@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.},
}

Animals
*Phylogeny
Humans
*CpG Islands/genetics
*Epigenesis, Genetic
*Evolution, Molecular
Hominidae/genetics
Pan troglodytes/genetics
DNA Methylation/genetics
Gorilla gorilla/genetics

@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.},
}

Animals
Female
Humans
Male
*DNA, Ancient
Fossils
*Genome, Human
*Neanderthals/genetics
Siberia

@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 & histology ; China ; DNA, Mitochondrial/genetics ; Bone and Bones/chemistry/anatomy & 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.},
}

Animals
*Caves
*Fossils
*Proteomics
*Hominidae/classification/genetics
History, Ancient
Humans
Mandible/anatomy & histology
China
DNA, Mitochondrial/genetics
Bone and Bones/chemistry/anatomy & histology
Archaeology
Phylogeny

@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.},
}

Papua New Guinea
Humans
Animals
*Haplotypes
*Neanderthals/genetics
Adaptation, Physiological/genetics
Genetics, Population

@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 Innovación/ ; GRC 2017 SGR 937//Generalitat de Catalunya/ ; 2017SGR:00738//Catalan Government/ ; PGC2018-098574-B-I00//Ministerio de Economía 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.

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 β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation.

CONCLUSIONS: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.},
}

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

@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 & 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 & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 GM117163/GM/NIGMS NIH HHS/United States ; EY032161//U.S. Department of Health & 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.},
}

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

@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.},
}

Humans
Japan
*Diabetes Mellitus, Type 2
Selection, Genetic
Whole Genome Sequencing
Exome

@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.},
}

Humans
*Saccharomyces cerevisiae/genetics
*Neanderthals/genetics
Animals
Genetic Variation
Mitochondria/genetics/metabolism
Alleles
Genetic Introgression
Saccharomyces cerevisiae Proteins/genetics/metabolism

@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.

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.

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 15 000 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 10 000 years.

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.},
}

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

@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.

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 ∼92% accuracy at the family-level for mammalian bone collagen previously analysed manually.

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).},
}

Animals
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
*Algorithms
*Peptides/chemistry
Databases, Factual
Automation
Mammals

@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 & 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.},
}

Child
Humans
Infant
Child, Preschool
Eye Movements
*Autism Spectrum Disorder/psychology
*Autistic Disorder
Saccades

@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.

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.

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.},
}

Animals
Humans
*Neanderthals/genetics
Phylogeny
Pan troglodytes/genetics
Bayes Theorem
*Hominidae/genetics
DNA, Mitochondrial/genetics

@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.},
}

Animals
Humans
*Neanderthals/genetics
Pharmacogenetics
Genome, Human
*Hominidae/genetics
Biological Evolution

@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.},
}

Animals
Phylogeny
*Trematoda
Fishes
Life Cycle Stages
DNA, Ribosomal/genetics

@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.},
}

Animals
Laos
*Forests
*Biological Evolution
Caves
China

@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.},
}

Animals
Humans
HEK293 Cells
*Hominidae/genetics
Homeostasis/genetics
Zinc
Human Genetics
Selection, Genetic
Haplotypes
Genome, Human

@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.},
}

Animals
Humans
*Neanderthals/genetics
*Hominidae
Biological Evolution
DNA
Genetic Research
Genome, Human

@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.},
}

Humans
Adaptor Proteins, Signal Transducing
Altitude
*Asian People/genetics
Haplotypes
Tibet

@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).},
}

Infant
Child
Humans
*Sleep/physiology
*Sleep, REM/physiology
Sleep Stages/physiology
Respiration
Eye Movements

@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.},
}

Humans
Female
*DNA, Ancient
*Anthropology
Body Remains
Sequence Analysis, DNA
Universities

@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.},
}

Animals
Humans
Fossils
Gene Flow
*Neanderthals/genetics
*Climate Change

@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 & 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.},
}

Animals
Humans
Mice
*Antimicrobial Peptides
*Anti-Infective Agents
Peptides/pharmacology
Anti-Bacterial Agents/pharmacology
Machine Learning
Peptide Hydrolases
Microbial Sensitivity Tests

@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.},
}

Humans
Male
Asian People/genetics
*Diploidy
*East Asian People/ethnology/genetics
*Genome, Human/genetics
Genomics
*Telomere/genetics

@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.},
}

Male
Animals
Humans
*Neanderthals/genetics
Semen
*Hominidae/genetics
Alleles
Gene Expression Regulation
Genome, Human

@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 & 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.},
}

Animals
Humans
*Hominidae/genetics
*Neanderthals/genetics
Alternative Splicing
Genome, Human
Population Density

@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 & purification ; DNA, Mitochondrial/analysis/isolation & 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.},
}

Animals
Female
Humans
Archaeology/methods
*Bone and Bones/chemistry
Deer/genetics
*DNA, Ancient/analysis/isolation & purification
DNA, Mitochondrial/analysis/isolation & purification
History, Ancient
Siberia
*Tooth/chemistry
Caves
Russia

@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.},
}

Animals
Humans
DNA
Genome, Human
*Hominidae/genetics
*Neanderthals/genetics

@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.},
}

Animals
Humans
Infant, Newborn
*Neanderthals/genetics
Rare Diseases/genetics
*Hominidae/genetics
Genome, Human
DNA

@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.},
}

Animals
Female
Humans
Breast Neoplasms/genetics
*Genetics, Population
Genome, Human
*Glucuronosyltransferase/genetics
Hominidae/genetics
Neanderthals/genetics
Phenotype

@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.

