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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Stoneking, M. An Introduction to Molecular Anthropology (Wiley, 2017).
Fuhlrott, J. C. & Schaaffhausen, H. Über die Knochenfunde aus dem Neandertal bei Mettmann. Verhandlungen naturwissenschaftlicher-historischer Ver. preussisch Rheinl. Westfal. Correspondenz-Bl. 14, 50–52 (1857).
Meyer, M. et al. Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins. Nature 531, 504–507 (2016).
Higham, T. et al. The timing and spatiotemporal patterning of Neanderthal disappearance. Nature 512, 306–309 (2014).
Krause, J. et al. The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature 464, 894–897 (2010).
Reich, D. et al. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468, 1053–1060 (2010). This study describes the first genome sequence from a Denisovan, demonstrating that Denisovans were a sister group to Neandertals and that they admixed with the ancestors of Melanesians.
Jacobs, Z. et al. Timing of archaic hominin occupation of Denisova Cave in southern Siberia. Nature 565, 594–599 (2019).
Green, R. E. et al. A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing. Cell 134, 416–426 (2008).
Sutikna, T. et al. Revised stratigraphy and chronology for Homo floresiensis at Liang Bua in Indonesia. Nature 532, 366–369 (2016).
Detroit, F. et al. A new species of Homo from the Late Pleistocene of the Philippines. Nature 568, 181–186 (2019).
Rizal, Y. et al. Last appearance of Homo erectus at Ngandong, Java, 117,000–108,000 years ago. Nature 577, 381–385 (2020).
Prüfer, K. et al. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science 358, 655–658 (2017).
Reich, D. et al. Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania. Am. J. Hum. Genet. 89, 516–528 (2011). This study is the first to estimate Denisovan ancestry proportions in a broad set of populations from Asia and Oceania, hinting at Denisovan contact with modern humans in Island Southeast Asia and suggesting that Denisovans were widespread.
Zavala, E. I. et al. Pleistocene sediment DNA reveals hominin and faunal turnovers at Denisova Cave. Nature 595, 399–403 (2021). By analysing the DNA recovered from 728 sediment samples from Denisova Cave, this study reconstructs the occupational history of Denisova Cave and reveals hominin and faunal turnovers. This provides evidence for alternating Denisovan and Neandertal presence at Denisova Cave over a period of around 200,000 years.
Brown, S. et al. The earliest Denisovans and their cultural adaptation. Nat. Ecol. Evol. 6, 28–35 (2022).
Douka, K. et al. Age estimates for hominin fossils and the onset of the Upper Palaeolithic at Denisova Cave. Nature 565, 640–644 (2019).
Chen, F. et al. A late middle Pleistocene Denisovan mandible from the Tibetan Plateau. Nature 569, 409–412 (2019). This study reports the discovery of a late Middle Pleistocene hemi-mandible in the Baishiya Karst Cave that was inferred to be Denisovan based on ancient protein analysis.
Zhang, D. et al. Denisovan DNA in Late Pleistocene sediments from Baishiya Karst cave on the Tibetan Plateau. Science 370, 584–587 (2020). This study reports the retrieval of Denisovan DNA from the sediment of Baishiya Karst Cave, thus confirming the presence of Denisovans in this cave.
Demeter, F. et al. A Middle Pleistocene Denisovan molar from the Annamite chain of northern Laos. Nat. Commun. 13, 2557 (2022).
Chang, C. H. et al. The first archaic Homo from Taiwan. Nat. Commun. 6, 6037 (2015).
Cooper, A. & Stringer, C. B. Did the Denisovans cross Wallace’s line? Science 342, 321–323 (2013).
Kaifu, Y. Archaic hominin populations in Asia before the arrival of modern humans: their phylogeny and implications for the “Southern Denisovans”. Curr. Anthropol. 58, S418–S433 (2017).
Li, Z. Y. et al. Late Pleistocene archaic human crania from Xuchang, China. Science 355, 969–972 (2017).
Ni, X. et al. Massive cranium from Harbin in northeastern China establishes a new Middle Pleistocene human lineage. Innovation 2, 100130 (2021).
Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012). This study describes the first high-quality genome sequence from a Denisovan, which reveals extremely low levels of heterozygosity, refines the population split time between modern and archaic humans, and allows catalogues of the genetic changes between the two groups to be generated.
Li, H. & Durbin, R. Inference of human population history from individual whole-genome sequences. Nature 475, 493–496 (2011).
Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014).
