV and Derevianko, AP and Prüfer, K and Kelso, J and Pääbo, S}, title = {Nuclear and mitochondrial DNA sequences from two Denisovan individuals.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {112}, number = {51}, pages = {15696-15700}, pmid = {26630009}, issn = {1091-6490}, mesh = {Animals ; Base Sequence ; Cell Nucleus/*genetics ; DNA, Mitochondrial/*chemistry ; Evolution, Molecular ; Molecular Sequence Data ; Neanderthals/*genetics ; Phylogeny ; Sequence Analysis, DNA ; }, abstract = {Denisovans, a sister group of Neandertals, have been described on the basis of a nuclear genome sequence from a finger phalanx (Denisova 3) found in Denisova Cave in the Altai Mountains. The only other Denisovan specimen described to date is a molar (Denisova 4) found at the same site. This tooth carries a mtDNA sequence similar to that of Denisova 3. Here we present nuclear DNA sequences from Denisova 4 and a morphological description, as well as mitochondrial and nuclear DNA sequence data, from another molar (Denisova 8) found in Denisova Cave in 2010. This new molar is similar to Denisova 4 in being very large and lacking traits typical of Neandertals and modern humans. Nuclear DNA sequences from the two molars form a clade with Denisova 3. The mtDNA of Denisova 8 is more diverged and has accumulated fewer substitutions than the mtDNAs of the other two specimens, suggesting Denisovans were present in the region over an extended period. The nuclear DNA sequence diversity among the three Denisovans is comparable to that among six Neandertals, but lower than that among present-day humans.}, }
@article {pmid26596347, year = {2016}, author = {Racimo, F}, title = {Testing for Ancient Selection Using Cross-population Allele Frequency Differentiation.}, journal = {Genetics}, volume = {202}, number = {2}, pages = {733-750}, pmid = {26596347}, issn = {1943-2631}, support = {R01 GM040282/GM/NIGMS NIH HHS/United States ; R01-GM40282/GM/NIGMS NIH HHS/United States ; }, mesh = {Algorithms ; *Alleles ; Animals ; Asian People/genetics ; Computer Simulation ; Evolution, Molecular ; *Gene Frequency ; *Genetics, Population ; Genome-Wide Association Study ; Genomics/methods ; Humans ; *Models, Genetic ; Neanderthals/genetics ; ROC Curve ; *Selection, Genetic ; White People/genetics ; }, abstract = {A powerful way to detect selection in a population is by modeling local allele frequency changes in a particular region of the genome under scenarios of selection and neutrality and finding which model is most compatible with the data. A previous method based on a cross-population composite likelihood ratio (XP-CLR) uses an outgroup population to detect departures from neutrality that could be compatible with hard or soft sweeps, at linked sites near a beneficial allele. However, this method is most sensitive to recent selection and may miss selective events that happened a long time ago. To overcome this, we developed an extension of XP-CLR that jointly models the behavior of a selected allele in a three-population tree. Our method - called "3-population composite likelihood ratio" (3P-CLR) - outperforms XP-CLR when testing for selection that occurred before two populations split from each other and can distinguish between those events and events that occurred specifically in each of the populations after the split. We applied our new test to population genomic data from the 1000 Genomes Project, to search for selective sweeps that occurred before the split of Yoruba and Eurasians, but after their split from Neanderthals, and that could have led to the spread of modern-human-specific phenotypes. We also searched for sweep events that occurred in East Asians, Europeans, and the ancestors of both populations, after their split from Yoruba. In both cases, we are able to confirm a number of regions identified by previous methods and find several new candidates for selection in recent and ancient times. For some of these, we also find suggestive functional mutations that may have driven the selective events.}, }
@article {pmid26567083, year = {2016}, author = {Vyas, DN and Kitchen, A and Miró-Herrans, AT and Pearson, LN and Al-Meeri, A and Mulligan, CJ}, title = {Bayesian analyses of Yemeni mitochondrial genomes suggest multiple migration events with Africa and Western Eurasia.}, journal = {American journal of physical anthropology}, volume = {159}, number = {3}, pages = {382-393}, doi = {10.1002/ajpa.22890}, pmid = {26567083}, issn = {1096-8644}, support = {//Howard Hughes Medical Institute/United States ; }, mesh = {Africa ; Anthropology, Physical ; Asia, Western ; Bayes Theorem ; Europe ; Genome, Mitochondrial/*genetics ; Haplotypes ; History, Ancient ; *Human Migration ; Humans ; Phylogeny ; Yemen ; }, abstract = {OBJECTIVES: Anatomically, modern humans are thought to have migrated out of Africa ∼60,000 years ago in the first successful global dispersal. This initial migration may have passed through Yemen, a region that has experienced multiple migrations events with Africa and Eurasia throughout human history. We use Bayesian phylogenetics to determine how ancient and recent migrations have shaped Yemeni mitogenomic variation.<br><br>MATERIALS AND METHODS: We sequenced 113 mitogenomes from multiple Yemeni regions with a focus on haplogroups M, N, and L3(xM,N) as these groups have the oldest evolutionary history outside of Africa. We performed Bayesian evolutionary analyses to generate time-measured phylogenies calibrated by Neanderthal and Denisovan mitogenomes in order to determine the age of Yemeni-specific clades.<br><br>RESULTS: As defined by Yemeni monophyly, Yemeni in situ evolution is limited to the Holocene or latest Pleistocene (ages of clades in subhaplogroups L3b1a1a, L3h2, L3x1, M1a1f, M1a5, N1a1a3, and N1a3 range from 2 to 14 kya) and is often situated within broader Horn of Africa/southern Arabia in situ evolution (L3h2, L3x1, M1a1f, M1a5, and N1a1a3 ages range from 7 to 29 kya). Five subhaplogroups show no monophyly and are candidates for Holocene migration into Yemen (L0a2a2a, L3d1a1a, L3i2, M1a1b, and N1b1a).<br><br>DISCUSSION: Yemeni mitogenomes are largely the product of Holocene migration, and subsequent in situ evolution, from Africa and western Eurasia. However, we hypothesize that recent population movements may obscure the genetic signature of more ancient migrations. Additional research, e.g., analyses of Yemeni nuclear genetic data, is needed to better reconstruct the complex population and migration histories associated with Out of Africa.}, }
@article {pmid26399483, year = {2015}, author = {Rogers, RL}, title = {Chromosomal Rearrangements as Barriers to Genetic Homogenization between Archaic and Modern Humans.}, journal = {Molecular biology and evolution}, volume = {32}, number = {12}, pages = {3064-3078}, pmid = {26399483}, issn = {1537-1719}, support = {R01 GM040282/GM/NIGMS NIH HHS/United States ; R01-GM40282/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Biological Evolution ; DNA Transposable Elements ; Evolution, Molecular ; Female ; Fossils ; Gene Flow/genetics ; *Gene Rearrangement ; Genetic Variation ; *Genome, Human ; Hominidae/*genetics ; Humans ; Male ; Neanderthals/*genetics ; Phylogeny ; Polymorphism, Genetic ; Recombination, Genetic/genetics ; Sequence Analysis, DNA ; Y Chromosome ; }, abstract = {Chromosomal rearrangements, which shuffle DNA throughout the genome, are an important source of divergence across taxa. Using a paired-end read approach with Illumina sequence data for archaic humans, I identify changes in genome structure that occurred recently in human evolution. Hundreds of rearrangements indicate genomic trafficking between the sex chromosomes and autosomes, raising the possibility of sex-specific changes. Additionally, genes adjacent to genome structure changes in Neanderthals are associated with testis-specific expression, consistent with evolutionary theory that new genes commonly form with expression in the testes. I identify one case of new-gene creation through transposition from the Y chromosome to chromosome 10 that combines the 5'-end of the testis-specific gene Fank1 with previously untranscribed sequence. This new transcript experienced copy number expansion in archaic genomes, indicating rapid genomic change. Among rearrangements identified in Neanderthals, 13% are transposition of selfish genetic elements, whereas 32% appear to be ectopic exchange between repeats. In Denisovan, the pattern is similar but numbers are significantly higher with 18% of rearrangements reflecting transposition and 40% ectopic exchange between distantly related repeats. There is an excess of divergent rearrangements relative to polymorphism in Denisovan, which might result from nonuniform rates of mutation, possibly reflecting a burst of transposable element activity in the lineage that led to Denisovan. Finally, loci containing genome structure changes show diminished rates of introgression from Neanderthals into modern humans, consistent with the hypothesis that rearrangements serve as barriers to gene flow during hybridization. Together, these results suggest that this previously unidentified source of genomic variation has important biological consequences in human evolution.}, }
@article {pmid26249230, year = {2015}, author = {Sudmant, PH and Mallick, S and Nelson, BJ and Hormozdiari, F and Krumm, N and Huddleston, J and Coe, BP and Baker, C and Nordenfelt, S and Bamshad, M and Jorde, LB and Posukh, OL and Sahakyan, H and Watkins, WS and Yepiskoposyan, L and Abdullah, MS and Bravi, CM and Capelli, C and Hervig, T and Wee, JT and Tyler-Smith, C and van Driem, G and Romero, IG and Jha, AR and Karachanak-Yankova, S and Toncheva, D and Comas, D and Henn, B and Kivisild, T and Ruiz-Linares, A and Sajantila, A and Metspalu, E and Parik, J and Villems, R and Starikovskaya, EB and Ayodo, G and Beall, CM and Di Rienzo, A and Hammer, MF and Khusainova, R and Khusnutdinova, E and Klitz, W and Winkler, C and Labuda, D and Metspalu, M and Tishkoff, SA and Dryomov, S and Sukernik, R and Patterson, N and Reich, D and Eichler, EE}, title = {Global diversity, population stratification, and selection of human copy-number variation.}, journal = {Science (New York, N.Y.)}, volume = {349}, number = {6253}, pages = {aab3761}, pmid = {26249230}, issn = {1095-9203}, support = {5DP1ES022577 05/DP/NCCDPHP CDC HHS/United States ; 261213/ERC_/European Research Council/International ; 1R01DK104339-01/DK/NIDDK NIH HHS/United States ; R01 DK104339/DK/NIDDK NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 HL119577/HL/NHLBI NIH HHS/United States ; 1R01GM113657-01/GM/NIGMS NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; 098051/WT_/Wellcome Trust/United Kingdom ; /ImNIH/Intramural NIH HHS/United States ; R01 GM113657/GM/NIGMS NIH HHS/United States ; R01 HG002385/HG/NHGRI NIH HHS/United States ; DP1 ES022577/ES/NIEHS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; T32 GM007266/GM/NIGMS NIH HHS/United States ; HHSN26120080001E//PHS HHS/International ; 2R01HG002385/HG/NHGRI NIH HHS/United States ; }, mesh = {Animals ; Black People/classification/genetics ; *DNA Copy Number Variations ; *Evolution, Molecular ; *Gene Duplication ; Genome, Human/*genetics ; Hominidae/genetics ; Humans ; Native Hawaiian or Other Pacific Islander/classification/genetics ; Phylogeny ; Polymorphism, Single Nucleotide ; Population/*genetics ; Selection, Genetic ; *Sequence Deletion ; }, abstract = {In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide-variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.}, }
@article {pmid26206078, year = {2015}, author = {Kutzner, A and Pramanik, S and Kim, PS and Heese, K}, title = {All-or-(N)One - an epistemological characterization of the human tumorigenic neuronal paralogous FAM72 gene loci.}, journal = {Genomics}, volume = {106}, number = {5}, pages = {278-285}, doi = {10.1016/j.ygeno.2015.07.003}, pmid = {26206078}, issn = {1089-8646}, mesh = {Animals ; Carrier Proteins/*genetics ; Chromosomes, Human, Pair 1 ; Computer Simulation ; Genes ; Genetic Loci ; Genomics ; Hominidae/genetics ; Humans ; Membrane Proteins ; Neanderthals/genetics ; Neoplasm Proteins/*genetics ; Phylogeny ; Proteins ; Segmental Duplications, Genomic ; }, abstract = {FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumourigenic effects of FAM72. Our in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic neighbour SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2 gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long non-coding (lnc) RNAs.}, }
@article {pmid26156123, year = {2015}, author = {Fish, I and Boissinot, S}, title = {Contrasted patterns of variation and evolutionary convergence at the antiviral OAS1 gene in old world primates.}, journal = {Immunogenetics}, volume = {67}, number = {9}, pages = {487-499}, pmid = {26156123}, issn = {1432-1211}, support = {P51 OD011133/OD/NIH HHS/United States ; P51 RR013986/RR/NCRR NIH HHS/United States ; }, mesh = {2',5'-Oligoadenylate Synthetase/*genetics ; Amino Acid Sequence ; Animals ; Base Sequence ; Disease Resistance/*genetics ; Evolution, Molecular ; Haplotypes/*genetics ; Macaca fascicularis/genetics/immunology ; Macaca mulatta/genetics/immunology ; Papio anubis/genetics/immunology ; Papio papio/genetics/immunology ; Polymorphism, Genetic/*genetics ; Protein Structure, Tertiary ; Sequence Alignment ; Sequence Analysis, DNA ; }, abstract = {The oligoadenylate synthetase 1 (OAS1) enzyme acts as an innate sensor of viral infection and plays a major role in the defense against a wide diversity of viruses. Polymorphisms at OAS1 have been shown to correlate with differential susceptibility to several infections of great public health significance, including hepatitis C virus, SARS coronavirus, and West Nile virus. Population genetics analyses in hominoids have revealed interesting evolutionary patterns. In Central African chimpanzee, OAS1 has evolved under long-term balancing selection, resulting in the persistence of polymorphisms since the origin of hominoids, whereas human populations have acquired and retained OAS1 alleles from Neanderthal and Denisovan origin. We decided to further investigate the evolution of OAS1 in primates by characterizing intra-specific variation in four species commonly used as models in infectious disease research: the rhesus macaque, the cynomolgus macaque, the olive baboon, and the Guinea baboon. In baboons, OAS1 harbors a very low level of variation. In contrast, OAS1 in macaques exhibits a level of polymorphism far greater than the genomic average, which is consistent with the action of balancing selection. The region of the enzyme that directly interacts with viral RNA, the RNA-binding domain, contains a number of polymorphisms likely to affect the RNA-binding affinity of OAS1. This strongly suggests that pathogen-driven balancing selection acting on the RNA-binding domain of OAS1 is maintaining variation at this locus. Interestingly, we found that a number of polymorphisms involved in RNA-binding were shared between macaques and chimpanzees. This represents an unusual case of convergent polymorphism.}, }