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.

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.

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.

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.},
}

Humans
Animals
*Neanderthals/genetics
Genome
Genome, Human
Membrane Proteins/genetics

@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.},
}

Humans
*Immune System
*Hominidae/genetics
*Neanderthals/genetics
Papua New Guinea
*Evolution, Molecular

@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.

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=3.57×10[-7]). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1×10[-7]), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69×10[-116]) and red hair color (rs60733936 beta=-0.86, p=4.49×10[-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=5.22×10[-7]).

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.},
}

Humans
Animals
*Neanderthals/genetics
Multifactorial Inheritance
Genome-Wide Association Study
Genome, Human
Asian People

@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.},
}

Humans
History, Ancient
Animals
*Human Migration
Genomics
Genome, Human
*Neanderthals
Brazil

@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.

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.

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.},
}

Animals
Female
*Hominidae/genetics
Humans
Male
Nucleotides
*Pseudoautosomal Regions
Receptor, PAR-1/genetics
Y Chromosome/genetics

@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.},
}

Humans
Animals
*Genome, Human
*Neanderthals/genetics
Genetics, Population

@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.},
}

Animals
Archaeology
Cognition/physiology
Evolution, Molecular
Genome, Human
*Hominidae/genetics
Humans
Mammals
*Neanderthals/genetics
Phenotype

@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.

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.

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.

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.},
}

Alleles
CpG Islands
*DNA Methylation
*Epigenesis, Genetic
Haplotypes
Humans

@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 & 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.},
}

Animals
Bayes Theorem
Female
Fossils
*Hominidae/anatomy & histology
Humans
Laos
Molar

@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.},
}

Animals
DNA, Ancient
Genome, Human
Genomics
*Hominidae/genetics
Humans
*Neanderthals/genetics
Phenotype

@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.},
}

Animals
Asia, Southeastern
*Asian People
Genetics, Population
Humans
*Neanderthals/genetics
Polymorphism, Single Nucleotide
Thailand

@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.},
}

Animals
*Caves
*DNA, Ancient
*Fossils
Hominidae/*genetics
Neanderthals/*genetics

@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.},
}

Animals
*DNA Methylation
*DNA, Ancient
*Epigenesis, Genetic
Epigenomics/trends
*Evolution, Molecular
Human Migration
Humans
Neanderthals/*genetics

@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.},
}

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

@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.},
}

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

@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 & 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.},
}

Acclimatization/genetics
*Adaptation, Physiological/genetics
*Altitude
Archaeology
Humans
Tibet

@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 & 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.},
}

Animals
Archaeology
Caves
DNA, Mitochondrial/genetics
*Hominidae/genetics
*Neanderthals/genetics

@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.},
}

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

@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.},
}

Alleles
Gene Frequency
*Genetics, Population
*Genomic Structural Variation
Haplotypes
Phenotype
*Selection, Genetic

@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//Università Cattolica del Sacro Cuore/ ; Linea D1 - 2017//Università Cattolica del Sacro Cuore/ ; },
mesh = {Animals ; *Biological Evolution ; Core Binding Factor Alpha 1 Subunit/*genetics/metabolism ; Cranial Sutures/growth & development ; Craniosynostoses/genetics ; Epigenesis, Genetic ; Genome, Human ; Hominidae/anatomy & histology/genetics ; Humans ; Mesenchymal Stem Cells ; MicroRNAs/genetics ; Neanderthals/anatomy & histology/genetics ; Osteogenesis/genetics ; RNA, Long Noncoding/genetics ; Skull/*anatomy & 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.},
}

Animals
*Biological Evolution
Core Binding Factor Alpha 1 Subunit/*genetics/metabolism
Cranial Sutures/growth & development
Craniosynostoses/genetics
Epigenesis, Genetic
Genome, Human
Hominidae/anatomy & histology/genetics
Humans
Mesenchymal Stem Cells
MicroRNAs/genetics
Neanderthals/anatomy & histology/genetics
Osteogenesis/genetics
RNA, Long Noncoding/genetics
Skull/*anatomy & histology

@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.},
}

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

@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.},
}

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

@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.},
}

Animals
Asia
Asia, Southeastern
Australia
*Hominidae/genetics
Humans
*Neanderthals/genetics
Philippines
Racial Groups

@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.},
}

Animals
Archaeology/*methods
Bone and Bones/pathology
Carnivora
Caves
Collagen/*chemistry
Fossils
Hominidae
Humans
Paleontology/*methods
Siberia