Mafessoni, F. et al. A high-coverage Neandertal genome from Chagyrskaya Cave. Proc. Natl Acad. Sci. USA 117, 15132 (2020).
Skov, L. et al. Genetic insights into the social organization of Neanderthals. Nature 610, 519–525 (2022).
Slon, V. et al. The genome of the offspring of a Neanderthal mother and a Denisovan father. Nature 561, 113–116 (2018). This study describes the genome of Denisova 11, the first-generation offspring of a Neandertal mother and a Denisovan father, providing unequivocal evidence that Neandertals and Denisovans had met and mixed.
Peter, B. M. 100,000 years of gene flow between Neandertals and Denisovans in the Altai Mountains. Preprint at bioRxiv https://doi.org/10.1101/2020.03.13.990523 (2020).
Kuhlwilm, M. et al. Ancient gene flow from early modern humans into eastern Neanderthals. Nature 530, 429–433 (2016).
Peyrégne, S., Kelso, J., Peter, B. M. & Pääbo, S. The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals. eLife https://doi.org/10.7554/eLife.75464 (2022).
Meyer, M. et al. A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature 505, 403–406 (2014).
Petr, M. et al. The evolutionary history of Neanderthal and Denisovan Y chromosomes. Science 369, 1653–1656 (2020).
Posth, C. et al. Deeply divergent archaic mitochondrial genome provides lower time boundary for African gene flow into Neanderthals. Nat. Commun. 8, 16046 (2017).
Peyrégne, S. et al. Nuclear DNA from two early Neandertals reveals 80,000 years of genetic continuity in Europe. Sci. Adv. 5, eaaw5873 (2019).
Hubisz, M. J., Williams, A. L. & Siepel, A. Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph. PLoS Genet. 16, e1008895 (2020).
Kim, B. Y. & Lohmueller, K. E. Selection and reduced population size cannot explain higher amounts of Neandertal ancestry in East Asian than in European human populations. Am. J. Hum. Genet. 96, 454–461 (2015).
Villanea, F. A. & Schraiber, J. G. Multiple episodes of interbreeding between Neanderthal and modern humans. Nat. Ecol. Evol. 3, 39–44 (2019).
Vernot, B. & Akey, J. M. Complex history of admixture between modern humans and Neandertals. Am. J. Hum. Genet. 96, 448–453 (2015).
Wall, J. D. et al. Higher levels of neanderthal ancestry in East Asians than in Europeans. Genetics 194, 199–209 (2013).
Qin, P. & Stoneking, M. Denisovan Ancestry in East Eurasian and Native American populations. Mol. Biol. Evol. 32, 2665–2674 (2015).
Skoglund, P. & Jakobsson, M. Archaic human ancestry in East Asia. Proc. Natl Acad. Sci. USA 108, 18301–18306 (2011).
Sankararaman, S., Mallick, S., Patterson, N. & Reich, D. The combined landscape of Denisovan and Neanderthal ancestry in present-day humans. Curr. Biol. 26, 1241–1247 (2016). This study generates a map of the Denisovan ancestry in the genomes of present-day humans, and also provides the first estimate of the time of admixture with Denisovans.
Lu, D. et al. Ancestral origins and genetic history of Tibetan highlanders. Am. J. Hum. Genet. 99, 580–594 (2016).
Larena, M. et al. Philippine Ayta possess the highest level of Denisovan ancestry in the world. Curr. Biol. 31, 4219–4230 e4210 (2021). This study reports genetic data from 118 present-day ethnic groups of the Philippines and identifies that the Ayta Magbukon have the highest level of Denisovan ancestry worldwide.
Skov, L. et al. The nature of Neanderthal introgression revealed by 27,566 Icelandic genomes. Nature 582, 78–83 (2020).
Bergstrom, A. et al. Insights into human genetic variation and population history from 929 diverse genomes. Science https://doi.org/10.1126/science.aay5012 (2020).
Groube, L., Chappell, J., Muke, J. & Price, D. A 40,000 year-old human occupation site at Huon Peninsula, Papua New Guinea. Nature 324, 453–455 (1986).
Roberts, R. G., Jones, R. & Smith, M. A. Thermoluminescence dating of a 50,000-year-old human occupation site in northern Australia. Nature 345, 153–156 (1990).
Barker, G. et al. The ‘human revolution’ in lowland tropical Southeast Asia: the antiquity and behavior of anatomically modern humans at Niah Cave (Sarawak, Borneo). J. Hum. Evol. 52, 243–261 (2007).