@article {pmid26104010, year = {2015}, author = {Qin, P and Stoneking, M}, title = {Denisovan Ancestry in East Eurasian and Native American Populations.}, journal = {Molecular biology and evolution}, volume = {32}, number = {10}, pages = {2665-2674}, doi = {10.1093/molbev/msv141}, pmid = {26104010}, issn = {1537-1719}, mesh = {Animals ; Consanguinity ; Gene Flow ; *Genealogy and Heraldry ; Geography ; Hominidae/genetics ; Humans ; Indians, North American/*genetics ; Models, Genetic ; Native Hawaiian or Other Pacific Islander/genetics ; Siberia ; }, abstract = {Although initial studies suggested that Denisovan ancestry was found only in modern human populations from island Southeast Asia and Oceania, more recent studies have suggested that Denisovan ancestry may be more widespread. However, the geographic extent of Denisovan ancestry has not been determined, and moreover the relationship between the Denisovan ancestry in Oceania and that elsewhere has not been studied. Here we analyze genome-wide single nucleotide polymorphism data from 2,493 individuals from 221 worldwide populations, and show that there is a widespread signal of a very low level of Denisovan ancestry across Eastern Eurasian and Native American (EE/NA) populations. We also verify a higher level of Denisovan ancestry in Oceania than that in EE/NA; the Denisovan ancestry in Oceania is correlated with the amount of New Guinea ancestry, but not the amount of Australian ancestry, indicating that recent gene flow from New Guinea likely accounts for signals of Denisovan ancestry across Oceania. However, Denisovan ancestry in EE/NA populations is equally correlated with their New Guinea or their Australian ancestry, suggesting a common source for the Denisovan ancestry in EE/NA and Oceanian populations. Our results suggest that Denisovan ancestry in EE/NA is derived either from common ancestry with, or gene flow from, the common ancestor of New Guineans and Australians, indicating a more complex history involving East Eurasians and Oceanians than previously suspected.}, }
@article {pmid26073780, year = {2015}, author = {Lou, H and Lu, Y and Lu, D and Fu, R and Wang, X and Feng, Q and Wu, S and Yang, Y and Li, S and Kang, L and Guan, Y and Hoh, BP and Chung, YJ and Jin, L and Su, B and Xu, S}, title = {A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence.}, journal = {American journal of human genetics}, volume = {97}, number = {1}, pages = {54-66}, pmid = {26073780}, issn = {1537-6605}, mesh = {Adaptation, Biological/*genetics ; Algorithms ; *Altitude ; Animals ; Base Sequence ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; DNA Copy Number Variations/*genetics ; Ethnicity/*genetics ; *Evolution, Molecular ; Genetics, Population ; Hemoglobins/genetics/metabolism ; Hominidae/*genetics ; Humans ; Linkage Disequilibrium ; Microarray Analysis/methods ; Molecular Sequence Data ; Polymerase Chain Reaction/methods ; Sequence Analysis, DNA ; Tibet ; }, abstract = {Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.}, }
@article {pmid26072518, year = {2015}, author = {Hoover, KC and Gokcumen, O and Qureshy, Z and Bruguera, E and Savangsuksa, A and Cobb, M and Matsunami, H}, title = {Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution.}, journal = {Chemical senses}, volume = {40}, number = {7}, pages = {481-488}, pmid = {26072518}, issn = {1464-3553}, support = {DC005782/DC/NIDCD NIH HHS/United States ; }, mesh = {Alleles ; Base Sequence ; DNA/genetics ; *Evolution, Molecular ; Genetic Variation/*genetics ; Humans ; Polymorphism, Single Nucleotide/genetics ; Receptors, Odorant/*genetics ; }, abstract = {Allelic variation at 4 loci in the human olfactory receptor gene OR7D4 is associated with perceptual variation in the sex steroid-derived odorants, androstenone, and androstadienone. Androstadienone has been linked with chemosensory identification whereas androstenone makes pork from uncastrated pigs distasteful ("boar taint"). In a sample of 2224 individuals from 43 populations, we identified 45 OR7D4 single nucleotide polymorphisms. Coalescent modeling of frequency-site-spectrum-based statistics identified significant deviation from neutrality in human OR7D4; individual populations with statistically significant deviations from neutrality include Gujarati, Beijing Han, Great Britain, Iberia, and Puerto Rico. Analysis of molecular variation values indicated statistically significant population differentiation driven mainly by the 4 alleles associated with androstenone perception variation; however, fixation values were low suggesting that genetic structure may not have played a strong role in creating these group divisions. We also studied OR7D4 in the genomes of extinct members of the human lineage: Altai Neandertal and Denisovan. No variants were identified in Altai but 2 were in Denisova, one of which is shared by modern humans and one of which is novel. A functional test of modern human and a synthesized mutant Denisova OR7D4 indicated no statistically significant difference in responses to androstenone between the 2 species. Our results suggest non-neutral evolution for an olfactory receptor gene.}, }
@article {pmid26000734, year = {2015}, author = {Kari, L and Hill, KA and Sayem, AS and Karamichalis, R and Bryans, N and Davis, K and Dattani, NS}, title = {Mapping the space of genomic signatures.}, journal = {PloS one}, volume = {10}, number = {5}, pages = {e0119815}, pmid = {26000734}, issn = {1932-6203}, mesh = {Animals ; DNA, Mitochondrial/*genetics ; *Models, Theoretical ; }, abstract = {We propose a computational method to measure and visualize interrelationships among any number of DNA sequences allowing, for example, the examination of hundreds or thousands of complete mitochondrial genomes. An "image distance" is computed for each pair of graphical representations of DNA sequences, and the distances are visualized as a Molecular Distance Map: Each point on the map represents a DNA sequence, and the spatial proximity between any two points reflects the degree of structural similarity between the corresponding sequences. The graphical representation of DNA sequences utilized, Chaos Game Representation (CGR), is genome- and species-specific and can thus act as a genomic signature. Consequently, Molecular Distance Maps could inform species identification, taxonomic classifications and, to a certain extent, evolutionary history. The image distance employed, Structural Dissimilarity Index (DSSIM), implicitly compares the occurrences of oligomers of length up to k (herein k = 9) in DNA sequences. We computed DSSIM distances for more than 5 million pairs of complete mitochondrial genomes, and used Multi-Dimensional Scaling (MDS) to obtain Molecular Distance Maps that visually display the sequence relatedness in various subsets, at different taxonomic levels. This general-purpose method does not require DNA sequence alignment and can thus be used to compare similar or vastly different DNA sequences, genomic or computer-generated, of the same or different lengths. We illustrate potential uses of this approach by applying it to several taxonomic subsets: phylum Vertebrata, (super)kingdom Protista, classes Amphibia-Insecta-Mammalia, class Amphibia, and order Primates. This analysis of an extensive dataset confirms that the oligomer composition of full mtDNA sequences can be a source of taxonomic information. This method also correctly finds the mtDNA sequences most closely related to that of the anatomically modern human (the Neanderthal, the Denisovan, and the chimp), and that the sequence most different from it in this dataset belongs to a cucumber.}, }
@article {pmid25575941, year = {2015}, author = {Rogers, AR and Bohlender, RJ}, title = {Bias in estimators of archaic admixture.}, journal = {Theoretical population biology}, volume = {100C}, number = {}, pages = {63-78}, doi = {10.1016/j.tpb.2014.12.006}, pmid = {25575941}, issn = {1096-0325}, abstract = {This article evaluates bias in one class of methods used to estimate archaic admixture in modern humans. These methods study the pattern of allele sharing among modern and archaic genomes. They are sensitive to "ghost" admixture, which occurs when a population receives archaic DNA from sources not acknowledged by the statistical model. The effect of ghost admixture depends on two factors: branch-length bias and population-size bias. Branch-length bias occurs because a given amount of admixture has a larger effect if the two populations have been separated for a long time. Population-size bias occurs because differences in population size distort branch lengths in the gene genealogy. In the absence of ghost admixture, these effects are small. They become important, however, in the presence of ghost admixture. Estimators differ in the pattern of response. Increasing a given parameter may inflate one estimator but deflate another. For this reason, comparisons among estimators are informative. Using such comparisons, this article supports previous findings that the archaic population was small and that Europeans received little gene flow from archaic populations other than Neanderthals. It also identifies an inconsistency in estimates of archaic admixture into Melanesia.}, }
@article {pmid25563409, year = {2015}, author = {Perry, GH and Kistler, L and Kelaita, MA and Sams, AJ}, title = {Insights into hominin phenotypic and dietary evolution from ancient DNA sequence data.}, journal = {Journal of human evolution}, volume = {79}, number = {}, pages = {55-63}, doi = {10.1016/j.jhevol.2014.10.018}, pmid = {25563409}, issn = {1095-8606}, mesh = {Animals ; Base Sequence ; *Biological Evolution ; DNA/analysis/genetics ; DNA Copy Number Variations ; Feeding Behavior/*physiology ; Fossils ; Genetic Variation ; Genomics ; Hominidae/*genetics/*physiology ; Humans ; Molecular Sequence Data ; Myosin Heavy Chains/genetics ; Neanderthals ; Paleontology ; Phenotype ; Receptors, G-Protein-Coupled/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; }, abstract = {Nuclear genome sequence data from Neandertals, Denisovans, and archaic anatomically modern humans can be used to complement our understanding of hominin evolutionary biology and ecology through i) direct inference of archaic hominin phenotypes, ii) indirect inference of those phenotypes by identifying the effects of previously-introgressed alleles still present among modern humans, or iii) determining the evolutionary timing of relevant hominin-specific genetic changes. Here we review and reanalyze published Neandertal and Denisovan genome sequence data to illustrate an example of the third approach. Specifically, we infer the timing of five human gene presence/absence changes that may be related to particular hominin-specific dietary changes and discuss these results in the context of our broader reconstructions of hominin evolutionary ecology. We show that pseudogenizing (gene loss) mutations in the TAS2R62 and TAS2R64 bitter taste receptor genes and the MYH16 masticatory myosin gene occurred after the hominin-chimpanzee divergence but before the divergence of the human and Neandertal/Denisovan lineages. The absence of a functional MYH16 protein may explain our relatively reduced jaw muscles; this gene loss may have followed the adoption of cooking behavior. In contrast, salivary amylase gene (AMY1) duplications were not observed in the Neandertal and Denisovan genomes, suggesting a relatively recent origin for the AMY1 copy number gains that are observed in modern humans. Thus, if earlier hominins were consuming large quantities of starch-rich underground storage organs, as previously hypothesized, then they were likely doing so without the digestive benefits of increased salivary amylase production. Our most surprising result was the observation of a heterozygous mutation in the first codon of the TAS2R38 bitter taste receptor gene in the Neandertal individual, which likely would have resulted in a non-functional protein and inter-individual PTC (phenylthiocarbamide) taste sensitivity variation, as also observed in both humans and chimpanzees.}, }
@article {pmid25556237, year = {2015}, author = {Lin, YL and Pavlidis, P and Karakoc, E and Ajay, J and Gokcumen, O}, title = {The evolution and functional impact of human deletion variants shared with archaic hominin genomes.}, journal = {Molecular biology and evolution}, volume = {32}, number = {4}, pages = {1008-1019}, pmid = {25556237}, issn = {1537-1719}, mesh = {Alleles ; Animals ; *Evolution, Molecular ; Genetic Variation ; *Genome ; Hominidae/*genetics ; Humans ; *Sequence Deletion ; }, abstract = {Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human-Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn's disease. Our analyses suggest that these "exonic" deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes.}, }
@article {pmid25509854, year = {2013}, author = {Maliarchuk, BA}, title = {[Mutation process in the protein-coding genes of human mitochondrial genome in context of evolution of the genus].}, journal = {Molekuliarnaia biologiia}, volume = {47}, number = {6}, pages = {927-933}, pmid = {25509854}, issn = {0026-8984}, mesh = {Animals ; DNA, Mitochondrial/genetics ; *Evolution, Molecular ; Genome, Human/*genetics ; *Genome, Mitochondrial ; Humans ; Mutation/*genetics ; Neanderthals ; Polymorphism, Genetic ; }, abstract = {The human mitochondrial genome, although it has a small size, is characterized by high level of variation, non-uniformly distributed in groups of nucleotide positions that differ in the degree of variability. Considering the mutation process in human mtDNA relative to the mitochondrial genomes of the genus Homo-neandertals, denisova hominin and other primate species, it appears that more than half (56.5%) variable positions in the human mtDNA protein-coding genes are characterized by back (reverse) mutations to the pre-H. sapiens state of mitochondrial genome. It has been found that hypervariable nucleotide positions show a minimal proportion of specific to H. sapiens mutations, and, conversely, a high proportion of mutations (both nucleotide and amino acid substitutions), leading to the loss of Homo-specific variants of polymorphisms. Most often, polymorphisms specific to H. sapiens arise in result of single forward mutations and disappear mainly due to multiple back mutations, including those in the mutational "hotspots".}, }