@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.},
}

Alleles
Animals
Blood Group Antigens/*genetics
Fossils
Genetic Variation
Genotype
Hominidae/*genetics
INDEL Mutation
Neanderthals/*genetics
Phenotype
Polymorphism, Genetic

@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.},
}

Animals
Genome, Human
Genomics
*Hominidae/genetics
Humans
*Neanderthals/genetics
Recombination, Genetic

@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.},
}

Animals
Archaeology
*Caves
DNA, Ancient/*analysis
DNA, Mitochondrial/analysis/genetics
Fossils
Geologic Sediments/*chemistry
History, Ancient
Hominidae/*genetics
Neanderthals/genetics
Siberia

@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 & 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).},
}

Animals
DNA, Ancient/analysis
Genetic Introgression/*genetics
Genomics/*methods
Hominidae/genetics
Humans
Neanderthals/*genetics

@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.},
}

Adaptation, Physiological/genetics
Altitude
Basic Helix-Loop-Helix Transcription Factors/*genetics
*Evolution, Molecular
*Haplotypes
Humans
Tibet

@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.},
}

Animals
Genome, Human
Genomics
*Hominidae/genetics
Humans
*Neanderthals/genetics
Pedigree

@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.},
}

Alleles
Animals
Humans
*Neanderthals/genetics
Population Density
Probability

@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.},
}

ABO Blood-Group System/*genetics
Animals
Genetic Variation
Genome, Human
Haplotypes
Humans
Neanderthals/*genetics

@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.},
}

Embryonic Stem Cells/*metabolism
*Gene Expression Regulation
Genome, Human
Humans
Osteoblasts/*metabolism
*Polymorphism, Single Nucleotide
Stem Cells/*metabolism
Transcription Factors/*metabolism

@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.},
}

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

@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 & 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.},
}

Animals
Asia, Southeastern
Fossils
*Hominidae/genetics
Humans
Islands
*Neanderthals

@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 & 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.},
}

Alleles
Alternative Splicing
Amino Acid Substitution
Animals
Binding Sites
Biological Evolution
CRISPR-Cas Systems
Cell Proliferation
Cerebral Cortex/cytology/*growth & 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

@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.},
}

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

@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 & 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.},
}

Animals
*Face/anatomy & histology
Genome-Wide Association Study
Genotype
Hispanic or Latino/genetics
Humans
Mice
Phenotype
*Polymorphism, Single Nucleotide
*Vesicular Transport Proteins/genetics

@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?

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.

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 ∼2%) present in non-African extant humans.

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.

Ancient DNA from six Neanderthals and two Denisovans dated between ∼82 000 and 43 000 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.

Among the eight extinct hominidae analyzed, a total of 9650 non-synonymous variants (only coverage ≥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.

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.

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.

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.

TRIAL REGISTRATION NUMBER: N/A.},
}

Animals
Europe
Genome, Human
*Hominidae/genetics
Humans
Male
*Neanderthals/genetics
Nuclear Proteins
Reproduction/genetics
Trans-Activators

@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.},
}

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

@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 & 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.},
}

Animals
*Caves
DNA, Ancient/*isolation & purification
DNA, Mitochondrial/genetics
Geologic Sediments/*chemistry
Hominidae/*classification/*genetics
Humans
Phylogeny
Tibet

@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.},
}

Animals
Asian People/*genetics
DNA, Ancient
*Evolution, Molecular
Female
Hominidae/*genetics
Humans
Mongolia
Population
Skull

@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 & purification ; DNA, Mitochondrial/*isolation & purification ; Geologic Sediments/*chemistry ; Hominidae/*genetics ; Humans ; Tibet ; },
}

Altitude
Animals
Caves
Cold Temperature
DNA, Ancient/*isolation & purification
DNA, Mitochondrial/*isolation & 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.},
}

Animals
Bicuspid
Asia, Eastern
Fossils
*Hominidae
Humans
*Neanderthals

@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.},
}

Animals
Chromosomes, Human, Y/genetics
DNA, Ancient
DNA, Mitochondrial/genetics
*Evolution, Molecular
Humans
*Life History Traits
Male
Neanderthals/classification/*genetics
Phylogeny
Y Chromosome/*genetics

@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 & 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.},
}

Animals
Biological Evolution
*Hominidae/genetics
Humans
*Neanderthals/genetics
Regulatory Sequences, Nucleic Acid
Selection, Genetic

@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.},
}

Animals
Evolution, Molecular
*Gene Flow
Human Migration
Humans
*Models, Genetic
Neanderthals/*genetics
Population/*genetics
*Recombination, Genetic

@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.},
}

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

@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 & 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.},
}

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 & inhibitors/genetics
RNA-Seq
Repressor Proteins/*genetics
Whole Genome Sequencing

@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 & 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.},
}

*DNA Methylation
*Epigenesis, Genetic
*Evolution, Molecular
*Genetic Variation
*Genome, Human
Humans