O’Connell, J. F. & Allen, J. The process, biotic impact, and global implications of the human colonization of Sahul about 47,000 years ago. J. Archaeol. Sci. 56, 73–84 (2015).
Summerhayes, G. R. et al. Human adaptation and plant use in highland New Guinea 49,000 to 44,000 years ago. Science 330, 78–81 (2010).
Mijares, A. S. et al. New evidence for a 67,000-year-old human presence at Callao Cave, Luzon, Philippines. J. Hum. Evol. 59, 123–132 (2010).
Demeter, F. et al. Anatomically modern human in Southeast Asia (Laos) by 46 ka. Proc. Natl Acad. Sci. USA 109, 14375–14380 (2012).
O’Connell, J. F. et al. When did Homo sapiens first reach Southeast Asia and Sahul? Proc. Natl Acad. Sci. USA 115, 8482–8490 (2018).
Clarkson, C. et al. Human occupation of northern Australia by 65,000 years ago. Nature 547, 306–310 (2017).
Jinam, T. A. et al. Discerning the origins of the Negritos, First Sundaland People: deep divergence and archaic admixture. Genome Biol. Evol. 9, 2013–2022 (2017).
Göllner, T. et al. Unveiling the genetic history of the Maniq, a primary hunter-gatherer society. Genome Biol. Evol. https://doi.org/10.1093/gbe/evac021 (2022).
Jacobs, G. S. et al. Multiple deeply divergent Denisovan ancestries in Papuans. Cell 177, 1010–1021 e1032 (2019). This study reports genomic data from 161 individuals from 14 island groups in Island Southeast Asia and New Guinea, revealing that Papuans carry DNA from two distinct Denisovan groups.
Malaspinas, A. S. et al. A genomic history of Aboriginal Australia. Nature 538, 207–214 (2016).
Larena, M. et al. Multiple migrations to the Philippines during the last 50,000 years. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2026132118 (2021).
Choin, J. et al. Genomic insights into population history and biological adaptation in Oceania. Nature 592, 583–589 (2021). This study reports whole genomes for 317 individuals from 20 populations in the Pacific region, revealing differences in the proportion and origin of Denisovan ancestry in these populations.
Browning, S. R., Browning, B. L., Zhou, Y., Tucci, S. & Akey, J. M. Analysis of human sequence data reveals two pulses of archaic Denisovan admixture. Cell 173, 53–61.e9 (2018).
Lipson, M. & Reich, D. A working model of the deep relationships of diverse modern human genetic lineages outside of Africa. Mol. Biol. Evol. 34, 889–902 (2017).
Ko, A. M. et al. Early Austronesians: into and out of Taiwan. Am. J. Hum. Genet. 94, 426–436 (2014).
Duggan, A. T. & Stoneking, M. Recent developments in the genetic history of East Asia and Oceania. Curr. Opin. Genet. Dev. 29, 9–14 (2014).
Wollstein, A. et al. Demographic history of Oceania inferred from genome-wide data. Curr. Biol. 20, 1983–1992 (2010).
Xu, S. et al. Genetic dating indicates that the Asian–Papuan admixture through Eastern Indonesia corresponds to the Austronesian expansion. Proc. Natl Acad. Sci. USA 109, 4574–4579 (2012).
McColl, H. et al. The prehistoric peopling of Southeast Asia. Science 361, 88–92 (2018).
Skoglund, P. et al. Genomic insights into the peopling of the Southwest Pacific. Nature 538, 510–513 (2016).
Lipson, M. et al. Population turnover in remote Oceania shortly after initial settlement. Curr. Biol. 28, 1157–1165.e7 (2018).
Mallick, S. et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature 538, 201–206 (2016).
Witt, K. E., Villanea, F., Loughran, E., Zhang, X. & Huerta-Sanchez, E. Apportioning archaic variants among modern populations. Philos. Trans. R. Soc. Lond. B Biol. Sci. 377, 20200411 (2022).
Massilani, D. et al. Denisovan ancestry and population history of early East Asians. Science 370, 579–583 (2020). This study describes the Denisovan ancestry in early East Asians who lived 34 and 40 ka, showing that their Denisovan segments derive from the same admixture event(s) that contributed Denisovan DNA to present-day mainland Asians but are distinct from those in present-day Papuans and Indigenous Australians.
Skoglund, P. et al. Genetic evidence for two founding populations of the Americas. Nature 525, 104–108 (2015).
Moreno-Mayar, J. V. et al. Early human dispersals within the Americas. Science https://doi.org/10.1126/science.aav2621 (2018).