@article {pmid25487326, year = {2015}, author = {Sánchez-Quinto, F and Lalueza-Fox, C}, title = {Almost 20 years of Neanderthal palaeogenetics: adaptation, admixture, diversity, demography and extinction.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {370}, number = {1660}, pages = {20130374}, pmid = {25487326}, issn = {1471-2970}, mesh = {Adaptation, Biological/*genetics ; Animals ; *Biological Evolution ; DNA, Mitochondrial/genetics ; *Extinction, Biological ; Fossils ; *Genetic Variation ; Genetics, Population ; Genomics/*methods/trends ; *Hybridization, Genetic ; Neanderthals/*genetics ; Population Dynamics ; }, abstract = {Nearly two decades since the first retrieval of Neanderthal DNA, recent advances in next-generation sequencing technologies have allowed the generation of high-coverage genomes from two archaic hominins, a Neanderthal and a Denisovan, as well as a complete mitochondrial genome from remains which probably represent early members of the Neanderthal lineage. This genomic information, coupled with diversity exome data from several Neanderthal specimens is shedding new light on evolutionary processes such as the genetic basis of Neanderthal and modern human-specific adaptations-including morphological and behavioural traits-as well as the extent and nature of the admixture events between them. An emerging picture is that Neanderthals had a long-term small population size, lived in small and isolated groups and probably practised inbreeding at times. Deleterious genetic effects associated with these demographic factors could have played a role in their extinction. The analysis of DNA from further remains making use of new large-scale hybridization-capture-based methods as well as of new approaches to discriminate contaminant DNA sequences will provide genetic information in spatial and temporal scales that could help clarify the Neanderthal's-and our very own-evolutionary history.}, }
@article {pmid25447821, year = {2015}, author = {Adel, S and Kakularam, KR and Horn, T and Reddanna, P and Kuhn, H and Heydeck, D}, title = {Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens.}, journal = {Archives of biochemistry and biophysics}, volume = {565}, number = {}, pages = {17-24}, doi = {10.1016/j.abb.2014.10.012}, pmid = {25447821}, issn = {1096-0384}, mesh = {Animals ; Databases, Genetic ; Genome, Human/*physiology ; Humans ; Leukotrienes/*genetics/metabolism ; Lipoxygenases/*genetics/metabolism ; Neanderthals/*genetics/metabolism ; Signal Transduction/*genetics ; Species Specificity ; }, abstract = {Mammalian lipoxygenases (LOXs) have been implicated in cell differentiation and in the biosynthesis of pro- and anti-inflammatory lipid mediators. The initial draft sequence of the Homo neanderthalensis genome (coverage of 1.3-fold) suggested defective leukotriene signaling in this archaic human subspecies since expression of essential proteins appeared to be corrupted. Meanwhile high quality genomic sequence data became available for two extinct human subspecies (H. neanderthalensis, Homo denisovan) and completion of the human 1000 genome project provided a comprehensive database characterizing the genetic variability of the human genome. For this study we extracted the nucleotide sequences of selected eicosanoid relevant genes (ALOX5, ALOX15, ALOX12, ALOX15B, ALOX12B, ALOXE3, COX1, COX2, LTA4H, LTC4S, ALOX5AP, CYSLTR1, CYSLTR2, BLTR1, BLTR2) from the corresponding databases. Comparison of the deduced amino acid sequences in connection with site-directed mutagenesis studies and structural modeling suggested that the major enzymes and receptors of leukotriene signaling as well as the two cyclooxygenase isoforms were fully functional in these two extinct human subspecies.}, }
@article {pmid25393762, year = {2014}, author = {Lesecque, Y and Glémin, S and Lartillot, N and Mouchiroud, D and Duret, L}, title = {The red queen model of recombination hotspots evolution in the light of archaic and modern human genomes.}, journal = {PLoS genetics}, volume = {10}, number = {11}, pages = {e1004790}, pmid = {25393762}, issn = {1553-7404}, mesh = {Animals ; Chromosomes/genetics ; *Crossing Over, Genetic ; DNA-Binding Proteins ; *Evolution, Molecular ; Gene Conversion ; Genome, Human ; Histone-Lysine N-Methyltransferase/*genetics ; Humans ; Meiosis/genetics ; Pan troglodytes ; *Recombination, Genetic ; }, abstract = {Recombination is an essential process in eukaryotes, which increases diversity by disrupting genetic linkage between loci and ensures the proper segregation of chromosomes during meiosis. In the human genome, recombination events are clustered in hotspots, whose location is determined by the PRDM9 protein. There is evidence that the location of hotspots evolves rapidly, as a consequence of changes in PRDM9 DNA-binding domain. However, the reasons for these changes and the rate at which they occur are not known. In this study, we investigated the evolution of human hotspot loci and of PRDM9 target motifs, both in modern and archaic human lineages (Denisovan) to quantify the dynamic of hotspot turnover during the recent period of human evolution. We show that present-day human hotspots are young: they have been active only during the last 10% of the time since the divergence from chimpanzee, starting to be operating shortly before the split between Denisovans and modern humans. Surprisingly, however, our analyses indicate that Denisovan recombination hotspots did not overlap with modern human ones, despite sharing similar PRDM9 target motifs. We further show that high-affinity PRDM9 target motifs are subject to a strong self-destructive drive, known as biased gene conversion (BGC), which should lead to the loss of the majority of them in the next 3 MYR. This depletion of PRDM9 genomic targets is expected to decrease fitness, and thereby to favor new PRDM9 alleles binding different motifs. Our refined estimates of the age and life expectancy of human hotspots provide empirical evidence in support of the Red Queen hypothesis of recombination hotspots evolution.}, }
@article {pmid25277105, year = {2014}, author = {Schneider, E and El Hajj, N and Haaf, T}, title = {Epigenetic information from ancient DNA provides new insights into human evolution. Commentary on Gokhman D et al. (2014): Reconstructing the DNA methylation maps of the Neanderthal and the Denisovan. Science 344:523-527.}, journal = {Brain, behavior and evolution}, volume = {84}, number = {3}, pages = {169-171}, doi = {10.1159/000365650}, pmid = {25277105}, issn = {1421-9743}, mesh = {Animals ; *DNA Methylation ; *Epigenesis, Genetic ; *Evolution, Molecular ; *Genome, Human ; Humans ; Neanderthals/*genetics ; }, }
@article {pmid25249249, year = {2015}, author = {Kang, L and Michalak, P}, title = {The evolution of cancer-related genes in hominoids.}, journal = {Journal of molecular evolution}, volume = {80}, number = {1}, pages = {37-41}, pmid = {25249249}, issn = {1432-1432}, mesh = {Animals ; Base Sequence ; *Evolution, Molecular ; *Genes, Tumor Suppressor ; Hominidae/*genetics ; Humans ; *Oncogenes ; Sequence Homology, Nucleic Acid ; }, abstract = {The evolution of cancer suppression is essential for the maintenance of multicellularity. The lack of correlation between body size and cancer risk across species, known as Peto's paradox, suggests that genetic variation in cancer resistance is sufficient to compensate for increases of cell numbers in bigger animals. To assess evolutionary dynamics of cancer-related genes, we analyzed Ka, Ks,and Ka/Ks values in 120 oncogenes and tumor suppressor genes (TSG) among seven hominoid species, including two extinct species, Neanderthal and Denisovan. Ka/Ks of tumor suppressor genes tended to be higher relative to that of oncogenes, consistent with relaxed purifying selection acting on the former. Ka/Ks values were positively correlated with TSG scores, but negatively correlated with oncogene scores, suggesting opposing selection pressures operating on the two groups of cancer-related genes. Additionally, we found 108 species-divergent substitutions that were prevalent germline genotypes in some species but in humans appeared only as somatic cancerous mutations. Better understanding the resistance to cancer may lead to new methods of cancer prevention in humans.}, }
@article {pmid25172957, year = {2014}, author = {Racimo, F and Kuhlwilm, M and Slatkin, M}, title = {A test for ancient selective sweeps and an application to candidate sites in modern humans.}, journal = {Molecular biology and evolution}, volume = {31}, number = {12}, pages = {3344-3358}, pmid = {25172957}, issn = {1537-1719}, support = {R01 GM040282/GM/NIGMS NIH HHS/United States ; R01-GM40282/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Bayes Theorem ; *Evolution, Molecular ; Genome, Human ; Humans ; *Models, Genetic ; Neanderthals/genetics ; Polymorphism, Single Nucleotide ; Selection, Genetic ; }, abstract = {We introduce a new method to detect ancient selective sweeps centered on a candidate site. We explored different patterns produced by sweeps around a fixed beneficial mutation, and found that a particularly informative statistic measures the consistency between majority haplotypes near the mutation and genotypic data from a closely related population. We incorporated this statistic into an approximate Bayesian computation (ABC) method that tests for sweeps at a candidate site. We applied this method to simulated data and show that it has some power to detect sweeps that occurred more than 10,000 generations in the past. We also applied it to 1,000 Genomes and Complete Genomics data combined with high-coverage Denisovan and Neanderthal genomes to test for sweeps in modern humans since the separation from the Neanderthal-Denisovan ancestor. We tested sites at which humans are fixed for the derived (i.e., nonchimpanzee allele) whereas the Neanderthal and Denisovan genomes are homozygous for the ancestral allele. We observe only weak differences in statistics indicative of selection between functional categories. When we compare patterns of scaled diversity or use our ABC approach, we fail to find a significant difference in signals of classic selective sweeps between regions surrounding nonsynonymous and synonymous changes, but we detect a slight enrichment for reduced scaled diversity around splice site changes. We also present a list of candidate sites that show high probability of having undergone a classic sweep in the modern human lineage since the split from Neanderthals and Denisovans.}, }
@article {pmid25142605, year = {2014}, author = {Lee, A and Huntley, D and Aiewsakun, P and Kanda, RK and Lynn, C and Tristem, M}, title = {Novel Denisovan and Neanderthal retroviruses.}, journal = {Journal of virology}, volume = {88}, number = {21}, pages = {12907-12909}, pmid = {25142605}, issn = {1098-5514}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Endogenous Retroviruses/classification/*genetics/*isolation &amp; purification ; Female ; Fossils/*virology ; Genome ; Hominidae/*virology ; }, abstract = {Following the recent availability of high-coverage genomes for Denisovan and Neanderthal hominids, we conducted a screen for endogenized retroviruses, identifying six novel, previously unreported HERV-K(HML2) elements (HERV-K is human endogenous retrovirus K). These elements are absent from the human genome (hg38) and appear to be unique to archaic hominids. These findings provide further evidence supporting the recent activity of the HERV-K(HML2) group, which has been implicated in human disease. They will also provide insights into the evolution of archaic hominids.}, }
@article {pmid25043035, year = {2014}, author = {Huerta-Sánchez, E and Jin, X and Asan,  and Bianba, Z and Peter, BM and Vinckenbosch, N and Liang, Y and Yi, X and He, M and Somel, M and Ni, P and Wang, B and Ou, X and Huasang,  and Luosang, J and Cuo, ZX and Li, K and Gao, G and Yin, Y and Wang, W and Zhang, X and Xu, X and Yang, H and Li, Y and Wang, J and Wang, J and Nielsen, R}, title = {Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.}, journal = {Nature}, volume = {512}, number = {7513}, pages = {194-197}, pmid = {25043035}, issn = {1476-4687}, support = {R01 HG003229/HG/NHGRI NIH HHS/United States ; R01HG003229-08S2/HG/NHGRI NIH HHS/United States ; R01HG003229/HG/NHGRI NIH HHS/United States ; }, mesh = {Adaptation, Physiological/*genetics ; *Altitude ; Animals ; Asian People/genetics ; Basic Helix-Loop-Helix Transcription Factors/genetics ; DNA/*genetics ; Gene Frequency ; *Genetic Variation ; Haplotypes ; Hominidae/*genetics ; Humans ; Polymorphism, Single Nucleotide ; Tibet ; }, abstract = {As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.}, }
@article {pmid25001002, year = {2014}, author = {Schwartz, JJ and Roach, DJ and Thomas, JH and Shendure, J}, title = {Primate evolution of the recombination regulator PRDM9.}, journal = {Nature communications}, volume = {5}, number = {}, pages = {4370}, pmid = {25001002}, issn = {2041-1723}, support = {R01 HG006283/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; HG006283/HG/NHGRI NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; *Evolution, Molecular ; Genetic Variation ; Histone-Lysine N-Methyltransferase/*genetics ; Molecular Sequence Data ; Primates/*genetics ; Selection, Genetic ; Sequence Analysis, DNA ; Zinc Fingers ; }, abstract = {The PRDM9 gene encodes a protein with a highly variable tandem-repeat zinc finger (ZF) DNA-binding domain that plays a key role in determining sequence-specific hotspots of meiotic recombination genome wide. Here we survey the diversity of the PRDM9 ZF domain by sequencing this region in 64 primates from 18 species, revealing 68 unique alleles across all groups. We report ubiquitous positive selection at nucleotide positions corresponding to DNA contact residues and the expansion of ZFs within clades, which confirms the rapid evolution of the ZF domain throughout the primate lineage. Alignment of Neandertal and Denisovan sequences suggests that PRDM9 in archaic hominins was closely related to present-day human alleles that are rare and specific to African populations. In the context of its role in reproduction, our results are consistent with variation in PRDM9 contributing to speciation events in primates.}, }
@article {pmid24832686, year = {2014}, author = {Wong, LP and Lai, JK and Saw, WY and Ong, RT and Cheng, AY and Pillai, NE and Liu, X and Xu, W and Chen, P and Foo, JN and Tan, LW and Koo, SH and Soong, R and Wenk, MR and Lim, WY and Khor, CC and Little, P and Chia, KS and Teo, YY}, title = {Insights into the genetic structure and diversity of 38 South Asian Indians from deep whole-genome sequencing.}, journal = {PLoS genetics}, volume = {10}, number = {5}, pages = {e1004377}, pmid = {24832686}, issn = {1553-7404}, mesh = {*Genetic Variation ; *Genetics, Population ; *Genome, Human ; Haplotypes ; Humans ; India ; Polymorphism, Single Nucleotide ; }, abstract = {South Asia possesses a significant amount of genetic diversity due to considerable intergroup differences in culture and language. There have been numerous reports on the genetic structure of Asian Indians, although these have mostly relied on genotyping microarrays or targeted sequencing of the mitochondria and Y chromosomes. Asian Indians in Singapore are primarily descendants of immigrants from Dravidian-language-speaking states in south India, and 38 individuals from the general population underwent deep whole-genome sequencing with a target coverage of 30X as part of the Singapore Sequencing Indian Project (SSIP). The genetic structure and diversity of these samples were compared against samples from the Singapore Sequencing Malay Project and populations in Phase 1 of the 1,000 Genomes Project (1 KGP). SSIP samples exhibited greater intra-population genetic diversity and possessed higher heterozygous-to-homozygous genotype ratio than other Asian populations. When compared against a panel of well-defined Asian Indians, the genetic makeup of the SSIP samples was closely related to South Indians. However, even though the SSIP samples clustered distinctly from the Europeans in the global population structure analysis with autosomal SNPs, eight samples were assigned to mitochondrial haplogroups that were predominantly present in Europeans and possessed higher European admixture than the remaining samples. An analysis of the relative relatedness between SSIP with two archaic hominins (Denisovan, Neanderthal) identified higher ancient admixture in East Asian populations than in SSIP. The data resource for these samples is publicly available and is expected to serve as a valuable complement to the South Asian samples in Phase 3 of 1 KGP.}, }