Raghavan, M. et al. Genomic evidence for the Pleistocene and recent population history of Native Americans. Science 349, aab3884 (2015).
Campelo Dos Santos, A. L. et al. Genomic evidence for ancient human migration routes along South America’s Atlantic coast. Proc. Biol. Sci. 289, 20221078 (2022).
Castro, E. S. M. A., Ferraz, T., Bortolini, M. C., Comas, D. & Hunemeier, T. Deep genetic affinity between coastal Pacific and Amazonian natives evidenced by Australasian ancestry. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2025739118 (2021).
Goebel, T., Waters, M. R. & O’Rourke, D. H. The Late Pleistocene dispersal of modern humans in the Americas. Science 319, 1497–1502 (2008).
Sankararaman, S., Patterson, N., Li, H., Paabo, S. & Reich, D. The date of interbreeding between Neandertals and modern humans. PLoS Genet. 8, e1002947 (2012).
Fu, Q. et al. Genome sequence of a 45,000-year-old modern human from western Siberia. Nature 514, 445–449 (2014).
Fu, Q. et al. DNA analysis of an early modern human from Tianyuan Cave, China. Proc. Natl Acad. Sci. USA 110, 2223–2227 (2013).
Yang, M. A. et al. 40,000-Year-old individual from Asia provides insight into early population structure in Eurasia. Curr. Biol. 27, 3202–3208.e9 (2017).
Huerta-Sanchez, E. et al. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 512, 194–197 (2014). By re-sequencing the region around the EPAS1 gene in Tibetans and Han Chinese, this study shows that variants in this gene that underlie adaptation to the hypoxic condition of the high-altitude Tibetan plateau were inherited from Denisovans or a related group.
Zhang, X. et al. The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2020803118 (2021).
Moreno-Mayar, J. V. et al. Terminal Pleistocene Alaskan genome reveals first founding population of Native Americans. Nature 553, 203–207 (2018).
Carlhoff, S. et al. Genome of a middle Holocene hunter-gatherer from Wallacea. Nature 596, 543–547 (2021).
Morwood, M. J. et al. Archaeology and age of a new hominin from Flores in eastern Indonesia. Nature 431, 1087–1091 (2004).
Evans, A. R. et al. The maximum rate of mammal evolution. Proc. Natl Acad. Sci. USA 109, 4187–4190 (2012).
Sutikna, T. et al. The spatio-temporal distribution of archaeological and faunal finds at Liang Bua (Flores, Indonesia) in light of the revised chronology for Homo floresiensis. J. Hum. Evol. 124, 52–74 (2018).
Tucci, S. et al. Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia. Science 361, 511–516 (2018).
Stoneking, M. & Krause, J. Learning about human population history from ancient and modern genomes. Nat. Rev. Genet. 12, 603–614 (2011).
Teixeira, J. C. & Cooper, A. Using hominin introgression to trace modern human dispersals. Proc. Natl Acad. Sci. USA 116, 15327–15332 (2019).
Lahr, M. M. & Foley, R. Multiple dispersals and modern human origins. Evolut. Anthropol. Issues, N., Rev. 3, 48–60 (1994).
Tassi, F. et al. Early modern human dispersal from Africa: genomic evidence for multiple waves of migration. Investig. Genet. 6, 13 (2015).
Pagani, L. et al. Genomic analyses inform on migration events during the peopling of Eurasia. Nature 538, 238–242 (2016).
Skoglund, P. & Mathieson, I. Ancient genomics of modern humans: the first decade. Annu. Rev. Genomics Hum. Genet. 19, 381–404 (2018).
Sawyer, S. et al. Nuclear and mitochondrial DNA sequences from two Denisovan individuals. Proc. Natl Acad. Sci. USA 112, 15696–15700 (2015).
Slon, V. et al. A fourth Denisovan individual. Sci. Adv. 3, e1700186 (2017).
Viola, B. T. et al. A parietal fragment from Denisova Cave. Am. J. Phys. Anthropol. 168, 1–283 (2019).
Kayser, M. & Schneider, P. M. DNA-based prediction of human externally visible characteristics in forensics: motivations, scientific challenges, and ethical considerations. Forensic Sci. Int. Genet. 3, 154–161 (2009).
Liu, F. et al. Eye color and the prediction of complex phenotypes from genotypes. Curr. Biol. 19, R192–R193 (2009).
Burga, A. & Lehner, B. Predicting phenotypic variation from genotypes, phenotypes and a combination of the two. Curr. Opin. Biotechnol. 24, 803–809 (2013).
Brand, C. M., Colbran, L. L. & Capra, J. A. Predicting archaic hominin phenotypes from genomic data. Annu. Rev. Genomics Hum. Genet. 23, 591–612 (2022).
Wang, Y., Tsuo, K., Kanai, M., Neale, B. M. & Martin, A. R. Challenges and opportunities for developing more generalizable polygenic risk scores. Annu. Rev. Biomed. Data Sci. 5, 293–320 (2022).
Castellano, S. et al. Patterns of coding variation in the complete exomes of three Neandertals. Proc. Natl Acad. Sci. USA 111, 6666–6671 (2014).
Cerqueira, C. C. et al. Predicting Homo pigmentation phenotype through genomic data: from Neanderthal to James Watson. Am. J. Hum. Biol. 24, 705–709 (2012).
Perry, G. H., Kistler, L., Kelaita, M. A. & Sams, A. J. Insights into hominin phenotypic and dietary evolution from ancient DNA sequence data. J. Hum. Evol. 79, 55–63 (2015).
Fellows Yates, J. A. et al. The evolution and changing ecology of the African hominid oral microbiome. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2021655118 (2021).
Henry, A. G., Brooks, A. S. & Piperno, D. R. Plant foods and the dietary ecology of Neanderthals and early modern humans. J. Hum. Evol. 69, 44–54 (2014).
Brand, C. M., Colbran, L. L. & Capra, J. A. Resurrecting the alternative splicing landscape of archaic hominins using machine learning. Nat. Ecol. Evol. 7, 939–953 (2023).
Condemi, S. et al. Blood groups of Neandertals and Denisova decrypted. PLoS ONE 16, e0254175 (2021).
King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).
Carroll, S. B. Genetics and the making of Homo sapiens. Nature 422, 849–857 (2003).
Yan, S. M. & McCoy, R. C. Archaic hominin genomics provides a window into gene expression evolution. Curr. Opin. Genet. Dev. 62, 44–49 (2020).
Colbran, L. L. et al. Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences. Nat. Ecol. Evol. 3, 1598–1606 (2019).
Briggs, A. W. et al. Removal of deaminated cytosines and detection of in vivo methylation in ancient DNA. Nucleic Acids Res. 38, e87 (2010).
Gokhman, D. et al. Reconstructing the DNA methylation maps of the Neandertal and the Denisovan. Science 344, 523–527 (2014).
Gokhman, D. et al. Reconstructing Denisovan anatomy using DNA methylation maps. Cell 179, 180–192.e10 (2019).
Weyer, S. & Paabo, S. Functional analyses of transcription factor binding sites that differ between present-day and archaic humans. Mol. Biol. Evol. 33, 316–322 (2016).
Uebbing, S. et al. Massively parallel discovery of human-specific substitutions that alter enhancer activity. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2007049118 (2021).
Weiss, C. V. et al. The cis-regulatory effects of modern human-specific variants. eLife https://doi.org/10.7554/eLife.63713 (2021).
Mora-Bermudez, F. et al. Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development. Sci. Adv. 8, eabn7702 (2022).
Pinson, A. et al. Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals. Science 377, eabl6422 (2022).
Dannemann, M. & Kelso, J. The contribution of Neanderthals to phenotypic variation in modern humans. Am. J. Hum. Genet. 101, 578–589 (2017).
Irving-Pease, E. K., Muktupavela, R., Dannemann, M. & Racimo, F. Quantitative human paleogenetics: what can ancient DNA tell us about complex trait evolution? Front. Genet. 12, 703541 (2021).
McArthur, E., Rinker, D. C. & Capra, J. A. Quantifying the contribution of Neanderthal introgression to the heritability of complex traits. Nat. Commun. 12, 4481 (2021).
Vernot, B. et al. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352, 235–239 (2016). This study generates a map of the Denisovan ancestry in the genomes of present-day humans including 35 individuals from the Bismarck Archipelago.
Harris, K. & Nielsen, R. The genetic cost of Neanderthal introgression. Genetics 203, 881–891 (2016).
Steinrucken, M., Spence, J. P., Kamm, J. A., Wieczorek, E. & Song, Y. S. Model-based detection and analysis of introgressed Neanderthal ancestry in modern humans. Mol. Ecol. 27, 3873–3888 (2018).
Juric, I., Aeschbacher, S. & Coop, G. The strength of selection against Neanderthal introgression. PLoS Genet. 12, e1006340 (2016).