@article {pmid24786081, year = {2014}, author = {Gokhman, D and Lavi, E and Prüfer, K and Fraga, MF and Riancho, JA and Kelso, J and Pääbo, S and Meshorer, E and Carmel, L}, title = {Reconstructing the DNA methylation maps of the Neandertal and the Denisovan.}, journal = {Science (New York, N.Y.)}, volume = {344}, number = {6183}, pages = {523-527}, doi = {10.1126/science.1250368}, pmid = {24786081}, issn = {1095-9203}, mesh = {Animals ; *DNA Methylation ; *Epigenesis, Genetic ; *Evolution, Molecular ; *Genome, Human ; Humans ; Neanderthals/*genetics ; }, abstract = {Ancient DNA sequencing has recently provided high-coverage archaic human genomes. However, the evolution of epigenetic regulation along the human lineage remains largely unexplored. We reconstructed the full DNA methylation maps of the Neandertal and the Denisovan by harnessing the natural degradation processes of methylated and unmethylated cytosines. Comparing these ancient methylation maps to those of present-day humans, we identified ~2000 differentially methylated regions (DMRs). Particularly, we found substantial methylation changes in the HOXD cluster that may explain anatomical differences between archaic and present-day humans. Additionally, we found that DMRs are significantly more likely to be associated with diseases. This study provides insight into the epigenetic landscape of our closest evolutionary relatives and opens a window to explore the epigenomes of extinct species.}, }
@article {pmid24667833, year = {2014}, author = {Sazzini, M and Schiavo, G and De Fanti, S and Martelli, PL and Casadio, R and Luiselli, D}, title = {Searching for signatures of cold adaptations in modern and archaic humans: hints from the brown adipose tissue genes.}, journal = {Heredity}, volume = {113}, number = {3}, pages = {259-267}, pmid = {24667833}, issn = {1365-2540}, mesh = {*Adaptation, Physiological/genetics ; *Adipose Tissue, Brown/metabolism ; Alleles ; Biological Evolution ; Climate ; Cold Temperature ; Fossils ; *Genome/genetics ; *Thermogenesis/genetics ; Humans ; }, abstract = {Adaptation to low temperatures has been reasonably developed in the human species during the colonization of the Eurasian landmass subsequent to Out of Africa migrations of anatomically modern humans. In addition to morphological and cultural changes, also metabolic ones are supposed to have favored human isolation from cold and body heat production and this can be hypothesized also for most Neandertal and at least for some Denisovan populations, which lived in geographical areas that strongly experienced the last glacial period. Modulation of non-shivering thermogenesis, for which adipocytes belonging to the brown adipose tissue are the most specialized cells, might have driven these metabolic adaptations. To perform an exploratory analysis aimed at looking into this hypothesis, variation at 28 genes involved in such functional pathway was investigated in modern populations from different climate zones, as well as in Neandertal and Denisovan genomes. Patterns of variation at the LEPR gene, strongly related to increased heat dissipation by mitochondria, appeared to have been shaped by positive selection in modern East Asians, but not in Europeans. Moreover, a single potentially cold-adapted LEPR allele, different from the supposed adaptive one identified in Homo sapiens, was found also in Neandertal and Denisovan genomes. These findings suggest that independent mechanisms for cold adaptations might have been developed in different non-African human groups, as well as that the evolution of possible enhanced thermal efficiency in Neandertals and in some Denisovan populations has plausibly entailed significant changes also in other functional pathways than in the examined one.}, }
@article {pmid24599118, year = {2014}, author = {Mariotti, M and Smith, TF and Sudmant, PH and Goldberger, G}, title = {Pseudogenization of testis-specific Lfg5 predates human/Neanderthal divergence.}, journal = {Journal of human genetics}, volume = {59}, number = {5}, pages = {288-291}, pmid = {24599118}, issn = {1435-232X}, mesh = {Animals ; *Evolution, Molecular ; Exons ; Genomics ; Humans ; Introns ; Male ; Multigene Family ; Mutation ; Neanderthals/*genetics ; Organ Specificity/*genetics ; Phylogeny ; Testis/*metabolism ; }, abstract = {Recent reviews discussed the critical roles of apoptosis in human spermatogenesis and infertility. These reviews highlight the FasL-induced caspase cascade in apoptosis lending importance to our discovery of the pseudogene status of the Lfg5 gene in modern humans, Neanderthal and the Denisovan. This gene is a member of the ancient and highly conserved apoptosis Lifeguard family. This pseudogenization is the result of a premature stop codon at the 3'-end of exon 8 not found in any other ortholog. With the current exception of the domesticated bovine and buffalo, Lfg5's expression in mammals is testis-specific. A full analysis of this gene, its phylogenetic context and its recent hominin changes suggest its inactivation was likely under selection in human evolution.}, }
@article {pmid24392153, year = {2014}, author = {Hughes, GM and Teeling, EC and Higgins, DG}, title = {Loss of olfactory receptor function in hominin evolution.}, journal = {PloS one}, volume = {9}, number = {1}, pages = {e84714}, pmid = {24392153}, issn = {1932-6203}, mesh = {Amino Acid Sequence ; Animals ; *Biological Evolution ; Databases, Nucleic Acid ; Evolution, Molecular ; Genome ; Genomics ; Hominidae/*genetics ; Humans ; Molecular Sequence Data ; Multigene Family ; Olfactory Receptor Neurons/*metabolism ; Phylogeny ; Receptors, Odorant/chemistry/classification/*genetics ; Sequence Alignment ; }, abstract = {The mammalian sense of smell is governed by the largest gene family, which encodes the olfactory receptors (ORs). The gain and loss of OR genes is typically correlated with adaptations to various ecological niches. Modern humans have 853 OR genes but 55% of these have lost their function. Here we show evidence of additional OR loss of function in the Neanderthal and Denisovan hominin genomes using comparative genomic methodologies. Ten Neanderthal and 8 Denisovan ORs show evidence of loss of function that differ from the reference modern human OR genome. Some of these losses are also present in a subset of modern humans, while some are unique to each lineage. Morphological changes in the cranium of Neanderthals suggest different sensory arrangements to that of modern humans. We identify differences in functional olfactory receptor genes among modern humans, Neanderthals and Denisovans, suggesting varied loss of function across all three taxa and we highlight the utility of using genomic information to elucidate the sensory niches of extinct species.}, }
@article {pmid24367647, year = {2013}, author = {Reno, PL and McLean, CY and Hines, JE and Capellini, TD and Bejerano, G and Kingsley, DM}, title = {A penile spine/vibrissa enhancer sequence is missing in modern and extinct humans but is retained in multiple primates with penile spines and sensory vibrissae.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e84258}, pmid = {24367647}, issn = {1932-6203}, support = {RR016483/RR/NCRR NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; RR014491/RR/NCRR NIH HHS/United States ; U42 RR015087/RR/NCRR NIH HHS/United States ; C06 RR016483/RR/NCRR NIH HHS/United States ; C06 RR014491/RR/NCRR NIH HHS/United States ; P50 HG002568/HG/NHGRI NIH HHS/United States ; 5P50HG2568/HG/NHGRI NIH HHS/United States ; RR015087/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Enhancer Elements, Genetic/*genetics ; *Extinction, Biological ; Genome, Human/genetics ; Humans ; Male ; Molecular Sequence Data ; Penis/*metabolism ; Primates/*genetics ; Receptors, Androgen/*genetics ; Sequence Analysis ; Somatosensory Cortex/physiology ; Species Specificity ; Vibrissae/*metabolism/physiology ; }, abstract = {Previous studies show that humans have a large genomic deletion downstream of the Androgen Receptor gene that eliminates an ancestral mammalian regulatory enhancer that drives expression in developing penile spines and sensory vibrissae. Here we use a combination of large-scale sequence analysis and PCR amplification to demonstrate that the penile spine/vibrissa enhancer is missing in all humans surveyed and in the Neandertal and Denisovan genomes, but is present in DNA samples of chimpanzees and bonobos, as well as in multiple other great apes and primates that maintain some form of penile integumentary appendage and facial vibrissae. These results further strengthen the association between the presence of the penile spine/vibrissa enhancer and the presence of penile spines and macro- or micro- vibrissae in non-human primates as well as show that loss of the enhancer is both a distinctive and characteristic feature of the human lineage.}, }
@article {pmid24336922, year = {2014}, author = {Ding, Q and Hu, Y and Xu, S and Wang, J and Jin, L}, title = {Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in East Asians.}, journal = {Molecular biology and evolution}, volume = {31}, number = {3}, pages = {683-695}, doi = {10.1093/molbev/mst260}, pmid = {24336922}, issn = {1537-1719}, mesh = {Adaptation, Physiological/genetics ; Alleles ; Animals ; Asian People/*genetics ; Chromosomes, Human, Pair 3/*genetics ; Asia, Eastern ; Genetic Variation ; Geography ; Haplotypes/genetics ; Humans ; Linkage Disequilibrium/genetics ; Models, Genetic ; Neanderthals/*genetics ; Pan troglodytes/genetics ; Phylogeny ; Polymorphism, Single Nucleotide/genetics ; Recombination, Genetic/genetics ; *Selection, Genetic ; Time Factors ; }, abstract = {Studies of the Neanderthal and Denisovan genomes demonstrate archaic hominin introgression in Eurasians. Here, we present evidence of Neanderthal introgression within the chromosome 3p21.31 region, occurring with a high frequency in East Asians (ranging from 49.4% to 66.5%) and at a low frequency in Europeans. We also detected a signal of strong positive selection in this region only in East Asians. Our data indicate that likely candidate targets of selection include rs12488302-T and its associated alleles--among which four are nonsynonymous, including rs35455589-G in HYAL2, a gene related to the cellular response to ultraviolet-B irradiation. Furthermore, suggestive evidence supports latitude-dependent selection, implicating a role of ultraviolet-B. Interestingly, the distribution of rs35455589-G suggests that this allele was lost during the exodus of ancestors of modern Eurasians from Africa and reintroduced to Eurasians from Neanderthals.}, }
@article {pmid24262833, year = {2013}, author = {Marchi, E and Kanapin, A and Byott, M and Magiorkinis, G and Belshaw, R}, title = {Neanderthal and Denisovan retroviruses in modern humans.}, journal = {Current biology : CB}, volume = {23}, number = {22}, pages = {R994-R995}, pmid = {24262833}, issn = {1879-0445}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/K010565/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Neanderthals/*genetics ; Retroviridae/*genetics ; }, abstract = {In the June 5th 2012 issue of Current Biology, Agoni et al. reported finding 14 endogenous retrovirus (ERV) loci in the genome sequences of Neanderthal and/or Denisovan fossils (both ∼40,000 years old) that are not found in the human reference genome sequence. The authors concluded that these retroviruses were infecting the germline of these archaic hominins at or subsequent to their divergence from modern humans (∼400,000 years ago). However, in our search for unfixed ERVs in the modern human population, we have found most of these loci. We explain this apparent contradiction using population genetic theory and suggest that it illustrates an important phenomenon for the study of transposable elements such as ERVs.}, }
@article {pmid24174545, year = {2013}, author = {Hochreiter, S}, title = {HapFABIA: identification of very short segments of identity by descent characterized by rare variants in large sequencing data.}, journal = {Nucleic acids research}, volume = {41}, number = {22}, pages = {e202}, pmid = {24174545}, issn = {1362-4962}, mesh = {*Genetic Variation ; Genomics ; Genotyping Techniques ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Inheritance Patterns ; Sequence Analysis, DNA/*methods ; }, abstract = {Identity by descent (IBD) can be reliably detected for long shared DNA segments, which are found in related individuals. However, many studies contain cohorts of unrelated individuals that share only short IBD segments. New sequencing technologies facilitate identification of short IBD segments through rare variants, which convey more information on IBD than common variants. Current IBD detection methods, however, are not designed to use rare variants for the detection of short IBD segments. Short IBD segments reveal genetic structures at high resolution. Therefore, they can help to improve imputation and phasing, to increase genotyping accuracy for low-coverage sequencing and to increase the power of association studies. Since short IBD segments are further assumed to be old, they can shed light on the evolutionary history of humans. We propose HapFABIA, a computational method that applies biclustering to identify very short IBD segments characterized by rare variants. HapFABIA is designed to detect short IBD segments in genotype data that were obtained from next-generation sequencing, but can also be applied to DNA microarray data. Especially in next-generation sequencing data, HapFABIA exploits rare variants for IBD detection. HapFABIA significantly outperformed competing algorithms at detecting short IBD segments on artificial and simulated data with rare variants. HapFABIA identified 160 588 different short IBD segments characterized by rare variants with a median length of 23 kb (mean 24 kb) in data for chromosome 1 of the 1000 Genomes Project. These short IBD segments contain 752 000 single nucleotide variants (SNVs), which account for 39% of the rare variants and 23.5% of all variants. The vast majority-152 000 IBD segments-are shared by Africans, while only 19 000 and 11 000 are shared by Europeans and Asians, respectively. IBD segments that match the Denisova or the Neandertal genome are found significantly more often in Asians and Europeans but also, in some cases exclusively, in Africans. The lengths of IBD segments and their sharing between continental populations indicate that many short IBD segments from chromosome 1 existed before humans migrated out of Africa. Thus, rare variants that tag these short IBD segments predate human migration from Africa. The software package HapFABIA is available from Bioconductor. All data sets, result files and programs for data simulation, preprocessing and evaluation are supplied at http://www.bioinf.jku.at/research/short-IBD.}, }