Wei, X. et al. The lingering effects of Neanderthal introgression on human complex traits. eLife https://doi.org/10.7554/eLife.80757 (2023).
Beall, C. M. et al. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc. Natl Acad. Sci. USA 107, 11459–11464 (2010).
Yi, X. et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329, 75–78 (2010).
Simonson, T. S. et al. Genetic evidence for high-altitude adaptation in Tibet. Science 329, 72–75 (2010).
Hackinger, S. et al. Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas. Hum. Genet. 135, 393–402 (2016).
Brantingham, P. J. & Xing, G. Peopling of the northern Tibetan Plateau. World Archaeol. 38, 387–414 (2006).
Gower, G., Picazo, P. I., Fumagalli, M. & Racimo, F. Detecting adaptive introgression in human evolution using convolutional neural networks. eLife https://doi.org/10.7554/eLife.64669 (2021).
Racimo, F., Marnetto, D. & Huerta-Sanchez, E. Signatures of Archaic adaptive introgression in present-day human populations. Mol. Biol. Evol. 34, 296–317 (2017).
Racimo, F. et al. Archaic adaptive introgression in TBX15/WARS2. Mol. Biol. Evol. 34, 509–524 (2017).
Bonfante, B. et al. A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation. Sci. Adv. https://doi.org/10.1126/sciadv.abc6160 (2021).
Jagoda, E. et al. Disentangling immediate adaptive introgression from selection on standing introgressed variation in humans. Mol. Biol. Evol. 35, 623–630 (2018).
Mendez, F. L., Watkins, J. C. & Hammer, M. F. A haplotype at STAT2 Introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea. Am. J. Hum. Genet. 91, 265–274 (2012).
Mendez, F. L., Watkins, J. C. & Hammer, M. F. Neandertal origin of genetic variation at the cluster of OAS immunity genes. Mol. Biol. Evol. 30, 798–801 (2013).
Mendez, F. L., Watkins, J. C. & Hammer, M. F. Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations. Mol. Biol. Evol. 29, 1513–1520 (2012).
Dannemann, M., Andres, A. M. & Kelso, J. Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human Toll-like receptors. Am. J. Hum. Genet. 98, 22–33 (2016).
Deschamps, M. et al. Genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes. Am. J. Hum. Genet. 98, 5–21 (2016).
Quach, H. et al. Genetic adaptation and neandertal admixture shaped the immune system of human populations. Cell 167, 643–656.e17 (2016).
Gittelman, R. M. et al. Archaic hominin admixture facilitated adaptation to out-of-Africa environments. Curr. Biol. 26, 3375–3382 (2016).
Nedelec, Y. et al. Genetic ancestry and natural selection drive population differences in immune responses to pathogens. Cell 167, 657–669.e21 (2016).
Sams, A. J. et al. Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans. Genome Biol. 17, 246 (2016).
Simonti, C. N. et al. The phenotypic legacy of admixture between modern humans and Neandertals. Science 351, 737–741 (2016).
Enard, D. & Petrov, D. A. Evidence that RNA viruses drove adaptive introgression between Neanderthals and modern humans. Cell 175, 360–371.e13 (2018).
Zeberg, H. & Paabo, S. A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2026309118 (2021).
Kerner, G., Patin, E. & Quintana-Murci, L. New insights into human immunity from ancient genomics. Curr. Opin. Immunol. 72, 116–125 (2021).
Abi-Rached, L. et al. The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334, 89–94 (2011).
Brucato, N. et al. Chronology of natural selection in Oceanian genomes. iScience 25, 104583 (2022).
Zammit, N. W. et al. Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. Nat. Immunol. 20, 1299–1310 (2019).
Hsieh, P. et al. Adaptive archaic introgression of copy number variants and the discovery of previously unknown human genes. Science 366, eaax2083 (2019).
Natri, H. M. et al. Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago. PLoS Genet. 16, e1008749 (2020).
Natri, H. M. et al. Genetic architecture of gene regulation in Indonesian populations identifies QTLs associated with global and local ancestries. Am. J. Hum. Genet. 109, 50–65 (2022).
Vespasiani, D. M. et al. Denisovan introgression has shaped the immune system of present-day Papuans. PLoS Genet. 18, e1010470 (2022).
Nagai, A. et al. Overview of the BioBank Japan project: study design and profile. J. Epidemiol. 27, S2–S8 (2017).
Wei, C. Y. et al. Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese. NPJ Genom. Med. 6, 10 (2021).
Claw, K. G. et al. A framework for enhancing ethical genomic research with Indigenous communities. Nat. Commun. 9, 2957 (2018).
Villanea, F. A. & Witt, K. E. Underrepresented populations at the archaic introgression frontier. Front. Genet. 13, 821170 (2022).
Paabo, S. The human condition — a molecular approach. Cell 157, 216–226 (2014).
Kuhlwilm, M. & Boeckx, C. A catalog of single nucleotide changes distinguishing modern humans from archaic hominins. Sci. Rep. 9, 8463 (2019).
Nuttle, X. et al. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. Nature 536, 205–209 (2016).
Giannuzzi, G. et al. The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism individuals. Am. J. Hum. Genet. 105, 947–958 (2019).
Vicedomini, R., Polit, L., Condemi, S., Longo, L. & Carbone, A. Dietary adaptation in Neandertal, Denisovan and Sapiens revealed by gene copy number variation. Preprint at bioRxiv https://doi.org/10.1101/2021.10.30.466563 (2021).
Ohta, T. The nearly neutral theory of molecular evolution. Annu. Rev. Ecol. Syst. 23, 263–286 (1992).
Moriano, J. & Boeckx, C. Modern human changes in regulatory regions implicated in cortical development. BMC Genom. 21, 304 (2020).
Srinivasan, S. et al. Genetic markers of human evolution are enriched in schizophrenia. Biol. Psychiatry 80, 284–292 (2016).
Gokhman, D. et al. Differential DNA methylation of vocal and facial anatomy genes in modern humans. Nat. Commun. 11, 1189 (2020).
Batyrev, D., Lapid, E., Carmel, L. & Meshorer, E. Predicted archaic 3D genome organization reveals genes related to head and spinal cord separating modern from archaic humans. Cells https://doi.org/10.3390/cells9010048 (2019).
Przeworski, M. The signature of positive selection at randomly chosen loci. Genetics 160, 1179–1189 (2002).
Przeworski, M. Estimating the time since the fixation of a beneficial allele. Genetics 164, 1667–1676 (2003).
Racimo, F. Testing for ancient selection using cross-population allele frequency differentiation. Genetics 202, 733–750 (2016).
Racimo, F., Kuhlwilm, M. & Slatkin, M. A test for ancient selective sweeps and an application to candidate sites in modern humans. Mol. Biol. Evol. 31, 3344–3358 (2014).
Peyrégne, S., Boyle, M. J., Dannemann, M. & Prüfer, K. Detecting ancient positive selection in humans using extended lineage sorting. Genome Res. 27, 1563–1572 (2017).
Schaefer, N. K., Shapiro, B. & Green, R. E. An ancestral recombination graph of human, Neanderthal, and Denisovan genomes. Sci. Adv. https://doi.org/10.1126/sciadv.abc0776 (2021).
Stepanova, V. et al. Reduced purine biosynthesis in humans after their divergence from Neandertals. eLife https://doi.org/10.7554/eLife.58741 (2021).
Petr, M., Paabo, S., Kelso, J. & Vernot, B. Limits of long-term selection against Neandertal introgression. Proc. Natl Acad. Sci. USA 116, 1639–1644 (2019).
Telis, N., Aguilar, R. & Harris, K. Selection against archaic hominin genetic variation in regulatory regions. Nat. Ecol. Evol. 4, 1558–1566 (2020).
Silvert, M., Quintana-Murci, L. & Rotival, M. Impact and evolutionary determinants of Neanderthal introgression on transcriptional and post-transcriptional regulation. Am. J. Hum. Genet. 104, 1241–1250 (2019).
Jégou, B., Sankararaman, S., Rolland, A. D., Reich, D. & Chalmel, F. Meiotic genes are enriched in regions of reduced archaic ancestry. Mol. Biol. Evol. 34, 1974–1980 (2017).
Chevy, E. T., Huerta-Sánchez, E. & Ramachandran, S. Integrating sex-bias into studies of archaic admixture on chromosome X. Preprint at bioRxiv https://doi.org/10.1101/2022.08.30.505789 (2022).
Lai, C. S., Fisher, S. E., Hurst, J. A., Vargha-Khadem, F. & Monaco, A. P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519–523 (2001).
Vargha-Khadem, F., Watkins, K., Alcock, K., Fletcher, P. & Passingham, R. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc. Natl Acad. Sci. USA 92, 930–933 (1995).
Fisher, S. E. & Scharff, C. FOXP2 as a molecular window into speech and language. Trends Genet. 25, 166–177 (2009).