@article {pmid23980394, year = {2013}, author = {Ovchinnikov, IV}, title = {Hominin evolution and gene flow in the Pleistocene Africa.}, journal = {Anthropologischer Anzeiger; Bericht uber die biologisch-anthropologische Literatur}, volume = {70}, number = {2}, pages = {221-227}, doi = {10.1127/0003-5548/2013/0313}, pmid = {23980394}, issn = {0003-5548}, mesh = {Africa ; Animals ; Anthropology, Physical ; DNA, Mitochondrial/genetics ; *Evolution, Molecular ; Fossils ; *Gene Flow ; Genome, Mitochondrial/genetics ; Hominidae/*genetics ; Humans ; Phylogeny ; }, abstract = {Africa demonstrates a complex process of the hominin evolution with a series of adaptive radiations during several millions of years that led to diverse morphological forms. Recently, Hammer et al. (2011) and Harvati et al. (2011) provided integrated morphological and genetic evidence of interbreeding between modern humans and unknown archaic hominins in Africa as recently as 35,000 years ago. However, a genetic evidence of hybridization between hominin lineages during the Lower and Middle Pleistocene epochs is unknown and the direct retrieval of DNA from extinct lineages of African hominins remains elusive. The availability of both nuclear and mitochondrial genome sequences from modern humans, Neanderthals, and Denisovans allows collecting nuclear DNA sequences of mitochondrial origin (numts) inserted into the nuclear genome of the ancestral hominin lineages and drawing conclusions about the hominin evolution in the remote past. The mtDNA and numt analysis uncovered a deep division of mtDNA lineages that existed in African hominins in the Middle Pleistocene. The first cluster included the human and Neanderthal-like mtDNA sequences while the second consisted of DNA sequences that are known today as mtAncestor-1, a nuclear fossil of the mtDNA, and the Denisova mtDNA isolated from a bone and a tooth found in southern Siberia. The two groups initially diverged 610,000-1,110,000 years ago. Approximately 220,000 years after the primary split, the Denisova - mtAncestor-1 mtDNA lineages mixed with the mtDNA pool of an ancestral population of Neanderthals and modern humans. This admixture after the profound division is demonstrated by the transposition of the Denisova-like mtDNA sequence into the nuclear genome of an ancestor of Neanderthals and modern humans. This finding suggests the matrilineal genetic structure among the Middle Pleistocene hominins as well as the existence of gene flow between African hominin lineages. Through paleogenomic analyses, it is impossible to exclude the theory that population structure and gene flow in African hominins influenced the admixture pattern observed in the nuclear genomes of non-Africans.}, }
@article {pmid23959642, year = {2012}, author = {Setó-Salvia, N and Sánchez-Quinto, F and Carbonell, E and Lorenzo, C and Comas, D and Clarimón, J}, title = {Using the neanderthal and denisova genetic data to understand the common MAPT 17q21 inversion in modern humans.}, journal = {Human biology}, volume = {84}, number = {6}, pages = {633-640}, doi = {10.3378/027.084.0605}, pmid = {23959642}, issn = {1534-6617}, mesh = {Alleles ; Animals ; Biological Evolution ; *Chromosome Inversion ; Genome, Human ; Haplotypes ; Hominidae/*genetics ; Humans ; Linkage Disequilibrium ; Neanderthals/genetics ; Polymorphism, Genetic ; tau Proteins/*genetics ; }, abstract = {The polymorphic inversion on 17q21, that includes the MAPT gene, represents a unique locus in the human genome characterized by a large region with strong linkage disequilibrium. Two distinct haplotypes, H1 and H2, exist in modern humans, and H1 has been unequivocally related to several neurodegenerative disorders. Recent data indicate that recurrent inversions of this genomic region have occurred through primate evolution, with the H2 haplotype being the ancestral state. Neandertals harbored the H1 haplotype; however, until now, no data were available for the Denisova hominin. Neandertals and Denisovans are sister groups that share a common ancestor with modern humans. We analyzed the MAPT sequence and assessed the differences between modern humans, Neandertals, Denisovans, and great apes. Our analysis indicated that the Denisova hominin carried the H1 haplotype, and the Neandertal and Denisova common ancestor probably shared the same subhaplotype (H1j). We also found 68 intronic variants within the MAPT gene, 23 exclusive to Denisova hominin, 6 limited to Neandertals, and 24 exclusive to present-day humans. Our results reinforce previous data; this suggests that the 17q21 inversion arose within the modern human lineage. The data also indicate that archaic hominins that coexisted in Eurasia probably shared the same MAPT subhaplotype, and this can be found in almost 2% of chromosomes from European ancestry.}, }
@article {pmid23906376, year = {2013}, author = {Hedrick, PW}, title = {Adaptive introgression in animals: examples and comparison to new mutation and standing variation as sources of adaptive variation.}, journal = {Molecular ecology}, volume = {22}, number = {18}, pages = {4606-4618}, doi = {10.1111/mec.12415}, pmid = {23906376}, issn = {1365-294X}, mesh = {Adaptation, Biological/*genetics ; Animals ; *Evolution, Molecular ; Genetic Variation ; Humans ; Models, Genetic ; Mutation ; *Selection, Genetic ; }, abstract = {Adaptive genetic variation has been thought to originate primarily from either new mutation or standing variation. Another potential source of adaptive variation is adaptive variants from other (donor) species that are introgressed into the (recipient) species, termed adaptive introgression. Here, the various attributes of these three potential sources of adaptive variation are compared. For example, the rate of adaptive change is generally thought to be faster from standing variation, slower from mutation and potentially intermediate from adaptive introgression. Additionally, the higher initial frequency of adaptive variation from standing variation and lower initial frequency from mutation might result in a higher probability of fixation of the adaptive variants for standing variation. Adaptive variation from introgression might have higher initial frequency than new adaptive mutations but lower than that from standing variation, again making the impact of adaptive introgression variation potentially intermediate. Adaptive introgressive variants might have multiple changes within a gene and affect multiple loci, an advantage also potentially found for adaptive standing variation but not for new adaptive mutants. The processes that might produce a common variant in two taxa, convergence, trans-species polymorphism from incomplete lineage sorting or from balancing selection and adaptive introgression, are also compared. Finally, potential examples of adaptive introgression in animals, including balancing selection for multiple alleles for major histocompatibility complex (MHC), S and csd genes, pesticide resistance in mice, black colour in wolves and white colour in coyotes, Neanderthal or Denisovan ancestry in humans, mimicry genes in Heliconius butterflies, beak traits in Darwin's finches, yellow skin in chickens and non-native ancestry in an endangered native salamander, are examined.}, }
@article {pmid23872234, year = {2013}, author = {Lowery, RK and Uribe, G and Jimenez, EB and Weiss, MA and Herrera, KJ and Regueiro, M and Herrera, RJ}, title = {Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.}, journal = {Gene}, volume = {530}, number = {1}, pages = {83-94}, doi = {10.1016/j.gene.2013.06.005}, pmid = {23872234}, issn = {1879-0038}, mesh = {Africa South of the Sahara ; Animals ; DNA, Mitochondrial/genetics ; Europe ; Fossils ; Genetic Drift ; Genetics, Population ; Genome, Human ; Humans ; Neanderthals/*genetics ; Pan troglodytes/genetics ; *Phylogeny ; *Polymorphism, Genetic ; }, abstract = {Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations.}, }
@article {pmid23687020, year = {2013}, author = {Pennisi, E}, title = {Human evolution. More genomes from Denisova Cave show mixing of early human groups.}, journal = {Science (New York, N.Y.)}, volume = {340}, number = {6134}, pages = {799}, doi = {10.1126/science.340.6134.799}, pmid = {23687020}, issn = {1095-9203}, mesh = {Animals ; Anthropology ; *Biological Evolution ; *Caves ; DNA/genetics ; *Genome, Human ; Humans ; Neanderthals/*genetics ; Sequence Analysis, DNA/*methods ; Siberia ; Toe Phalanges ; }, }
@article {pmid23666864, year = {2013}, author = {Elhaik, E and Greenspan, E and Staats, S and Krahn, T and Tyler-Smith, C and Xue, Y and Tofanelli, S and Francalacci, P and Cucca, F and Pagani, L and Jin, L and Li, H and Schurr, TG and Greenspan, B and Spencer Wells, R and , }, title = {The GenoChip: a new tool for genetic anthropology.}, journal = {Genome biology and evolution}, volume = {5}, number = {5}, pages = {1021-1031}, pmid = {23666864}, issn = {1759-6653}, support = {/WT_/Wellcome Trust/United Kingdom ; T32 MH014592/MH/NIMH NIH HHS/United States ; 098051/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Anthropology, Cultural ; DNA, Mitochondrial/*genetics ; Genes, Y-Linked ; History, Ancient ; Human Genome Project ; Human Migration/history ; Humans ; *Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide/*genetics ; }, abstract = {The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project's new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. The GenoChip includes ancestry informative markers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all known Y-chromosome and mtDNA haplogroups. The chip was carefully vetted to avoid inclusion of medically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPs without any known health, medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics.}, }
@article {pmid23657884, year = {2013}, author = {Contreras-Galindo, R and Kaplan, MH and He, S and Contreras-Galindo, AC and Gonzalez-Hernandez, MJ and Kappes, F and Dube, D and Chan, SM and Robinson, D and Meng, F and Dai, M and Gitlin, SD and Chinnaiyan, AM and Omenn, GS and Markovitz, DM}, title = {HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses.}, journal = {Genome research}, volume = {23}, number = {9}, pages = {1505-1513}, pmid = {23657884}, issn = {1549-5469}, support = {R01 AI062248/AI/NIAID NIH HHS/United States ; T32 AI007528/AI/NIAID NIH HHS/United States ; 1F31CA150523-01/CA/NCI NIH HHS/United States ; 5T32AI007528-13/AI/NIAID NIH HHS/United States ; UL1RR24986/RR/NCRR NIH HHS/United States ; T32 GM145304/GM/NIGMS NIH HHS/United States ; U54DA021519/DA/NIDA NIH HHS/United States ; F31 CA150523/CA/NCI NIH HHS/United States ; 3R01CA144043-03S1/CA/NCI NIH HHS/United States ; R01AI062248/AI/NIAID NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; U54 DA021519/DA/NIDA NIH HHS/United States ; UL1 RR024986/RR/NCRR NIH HHS/United States ; P30U54ES017885/ES/NIEHS NIH HHS/United States ; R01 CA144043/CA/NCI NIH HHS/United States ; T32 GM007315/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Centromere/genetics/virology ; Chromosomes, Human/genetics/virology ; Endogenous Retroviruses/*genetics ; Evolution, Molecular ; *Genome, Human ; HIV Infections/*genetics ; Hominidae/genetics/virology ; Humans ; Proviruses/*genetics ; *Virus Integration ; tat Gene Products, Human Immunodeficiency Virus/genetics/metabolism ; }, abstract = {Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV-K (HML-2) family is the most recent group of these viruses to have inserted into the genome, and we have detected the activation of HERV-K (HML-2) proviruses in the blood of patients with HIV-1 infection. We report that HIV-1 infection activates expression of a novel HERV-K (HML-2) provirus, termed K111, present in multiple copies in the centromeres of chromosomes throughout the human genome yet not annotated in the most recent human genome assembly. Infection with HIV-1 or stimulation with the HIV-1 Tat protein leads to the activation of K111 proviruses. K111 is present as a single copy in the genome of the chimpanzee, yet K111 is not found in the genomes of other primates. Remarkably, K111 proviruses appear in the genomes of the extinct Neanderthal and Denisovan, while modern humans have at least 100 K111 proviruses spread across the centromeres of 15 chromosomes. Our studies suggest that the progenitor K111 integrated before the Homo-Pan divergence and expanded in copy number during the evolution of hominins, perhaps by recombination. The expansion of K111 provides sequence evidence suggesting that recombination between the centromeres of various chromosomes took place during the evolution of humans. K111 proviruses show significant sequence variations in each individual centromere, which may serve as markers in future efforts to annotate human centromere sequences. Further, this work is an example of the potential to discover previously unknown genomic sequences through the analysis of nucleic acids found in the blood of patients.}, }