Krause, J. et al. The derived FOXP2 variant of modern humans was shared with Neandertals. Curr. Biol. 17, 1908–1912 (2007).
Maricic, T. et al. A recent evolutionary change affects a regulatory element in the human FOXP2 gene. Mol. Biol. Evol. 30, 844–852 (2013).
Maricic, T. et al. Comment on “Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment”. Science 374, eabi6060 (2021).
Trujillo, C. A. et al. Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment. Science https://doi.org/10.1126/science.aax2537 (2021).
Bennett, E. A. et al. Morphology of the Denisovan phalanx closer to modern humans than to Neanderthals. Sci. Adv. 5, eaaw3950 (2019).
Brown, S. et al. Identification of a new hominin bone from Denisova Cave, Siberia using collagen fingerprinting and mitochondrial DNA analysis. Sci. Rep. 6, 23559 (2016).
Iasi, L. N. M., Ringbauer, H. & Peter, B. M. An extended admixture pulse model reveals the limitations to human–Neandertal introgression dating. Mol. Biol. Evol. https://doi.org/10.1093/molbev/msab210 (2021).
Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).
Reich, D., Thangaraj, K., Patterson, N., Price, A. L. & Singh, L. Reconstructing Indian population history. Nature 461, 489–494 (2009).
Patterson, N. et al. Ancient admixture in human history. Genetics 192, 1065–1093 (2012).
Bailey, S. E., Hublin, J. J. & Anton, S. C. Rare dental trait provides morphological evidence of archaic introgression in Asian fossil record. Proc. Natl Acad. Sci. USA 116, 14806–14807 (2019).
Bailey, S. E., Kupczik, K., Hublin, J. J. & Anton, S. C. Reply to Scott et al: a closer look at the 3-rooted lower second molar of an archaic human from Xiahe. Proc. Natl Acad. Sci. USA 117, 39–40 (2020).
Scott, G. R., Irish, J. D. & Martinon-Torres, M. A more comprehensive view of the Denisovan 3-rooted lower second molar from Xiahe. Proc. Natl Acad. Sci. USA 117, 37–38 (2020).
Setter, D. et al. VolcanoFinder: genomic scans for adaptive introgression. PLoS Genet. 16, e1008867 (2020).
Zhang, X. et al. MaLAdapt reveals novel targets of adaptive introgression from Neanderthals and Denisovans in worldwide human populations. Mol. Biol. Evol. https://doi.org/10.1093/molbev/msad001 (2023).
Acknowledgements
The authors thank B. Viola for providing the photographs of Denisovan remains used in Fig. 1 and Fig. 2, and R. Barr for help preparing Fig. 1. They thank S. Pääbo and M. Stoneking for many helpful discussions and for their comments on the manuscript. This project was funded by the Max Planck Society and the European Research Council (grant agreement no. 694707). V.S. acknowledges funding from the Alon Fellowship.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Genetics thanks Omer Gokcumen, who co-reviewed with Alber Aqil, and Mattias Jakobsson, Lluís Quintana-Murci and Shuhua Xu for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Admixture
-
The interbreeding of individuals from two or more previously isolated populations.
- Gene flow
-
The transfer of genetic material from one population to another through interbreeding.
- Genetic drift
-
The random fluctuation in the frequency of genetic variants in a population over time.
- Heterozygosity
-
The presence of two different alleles at a genomic locus.
- Homozygous by descent
-
When both parents share a genomic segment from a recent common ancestor.
- Introgression
-
The acquisition of genetic material from a genetically distinct population.
- Melanesians
-
Present-day Indigenous inhabitants of New Guinea, the Solomon islands, New Caledonia, Fiji and Vanuatu. While the geographic descriptor ‘Melanesia’ should be avoided given its colonialist origin, the term ‘Melanesians’ is widely used by present-day people in the region to describe themselves.
- Negritos
-
Several ethnic groups indigenous to the Andaman Islands, the Malaysian Peninsula, the Philippines and Thailand. Although the term has colonialist origins, these groups today self-identify as Negrito.
- Negative selection
-
The selective removal of deleterious alleles in a population.
- Positive selection
-
The selective increase in the frequency of a beneficial allele in a population.
- Wallace’s line
-
An imaginary boundary separating the biogeographical regions of Asia and Australia.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Peyrégne, S., Slon, V. & Kelso, J. More than a decade of genetic research on the Denisovans. Nat Rev Genet 25, 83–103 (2024). https://doi.org/10.1038/s41576-023-00643-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41576-023-00643-4