@article {pmid23553074, year = {2013}, author = {Khairat, R and Ball, M and Chang, CC and Bianucci, R and Nerlich, AG and Trautmann, M and Ismail, S and Shanab, GM and Karim, AM and Gad, YZ and Pusch, CM}, title = {First insights into the metagenome of Egyptian mummies using next-generation sequencing.}, journal = {Journal of applied genetics}, volume = {54}, number = {3}, pages = {309-325}, pmid = {23553074}, issn = {2190-3883}, mesh = {Base Sequence ; Biopsy ; Egypt, Ancient ; Embalming/history/*methods ; Gene Library ; History, Ancient ; Humans ; *Metagenome ; Molecular Sequence Data ; *Mummies ; Phylogeny ; Plasmodium falciparum/genetics ; Polymerase Chain Reaction/methods ; Sequence Analysis, DNA/methods ; Temperature ; Toxoplasma/genetics ; }, abstract = {We applied, for the first time, next-generation sequencing (NGS) technology on Egyptian mummies. Seven NGS datasets obtained from five randomly selected Third Intermediate to Graeco-Roman Egyptian mummies (806 BC-124AD) and two unearthed pre-contact Bolivian lowland skeletons were generated and characterised. The datasets were contrasted to three recently published NGS datasets obtained from cold-climate regions, i.e. the Saqqaq, the Denisova hominid and the Alpine Iceman. Analysis was done using one million reads of each newly generated or published dataset. Blastn and megablast results were analysed using MEGAN software. Distinct NGS results were replicated by specific and sensitive polymerase chain reaction (PCR) protocols in ancient DNA dedicated laboratories. Here, we provide unambiguous identification of authentic DNA in Egyptian mummies. The NGS datasets showed variable contents of endogenous DNA harboured in tissues. Three of five mummies displayed a human DNA proportion comparable to the human read count of the Saqqaq permafrost-preserved specimen. Furthermore, a metagenomic signature unique to mummies was displayed. By applying a "bacterial fingerprint", discrimination among mummies and other remains from warm areas outside Egypt was possible. Due to the absence of an adequate environment monitoring, a bacterial bloom was identified when analysing different biopsies from the same mummies taken after a lapse of time of 1.5 years. Plant kingdom representation in all mummy datasets was unique and could be partially associated with their use in embalming materials. Finally, NGS data showed the presence of Plasmodium falciparum and Toxoplasma gondii DNA sequences, indicating malaria and toxoplasmosis in these mummies. We demonstrate that endogenous ancient DNA can be extracted from mummies and serve as a proper template for the NGS technique, thus, opening new pathways of investigation for future genome sequencing of ancient Egyptian individuals.}, }
@article {pmid23413113, year = {2012}, author = {Paixão-Côrtes, VR and Viscardi, LH and Salzano, FM and Hünemeier, T and Bortolini, MC}, title = {Homo sapiens, Homo neanderthalensis and the Denisova specimen: New insights on their evolutionary histories using whole-genome comparisons.}, journal = {Genetics and molecular biology}, volume = {35}, number = {4 (suppl)}, pages = {904-911}, pmid = {23413113}, issn = {1415-4757}, abstract = {After a brief review of the most recent findings in the study of human evolution, an extensive comparison of the complete genomes of our nearest relative, the chimpanzee (Pan troglodytes), of extant Homo sapiens, archaic Homo neanderthalensis and the Denisova specimen were made. The focus was on non-synonymous mutations, which consequently had an impact on protein levels and these changes were classified according to degree of effect. A total of 10,447 non-synonymous substitutions were found in which the derived allele is fixed or nearly fixed in humans as compared to chimpanzee. Their most frequent location was on chromosome 21. Their presence was then searched in the two archaic genomes. Mutations in 381 genes would imply radical amino acid changes, with a fraction of these related to olfaction and other important physiological processes. Eight new alleles were identified in the Neanderthal and/or Denisova genetic pools. Four others, possibly affecting cognition, occured both in the sapiens and two other archaic genomes. The selective sweep that gave rise to Homo sapiens could, therefore, have initiated before the modern/archaic human divergence.}, }
@article {pmid23315957, year = {2013}, author = {Mendez, FL and Watkins, JC and Hammer, MF}, title = {Neandertal origin of genetic variation at the cluster of OAS immunity genes.}, journal = {Molecular biology and evolution}, volume = {30}, number = {4}, pages = {798-801}, doi = {10.1093/molbev/mst004}, pmid = {23315957}, issn = {1537-1719}, mesh = {2',5'-Oligoadenylate Synthetase/*genetics ; Animals ; Evolution, Molecular ; Genetic Loci/*immunology ; Genetic Speciation ; Gorilla gorilla/genetics ; Haplotypes ; Humans ; Linkage Disequilibrium ; Models, Genetic ; Multigene Family ; Neanderthals/*genetics ; Pan troglodytes/genetics ; Phylogeography ; *Polymorphism, Single Nucleotide ; }, abstract = {Analyses of ancient DNA from extinct humans reveal signals of at least two independent hybridization events in the history of non-African populations. To date, there are very few examples of specific genetic variants that have been rigorously identified as introgressive. Here, we survey DNA sequence variation in the OAS gene cluster on chromosome 12 and provide strong evidence that a haplotype extending for ~185 kb introgressed from Neandertals. This haplotype is nearly restricted to Eurasians and is estimated to have diverged from the Neandertal sequence ~125 kya. Despite the potential for novel functional variation, the observed frequency of this haplotype is consistent with neutral introgression. This is the second locus in the human genome, after STAT2, carrying distinct haplotypes that appear to have introgressed separately from both Neandertals and Denisova.}, }
@article {pmid23112842, year = {2012}, author = {McIntosh, AM and Bennett, C and Dickson, D and Anestis, SF and Watts, DP and Webster, TH and Fontenot, MB and Bradley, BJ}, title = {The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes).}, journal = {PloS one}, volume = {7}, number = {10}, pages = {e47760}, pmid = {23112842}, issn = {1932-6203}, support = {RR016483/RR/NCRR NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; RR014491/RR/NCRR NIH HHS/United States ; U42 RR015087/RR/NCRR NIH HHS/United States ; RR015087/RR/NCRR NIH HHS/United States ; C06 RR016483/RR/NCRR NIH HHS/United States ; C06 RR014491/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Apolipoproteins E/*genetics ; Genetic Variation ; Hominidae/genetics ; Humans ; Mutation ; Pan troglodytes/*genetics ; Polymorphism, Single Nucleotide ; Sequence Analysis ; }, abstract = {BACKGROUND: The human apolipoprotein E (APOE) gene is polymorphic, with three primary alleles (E2, E3, E4) that differ at two key non-synonymous sites. These alleles are functionally different in how they bind to lipoproteins, and this genetic variation is associated with phenotypic variation for several medical traits, including cholesterol levels, cardiovascular health, Alzheimer's disease risk, and longevity. The relative frequencies of these alleles vary across human populations, and the evolution and maintenance of this diversity is much debated. Previous studies comparing human and chimpanzee APOE sequences found that the chimpanzee sequence is most similar to the human E4 allele, although the resulting chimpanzee protein might function like the protein coded for by the human E3 allele. However, these studies have used sequence data from a single chimpanzee and do not consider whether chimpanzees, like humans, show intra-specific and subspecific variation at this locus.<br><br>To examine potential intraspecific variation, we sequenced the APOE gene of 32 chimpanzees. This sample included 20 captive individuals representing the western subspecies (P. troglodytes verus) and 12 wild individuals representing the eastern subspecies (P. t. schweinfurthii). Variation in our resulting sequences was limited to one non-coding, intronic SNP, which showed fixed differences between the two subspecies. We also compared APOE sequences for all available ape genera and fossil hominins. The bonobo APOE protein is identical to that of the chimpanzee, and the Denisovan APOE exhibits all four human-specific, non-synonymous changes and appears functionally similar to the human E4 allele.<br><br>CONCLUSIONS: We found no coding variation within and between chimpanzee populations, suggesting that the maintenance of functionally diverse APOE polymorphisms is a unique feature of human evolution.}, }
@article {pmid22946817, year = {2012}, author = {Bokma, F and van den Brink, V and Stadler, T}, title = {Unexpectedly many extinct hominins.}, journal = {Evolution; international journal of organic evolution}, volume = {66}, number = {9}, pages = {2969-2974}, doi = {10.1111/j.1558-5646.2012.01660.x}, pmid = {22946817}, issn = {1558-5646}, mesh = {Animals ; *Extinction, Biological ; *Genetic Speciation ; Hominidae/*genetics ; Humans ; Models, Genetic ; }, abstract = {Recent studies indicate that Neanderthal and Denisova hominins may have been separate species, while debate continues on the status of Homo floresiensis. The decade-long debate between "splitters," who recognize over 20 hominin species, and "lumpers," who maintain that all these fossils belong to just a few lineages, illustrates that we do not know how many extinct hominin species to expect. Here, we present probability distributions for the number of speciation events and the number of contemporary species along a branch of a phylogeny. With estimates of hominin speciation and extincton rates, we then show that the expected total number of extinct hominin species is 8, but may be as high as 27. We also show that it is highly unlikely that three very recent species disappeared due to natural, background extinction. This may indicate that human-like remains are too easily considered distinct species. Otherwise, the evidence suggesting that Neanderthal and the Denisova hominin represent distinct species implies a recent wave of extinctions, ostensibly driven by the only survivor, H. sapiens.}, }
@article {pmid22936568, year = {2012}, author = {Meyer, M and Kircher, M and Gansauge, MT and Li, H and Racimo, F and Mallick, S and Schraiber, JG and Jay, F and Prüfer, K and de Filippo, C and Sudmant, PH and Alkan, C and Fu, Q and Do, R and Rohland, N and Tandon, A and Siebauer, M and Green, RE and Bryc, K and Briggs, AW and Stenzel, U and Dabney, J and Shendure, J and Kitzman, J and Hammer, MF and Shunkov, MV and Derevianko, AP and Patterson, N and Andrés, AM and Eichler, EE and Slatkin, M and Reich, D and Kelso, J and Pääbo, S}, title = {A high-coverage genome sequence from an archaic Denisovan individual.}, journal = {Science (New York, N.Y.)}, volume = {338}, number = {6104}, pages = {222-226}, pmid = {22936568}, issn = {1095-9203}, support = {R01-GM40282/GM/NIGMS NIH HHS/United States ; R01 GM100233/GM/NIGMS NIH HHS/United States ; R01 GM040282/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; GM100233/GM/NIGMS NIH HHS/United States ; }, mesh = {Alleles ; Animals ; Base Sequence ; Fossils ; Gene Flow ; Gene Library ; *Genetic Variation ; Genome, Human/*genetics ; *Heterozygote ; Humans ; Molecular Sequence Data ; Neanderthals/*genetics ; Sequence Analysis, DNA ; }, abstract = {We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of "missing evolution" in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.}, }
@article {pmid22883142, year = {2012}, author = {Mendez, FL and Watkins, JC and Hammer, MF}, title = {A haplotype at STAT2 Introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea.}, journal = {American journal of human genetics}, volume = {91}, number = {2}, pages = {265-274}, pmid = {22883142}, issn = {1537-6605}, mesh = {Adaptation, Biological/genetics ; Animals ; Base Sequence ; Evolution, Molecular ; Gene Components ; *Genetics, Population ; Genotype ; Haplotypes/*genetics ; Humans ; Linkage Disequilibrium ; Molecular Sequence Data ; Mutation/genetics ; Neanderthals/*genetics ; Papua New Guinea ; *Phylogeny ; Receptor, ErbB-3/genetics ; STAT2 Transcription Factor/*genetics ; *Selection, Genetic ; Sequence Analysis, DNA ; }, abstract = {Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans. Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations. However, no definitive case of adaptive introgression has yet been described. Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians (but not sub-Saharan Africans) has a sequence that closely matches that of the Neanderthal STAT2. This haplotype, referred to as N, was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals. Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence (~80 thousand years ago) and is found throughout Eurasia at an average frequency of ~5%. Interestingly, N is found in Melanesian populations at ~10-fold higher frequency (~54%) than in Eurasian populations. A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone. Although we are not able to pinpoint the precise target of positive selection, we identify nonsynonymous mutations in ERBB3, ESYT1, and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates.}, }
@article {pmid22677281, year = {2012}, author = {Agoni, L and Golden, A and Guha, C and Lenz, J}, title = {Neandertal and Denisovan retroviruses.}, journal = {Current biology : CB}, volume = {22}, number = {11}, pages = {R437-8}, doi = {10.1016/j.cub.2012.04.049}, pmid = {22677281}, issn = {1879-0445}, support = {EB009040/EB/NIBIB NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Humans ; Molecular Sequence Data ; Neanderthals/*genetics/virology ; Retroviridae/*genetics ; }, }
@article {pmid22665810, year = {2012}, author = {Wang, X and Mitra, N and Secundino, I and Banda, K and Cruz, P and Padler-Karavani, V and Verhagen, A and Reid, C and Lari, M and Rizzi, E and Balsamo, C and Corti, G and De Bellis, G and Longo, L and ,  and Beggs, W and Caramelli, D and Tishkoff, SA and Hayakawa, T and Green, ED and Mullikin, JC and Nizet, V and Bui, J and Varki, A}, title = {Specific inactivation of two immunomodulatory SIGLEC genes during human evolution.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, number = {25}, pages = {9935-9940}, pmid = {22665810}, issn = {1091-6490}, support = {DP1 ES022577/ES/NIEHS NIH HHS/United States ; P01 HL107150/HL/NHLBI NIH HHS/United States ; R01 HD051796/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; *Evolution, Molecular ; Gene Deletion ; *Gene Silencing ; Humans ; Immune System ; Lectins/*genetics ; Primates ; Sialic Acid Binding Immunoglobulin-like Lectins ; }, abstract = {Sialic acid-recognizing Ig-like lectins (Siglecs) are signaling receptors that modulate immune responses, and are targeted for interactions by certain pathogens. We describe two primate Siglecs that were rendered nonfunctional by single genetic events during hominin evolution after our common ancestor with the chimpanzee. SIGLEC13 was deleted by an Alu-mediated recombination event, and a single base pair deletion disrupted the ORF of SIGLEC17. Siglec-13 is expressed on chimpanzee monocytes, innate immune cells that react to bacteria. The human SIGLEC17P pseudogene mRNA is still expressed at high levels in human natural killer cells, which bridge innate and adaptive immune responses. As both resulting pseudogenes are homozygous in all human populations, we resurrected the originally encoded proteins and examined their functions. Chimpanzee Siglec-13 and the resurrected human Siglec-17 recruit a signaling adapter and bind sialic acids. Expression of either Siglec in innate immune cells alters inflammatory cytokine secretion in response to Toll-like receptor-4 stimulation. Both Siglecs can also be engaged by two potentially lethal sialylated bacterial pathogens of newborns and infants, agents with a potential impact on reproductive fitness. Neanderthal and Denisovan genomes show human-like sequences at both loci, corroborating estimates that the initial pseudogenization events occurred in the common ancestral population of these hominins. Both loci also show limited polymorphic diversity, suggesting selection forces predating the origin of modern humans. Taken together, these data suggest that genetic elimination of Siglec-13 and/or Siglec-17 represents signatures of infectious and/or other inflammatory selective processes contributing to population restrictions during hominin origins.}, }
@article {pmid22412940, year = {2012}, author = {Burbano, HA and Green, RE and Maricic, T and Lalueza-Fox, C and de la Rasilla, M and Rosas, A and Kelso, J and Pollard, KS and Lachmann, M and Pääbo, S}, title = {Analysis of human accelerated DNA regions using archaic hominin genomes.}, journal = {PloS one}, volume = {7}, number = {3}, pages = {e32877}, pmid = {22412940}, issn = {1932-6203}, support = {R01 GM082901/GM/NIGMS NIH HHS/United States ; GM082901/GM/NIGMS NIH HHS/United States ; }, mesh = {Adaptation, Biological/genetics ; Animals ; Cluster Analysis ; DNA/chemistry ; Evolution, Molecular ; *Genome ; *Genome, Human ; Hominidae/*genetics ; Humans ; Male ; Mutation ; Neanderthals/genetics ; }, abstract = {Several previous comparisons of the human genome with other primate and vertebrate genomes identified genomic regions that are highly conserved in vertebrate evolution but fast-evolving on the human lineage. These human accelerated regions (HARs) may be regions of past adaptive evolution in humans. Alternatively, they may be the result of non-adaptive processes, such as biased gene conversion. We captured and sequenced DNA from a collection of previously published HARs using DNA from an Iberian Neandertal. Combining these new data with shotgun sequence from the Neandertal and Denisova draft genomes, we determine at least one archaic hominin allele for 84% of all positions within HARs. We find that 8% of HAR substitutions are not observed in the archaic hominins and are thus recent in the sense that the derived allele had not come to fixation in the common ancestor of modern humans and archaic hominins. Further, we find that recent substitutions in HARs tend to have come to fixation faster than substitutions elsewhere in the genome and that substitutions in HARs tend to cluster in time, consistent with an episodic rather than a clock-like process underlying HAR evolution. Our catalog of sequence changes in HARs will help prioritize them for functional studies of genomic elements potentially responsible for modern human adaptations.}, }
@article {pmid22393781, year = {2011}, author = {Maliarchuk, BA}, title = {[Adaptive evolution of the Homo mitochondrial genome].}, journal = {Molekuliarnaia biologiia}, volume = {45}, number = {5}, pages = {845-850}, pmid = {22393781}, issn = {0026-8984}, mesh = {Adaptation, Biological/*genetics ; Amino Acid Sequence ; Amino Acid Substitution/*genetics ; Animals ; *Biological Evolution ; DNA, Mitochondrial/genetics ; Electron Transport Complex IV/*genetics/metabolism ; Genes, Mitochondrial ; *Genome, Mitochondrial ; Hominidae/*genetics ; Humans ; Molecular Sequence Data ; Neanderthals/*genetics ; Phylogeny ; Sequence Homology, Amino Acid ; }, abstract = {Adaptive evolution of 12 protein-coding mitochondrial genes in members of genus Homo (Denisova hominin (H. sp. Altai), Neandertals (H. neanderthalensis) and modern humans (H. sapiens)) has been evaluated by assessing the pattern of changes in the physicochemical properties of amino acid replacements during the primate evolution. It has been found that in the Homo molecular adaptation (positive destabilizing selection) become apparent in the form of 12 radical amino acid replacements accompanied by statistically significant (P < 0.001) changes of physicochemical properties that probably had the functional consequences. These replacements have occurred on the stage of a common ancestor of the Homo (in CO2 and CytB genes) as well as with the appearance of the common ancestor of Neandertals and modern humans (in CO1 and ND5 genes). Radical amino acid replacements were mainly revealed in the cytochrome c oxidase complex IV and cytochrome bc1 complex III, thus coinciding with general trend of increasing of non-synonymous changes in mtDNA genes coding subunits of complexes III and IV proteins in anthropoid primates.}, }
@article {pmid22319157, year = {2012}, author = {Mendez, FL and Watkins, JC and Hammer, MF}, title = {Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations.}, journal = {Molecular biology and evolution}, volume = {29}, number = {6}, pages = {1513-1520}, doi = {10.1093/molbev/msr301}, pmid = {22319157}, issn = {1537-1719}, mesh = {2',5'-Oligoadenylate Synthetase/*genetics ; 5' Untranslated Regions/genetics ; Animals ; Asian People/genetics ; Black People/*genetics ; Chromosomes, Human, Pair 12/genetics ; Genetic Speciation ; Genotyping Techniques ; Haplotypes ; Hominidae/genetics ; Humans ; *Hybridization, Genetic ; Linkage Disequilibrium ; Melanesia ; Models, Genetic ; Native Hawaiian or Other Pacific Islander/genetics ; *Polymorphism, Genetic ; Sequence Analysis, DNA ; }, abstract = {Recent analysis of DNA extracted from two Eurasian forms of archaic human shows that more genetic variants are shared with humans currently living in Eurasia than with anatomically modern humans in sub-Saharan Africa. Although these genome-wide average measures of genetic similarity are consistent with the hypothesis of archaic admixture in Eurasia, analyses of individual loci exhibiting the signal of archaic introgression are needed to test alternative hypotheses and investigate the admixture process. Here, we provide a detailed sequence analysis of the innate immune gene OAS1, a locus with a divergent Melanesian haplotype that is very similar to the Denisova sequence from the Altai region of Siberia. We resequenced a 7-kb region encompassing the OAS1 gene in 88 individuals from six Old World populations (San, Biaka, Mandenka, French Basque, Han Chinese, and Papua New Guineans) and discovered previously unknown and ancient genetic variation. The 5' region of this gene has unusual patterns of diversity, including 1) higher levels of nucleotide diversity in Papuans than in sub-Saharan Africans, 2) very deep ancestry with an estimated time to the most recent common ancestor of >3 myr, and 3) a basal branching pattern with Papuan individuals on either side of the rooted network. A global geographic survey of >1,500 individuals showed that the divergent Papuan haplotype is nearly restricted to populations from eastern Indonesia and Melanesia. Polymorphic sites within this haplotype are shared with the draft Denisova genome over a span of ∼90 kb and are associated with an extended block of linkage disequilibrium, supporting the hypothesis that this haplotype introgressed from an archaic source that likely lived in Eurasia.}, }
@article {pmid22192823, year = {2011}, author = {Lalueza-Fox, C and Gilbert, MT}, title = {Paleogenomics of archaic hominins.}, journal = {Current biology : CB}, volume = {21}, number = {24}, pages = {R1002-9}, doi = {10.1016/j.cub.2011.11.021}, pmid = {22192823}, issn = {1879-0445}, mesh = {Animals ; *Biological Evolution ; Cell Nucleus/genetics ; DNA, Mitochondrial/genetics ; Demography ; *Evolution, Molecular ; Fossils ; Gene Flow ; Genetic Variation ; Genome, Human ; Hominidae/anatomy &amp; histology/*genetics/physiology ; Humans/anatomy &amp; histology/genetics/physiology ; Neanderthals/anatomy &amp; histology/*genetics/physiology ; Phylogeny ; Species Specificity ; }, abstract = {In order to understand the genetic basis for the evolutionary success of modern humans, it is necessary to compare their genetic makeup to that of closely related species. Unfortunately, our closest living relatives, the chimpanzees, are evolutionarily quite distant. With the advent of ancient DNA study and more recently paleogenomics - the study of the genomes of ancient organisms - it has become possible to compare human genomes to those of much more closely related groups. Our closest known relatives are the Neanderthals, which evolved and lived in Europe and Western Asia, from about 600,000 years ago until their disappearance around 30,000 years ago following the expansion of anatomically modern humans into their range. The closely related Denisovans are only known by virtue of their DNA, which has been extracted from bone fragments dating around 30,000 to 50,000 years ago found in a single Siberian cave. Analyses of Neanderthal and Denisovan nuclear and mitochondrial genomes have revealed surprising insights into these archaic humans as well as our own species. The genomes provide a preliminary catalogue of derived amino acids that are specific to all extant modern humans, thus offering insights into the functional differences between the three lineages. In addition, the genomes provide evidence of gene flow between the three lineages after anatomically modern humans left Africa, drastically changing our view of human evolution.}, }
@article {pmid22042846, year = {2011}, author = {Skoglund, P and Jakobsson, M}, title = {Archaic human ancestry in East Asia.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {108}, number = {45}, pages = {18301-18306}, pmid = {22042846}, issn = {1091-6490}, mesh = {Asia ; *Fossils ; Genetic Drift ; Genotype ; History, Ancient ; Humans ; Principal Component Analysis ; }, abstract = {Recent studies of ancient genomes have suggested that gene flow from archaic hominin groups to the ancestors of modern humans occurred on two separate occasions during the modern human expansion out of Africa. At the same time, decreasing levels of human genetic diversity have been found at increasing distance from Africa as a consequence of human expansion out of Africa. We analyzed the signal of archaic ancestry in modern human populations, and we investigated how serial founder models of human expansion affect the signal of archaic ancestry using simulations. For descendants of an archaic admixture event, we show that genetic drift coupled with ascertainment bias for common alleles can cause artificial but largely predictable differences in similarity to archaic genomes. In genotype data from non-Africans, this effect results in a biased genetic similarity to Neandertals with increasing distance from Africa. However, in addition to the previously reported gene flow between Neandertals and non-Africans as well as gene flow between an archaic human population from Siberia ("Denisovans") and Oceanians, we found a significant affinity between East Asians, particularly Southeast Asians, and the Denisova genome--a pattern that is not expected under a model of solely Neandertal admixture in the ancestry of East Asians. These results suggest admixture between Denisovans or a Denisova-related population and the ancestors of East Asians, and that the history of anatomically modern and archaic humans might be more complex than previously proposed.}, }
@article {pmid21944045, year = {2011}, author = {Reich, D and Patterson, N and Kircher, M and Delfin, F and Nandineni, MR and Pugach, I and Ko, AM and Ko, YC and Jinam, TA and Phipps, ME and Saitou, N and Wollstein, A and Kayser, M and Pääbo, S and Stoneking, M}, title = {Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania.}, journal = {American journal of human genetics}, volume = {89}, number = {4}, pages = {516-528}, pmid = {21944045}, issn = {1537-6605}, mesh = {Animals ; Asia, Southeastern ; Biological Evolution ; DNA, Mitochondrial/genetics ; *Gene Flow ; Genotype ; Geography ; Hominidae/*genetics ; Humans ; Models, Genetic ; Models, Statistical ; Native Hawaiian or Other Pacific Islander ; Oceania ; Pan troglodytes ; Polymorphism, Single Nucleotide ; }, abstract = {It has recently been shown that ancestors of New Guineans and Bougainville Islanders have inherited a proportion of their ancestry from Denisovans, an archaic hominin group from Siberia. However, only a sparse sampling of populations from Southeast Asia and Oceania were analyzed. Here, we quantify Denisova admixture in 33 additional populations from Asia and Oceania. Aboriginal Australians, Near Oceanians, Polynesians, Fijians, east Indonesians, and Mamanwa (a "Negrito" group from the Philippines) have all inherited genetic material from Denisovans, but mainland East Asians, western Indonesians, Jehai (a Negrito group from Malaysia), and Onge (a Negrito group from the Andaman Islands) have not. These results indicate that Denisova gene flow occurred into the common ancestors of New Guineans, Australians, and Mamanwa but not into the ancestors of the Jehai and Onge and suggest that relatives of present-day East Asians were not in Southeast Asia when the Denisova gene flow occurred. Our finding that descendants of the earliest inhabitants of Southeast Asia do not all harbor Denisova admixture is inconsistent with a history in which the Denisova interbreeding occurred in mainland Asia and then spread over Southeast Asia, leading to all its earliest modern human inhabitants. Instead, the data can be most parsimoniously explained if the Denisova gene flow occurred in Southeast Asia itself. Thus, archaic Denisovans must have lived over an extraordinarily broad geographic and ecological range, from Siberia to tropical Asia.}, }
@article {pmid21897868, year = {2011}, author = {Vorobieva, NV and Sherbakov, DY and Druzhkova, AS and Stanyon, R and Tsybankov, AA and Vasil'ev, SK and Shunkov, MV and Trifonov, VA and Graphodatsky, AS}, title = {Genotyping of Capreolus pygargus fossil DNA from Denisova cave reveals phylogenetic relationships between ancient and modern populations.}, journal = {PloS one}, volume = {6}, number = {8}, pages = {e24045}, pmid = {21897868}, issn = {1932-6203}, mesh = {Animals ; DNA/*genetics/isolation &amp; purification ; Deer/*genetics ; *Evolution, Molecular ; *Fossils ; Genetic Variation ; *Genotyping Techniques ; Geology ; Haplotypes ; *Phylogeny ; Sequence Analysis, DNA ; Siberia ; }, abstract = {BACKGROUND: The extant roe deer (Capreolus Gray, 1821) includes two species: the European roe deer (C. capreolus) and the Siberian roe deer (C. pygargus) that are distinguished by morphological and karyotypical differences. The Siberian roe deer occupies a vast area of Asia and is considerably less studied than the European roe deer. Modern systematics of the Siberian roe deer remain controversial with 4 morphological subspecies. Roe deer fossilized bones are quite abundant in Denisova cave (Altai Mountains, South Siberia), where dozens of both extant and extinct mammalian species from modern Holocene to Middle Pleistocene have been retrieved.<br><br>We analyzed a 629 bp fragment of the mitochondrial control region from ancient bones of 10 Holocene and four Pleistocene Siberian roe deer from Denisova cave as well as 37 modern specimen belonging to populations from Altai, Tian Shan (Kyrgyzstan), Yakutia, Novosibirsk region and the Russian Far East. Genealogical reconstructions indicated that most Holocene haplotypes were probably ancestral for modern roe deer populations of Western Siberia and Tian Shan. One of the Pleistocene haplotypes was possibly ancestral for modern Yakutian populations, and two extinct Pleistocene haplotypes were close to modern roe deer from Tian Shan and Yakutia. Most modern geographical populations (except for West Siberian Plains) are heterogeneous and there is some tentative evidence for structure. However, we did not find any distinct phylogenetic signal characterizing particular subspecies in either modern or ancient samples.<br><br>CONCLUSION/SIGNIFICANCE: Analysis of mitochondrial DNA from both ancient and modern samples of Siberian roe deer shed new light on understanding the evolutionary history of roe deer. Our data indicate that during the last 50,000 years multiple replacements of populations of the Siberian roe deer took place in the Altai Mountains correlating with climatic changes. The Siberian roe deer represent a complex and heterogeneous species with high migration rates and without evident subspecies structure. Low genetic diversity of the West Siberian Plain population indicates a recent bottleneck or founder effect.}, }
@article {pmid21868647, year = {2011}, author = {Gibbons, A}, title = {Paleoanthropology. A Denisovan legacy in the immune system?.}, journal = {Science (New York, N.Y.)}, volume = {333}, number = {6046}, pages = {1086}, doi = {10.1126/science.333.6046.1086}, pmid = {21868647}, issn = {1095-9203}, mesh = {Alleles ; Animals ; Asian People/genetics ; Female ; *Fossils ; *Genes, MHC Class I ; HLA-B Antigens/*genetics ; HLA-C Antigens/*genetics ; Hominidae/*genetics/*immunology ; Humans ; White People/genetics ; }, }
@article {pmid21868630, year = {2011}, author = {Abi-Rached, L and Jobin, MJ and Kulkarni, S and McWhinnie, A and Dalva, K and Gragert, L and Babrzadeh, F and Gharizadeh, B and Luo, M and Plummer, FA and Kimani, J and Carrington, M and Middleton, D and Rajalingam, R and Beksac, M and Marsh, SG and Maiers, M and Guethlein, LA and Tavoularis, S and Little, AM and Green, RE and Norman, PJ and Parham, P}, title = {The shaping of modern human immune systems by multiregional admixture with archaic humans.}, journal = {Science (New York, N.Y.)}, volume = {334}, number = {6052}, pages = {89-94}, pmid = {21868630}, issn = {1095-9203}, support = {R01 AI031168/AI/NIAID NIH HHS/United States ; AI031168/AI/NIAID NIH HHS/United States ; RR000165/RR/NCRR NIH HHS/United States ; P51 RR000165/RR/NCRR NIH HHS/United States ; HHSN261200800001C/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {Adaptation, Biological ; Alleles ; Animals ; Asian People/genetics ; Black People/genetics ; Evolution, Molecular ; *Genes, MHC Class I ; Genetic Variation ; HLA-A Antigens/*genetics/immunology/metabolism ; HLA-B Antigens/*genetics/immunology/metabolism ; HLA-C Antigens/*genetics/immunology ; Haplotypes ; Hominidae/*genetics/*immunology ; Humans ; *Hybridization, Genetic ; Killer Cells, Natural/immunology ; Ligands ; Linkage Disequilibrium ; Molecular Sequence Data ; Native Hawaiian or Other Pacific Islander/genetics ; Racial Groups/*genetics ; Receptors, KIR/immunology/metabolism ; Selection, Genetic ; White People/genetics ; }, abstract = {Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.}, }
@article {pmid21807602, year = {2011}, author = {Zhang, G and Pei, Z and Ball, EV and Mort, M and Kehrer-Sawatzki, H and Cooper, DN}, title = {Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations.}, journal = {Human genomics}, volume = {5}, number = {5}, pages = {453-484}, pmid = {21807602}, issn = {1479-7364}, mesh = {Animals ; Databases, Genetic ; *Genome ; Genome, Human ; Hominidae/*genetics ; Humans ; *Mutation ; Neanderthals/genetics ; Pan troglodytes/*genetics ; }, abstract = {The recent publication of the draft genome sequences of the Neanderthal and a ∼50,000-year-old archaic hominin from Denisova Cave in southern Siberia has ushered in a new age in molecular archaeology. We previously cross-compared the human, chimpanzee and Neanderthal genome sequences with respect to a set of disease-causing/disease-associated missense and regulatory mutations (Human Gene Mutation Database) and succeeded in identifying genetic variants which, although apparently pathogenic in humans, may represent a 'compensated' wild-type state in at least one of the other two species. Here, in an attempt to identify further 'potentially compensated mutations' (PCMs) of interest, we have compared our dataset of disease-causing/disease-associated mutations with their corresponding nucleotide positions in the Denisovan hominin, Neanderthal and chimpanzee genomes. Of the 15 human putatively disease-causing mutations that were found to be compensated in chimpanzee, Denisovan or Neanderthal, only a solitary F5 variant (Val1736Met) was specific to the Denisovan. In humans, this missense mutation is associated with activated protein C resistance and an increased risk of thromboembolism and recurrent miscarriage. It is unclear at this juncture whether this variant was indeed a PCM in the Denisovan or whether it could instead have been associated with disease in this ancient hominin.}, }
@article {pmid21803765, year = {2011}, author = {Crisci, JL and Wong, A and Good, JM and Jensen, JD}, title = {On characterizing adaptive events unique to modern humans.}, journal = {Genome biology and evolution}, volume = {3}, number = {}, pages = {791-798}, pmid = {21803765}, issn = {1759-6653}, mesh = {Adaptation, Biological/genetics ; Amino Acid Substitution/*genetics ; Animals ; Biological Evolution ; Genome, Human/*genetics ; Hominidae/*genetics ; Humans ; Neanderthals/*genetics ; Pan troglodytes/genetics ; Selection, Genetic ; }, abstract = {Ever since the first draft of the human genome was completed in 2001, there has been increased interest in identifying genetic changes that are uniquely human, which could account for our distinct morphological and cognitive capabilities with respect to other apes. Recently, draft sequences of two extinct hominin genomes, a Neanderthal and Denisovan, have been released. These two genomes provide a much greater resolution to identify human-specific genetic differences than the chimpanzee, our closest extant relative. The Neanderthal genome paper presented a list of regions putatively targeted by positive selection around the time of the human-Neanderthal split. We here seek to characterize the evolutionary history of these candidate regions-examining evidence for selective sweeps in modern human populations as well as for accelerated adaptive evolution across apes. Results indicate that 3 of the top 20 candidate regions show evidence of selection in at least one modern human population (P < 5 × 10(5)). Additionally, four genes within the top 20 regions show accelerated amino acid substitutions across multiple apes (P < 0.01), suggesting importance across deeper evolutionary time. These results highlight the importance of evaluating evolutionary processes across both recent and ancient evolutionary timescales and intriguingly suggest a list of candidate genes that may have been uniquely important around the time of the human-Neanderthal split.}, }
@article {pmid21796732, year = {2011}, author = {Sauter, D and Vogl, M and Kirchhoff, F}, title = {Ancient origin of a deletion in human BST2/Tetherin that confers protection against viral zoonoses.}, journal = {Human mutation}, volume = {32}, number = {11}, pages = {1243-1245}, doi = {10.1002/humu.21571}, pmid = {21796732}, issn = {1098-1004}, mesh = {Amino Acid Sequence ; Animals ; Antigens, CD/*genetics ; *Evolution, Molecular ; GPI-Linked Proteins/genetics ; Host-Pathogen Interactions ; Humans ; Molecular Sequence Data ; Neanderthals ; Primates ; *Sequence Deletion ; Simian Acquired Immunodeficiency Syndrome/genetics/transmission/virology ; Simian Immunodeficiency Virus/genetics/immunology/pathogenicity ; Zoonoses/*virology ; }, abstract = {Bone marrow stromal antigen 2 (BST2)/Tetherin is an antiviral factor that blocks the release of enveloped virions from infected cells. Recent data suggest that efficient BST2 antagonism was a prerequisite for the global spread of HIV/AIDS. Most simian immunodeficiency viruses (SIVs), including the direct precursors of HIV, use their Nef protein to antagonize BST2 of their respective host species. Human BST2, however, contains a five amino acid deletion in its cytoplasmic domain that confers resistance to Nef. Thus, this antiviral factor constitutes a major barrier to effective zoonotic transmissions of SIVs to humans. Here, we show that this protective deletion has already been present in Neanderthal and Denisovan BST2 and thus evolved at least 800,000 years ago. This ancient origin helps to explain why effectively spreading zoonotic transmissions of SIVs to humans have been rare, although SIVs are widespread in African nonhuman primates and humans must have been exposed to these viruses many times.}, }
@article {pmid21179161, year = {2010}, author = {Reich, D and Green, RE and Kircher, M and Krause, J and Patterson, N and Durand, EY and Viola, B and Briggs, AW and Stenzel, U and Johnson, PL and Maricic, T and Good, JM and Marques-Bonet, T and Alkan, C and Fu, Q and Mallick, S and Li, H and Meyer, M and Eichler, EE and Stoneking, M and Richards, M and Talamo, S and Shunkov, MV and Derevianko, AP and Hublin, JJ and Kelso, J and Slatkin, M and Pääbo, S}, title = {Genetic history of an archaic hominin group from Denisova Cave in Siberia.}, journal = {Nature}, volume = {468}, number = {7327}, pages = {1053-1060}, pmid = {21179161}, issn = {1476-4687}, support = {R01 GM040282/GM/NIGMS NIH HHS/United States ; R01-GM40282/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Asia ; DNA, Mitochondrial/genetics ; Europe ; Finger Phalanges/chemistry ; *Fossils ; *Gene Flow ; Genome/*genetics ; Hominidae/*classification/*genetics ; Humans ; Melanesia ; Molecular Sequence Data ; Phylogeny ; Siberia ; Tooth/anatomy &amp; histology/chemistry ; }, abstract = {Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.}, }
@article {pmid21129766, year = {2011}, author = {Martinón-Torres, M and Dennell, R and Bermúdez de Castro, JM}, title = {The Denisova hominin need not be an out of Africa story.}, journal = {Journal of human evolution}, volume = {60}, number = {2}, pages = {251-255}, doi = {10.1016/j.jhevol.2010.10.005}, pmid = {21129766}, issn = {1095-8606}, mesh = {Africa ; *Animal Migration ; Animals ; DNA, Mitochondrial/genetics ; Fossils ; Hominidae/*genetics ; Siberia ; }, }
@article {pmid20336068, year = {2010}, author = {Krause, J and Fu, Q and Good, JM and Viola, B and Shunkov, MV and Derevianko, AP and Pääbo, S}, title = {The complete mitochondrial DNA genome of an unknown hominin from southern Siberia.}, journal = {Nature}, volume = {464}, number = {7290}, pages = {894-897}, pmid = {20336068}, issn = {1476-4687}, mesh = {Africa/ethnology ; Animals ; DNA, Mitochondrial/*genetics/isolation &amp; purification ; Emigration and Immigration ; Extinction, Biological ; Finger Phalanges ; Genome, Mitochondrial/*genetics ; Hominidae/*classification/*genetics ; Humans ; Molecular Sequence Data ; *Phylogeny ; Sequence Alignment ; Siberia ; Time Factors ; }, abstract = {With the exception of Neanderthals, from which DNA sequences of numerous individuals have now been determined, the number and genetic relationships of other hominin lineages are largely unknown. Here we report a complete mitochondrial (mt) DNA sequence retrieved from a bone excavated in 2008 in Denisova Cave in the Altai Mountains in southern Siberia. It represents a hitherto unknown type of hominin mtDNA that shares a common ancestor with anatomically modern human and Neanderthal mtDNAs about 1.0 million years ago. This indicates that it derives from a hominin migration out of Africa distinct from that of the ancestors of Neanderthals and of modern humans. The stratigraphy of the cave where the bone was found suggests that the Denisova hominin lived close in time and space with Neanderthals as well as with modern humans.}, }
@article {pmid9223495, year = {1997}, author = {Lee, S and Peden, K and Dimitrov, DS and Broder, CC and Manischewitz, J and Denisova, G and Gershoni, JM and Golding, H}, title = {Enhancement of human immunodeficiency virus type 1 envelope-mediated fusion by a CD4-gp120 complex-specific monoclonal antibody.}, journal = {Journal of virology}, volume = {71}, number = {8}, pages = {6037-6043}, pmid = {9223495}, issn = {0022-538X}, mesh = {Animals ; Antibodies, Monoclonal/*immunology ; CD4 Antigens/*physiology ; Chemokine CCL4 ; HIV Envelope Protein gp120/*physiology ; HIV-1/*physiology ; HeLa Cells ; Humans ; Immunoglobulin Fab Fragments/immunology ; Macrophage Inflammatory Proteins/physiology ; Mice ; Mice, Inbred BALB C ; Tetradecanoylphorbol Acetate/pharmacology ; }, abstract = {The entry of human immunodeficiency virus type 1 (HIV-1) into cells is initiated by binding of the viral glycoprotein gp120-gp41 to its cellular receptor CD4. The gp120-CD4 complex formed at the cell surface undergoes conformational changes that may allow its association with an additional membrane component(s) and the eventual formation of the fusion complex. These conformational rearrangements are accompanied by immunological changes manifested by altered reactivity with monoclonal antibodies specific for the individual components and presentation of new epitopes unique to the postbinding complex. In order to analyze the structure and function of the gp120-CD4 complex, monoclonal antibodies were generated from splenocytes of BALB/c mice immunized with soluble CD4-gp120 (IIIB) molecules (J. M. Gershoni, G. Denisova, D. Raviv, N. I. Smorodinsky, and D. Buyaner, FASEB J. 7:1185-1187 1993). One of those monoclonal antibodies, CG10, was found to be strictly complex specific. Here we demonstrate that this monoclonal antibody can significantly enhance the fusion of CD4+ cells with effector cells expressing multiple HIV-1 envelopes. Both T-cell-line-tropic and macrophage-tropic envelope-mediated cell fusion were enhanced, albeit at different optimal doses. Furthermore, infection of HeLa CD4+ (MAGI) cells by HIV-1 LAI, ELI1, and ELI2 strains was increased two- to fourfold in the presence of CG10 monoclonal antibodies, suggesting an effect on viral entry. These findings indicate the existence of a novel, conserved CD4-gp120 intermediate structure that plays an important role in HIV-1 cell fusion.}, }
@article {pmid1114020, year = {1975}, author = {Danilov, VN}, title = {[The probable identity of mosquitoes aedes (ochlerotatus) beklemishevi denisova and a. (o.) barri rueger (diptera, culicidae)].}, journal = {Parazitologiia}, volume = {09}, number = {1}, pages = {61-63}, pmid = {1114020}, issn = {0031-1847}, mesh = {Aedes/*classification ; Animals ; Canada ; Classification ; Europe ; Terminology as Topic ; USSR ; United States ; }, }