1932

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.

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2022-08-31
2024-04-25
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Literature Cited

  1. 1.
    Ackermann RR, Mackay A, Arnold ML. 2016. The hybrid origin of “modern” humans. Evol. Biol. 43:1–11
    [Google Scholar]
  2. 2.
    Ahlquist KD, Bañuelos MM, Funk A, Lai J, Rong S et al. 2021. Our tangled family tree: new genomic methods offer insight into the legacy of archaic admixture. Genome Biol. Evol. 13:evab115
    [Google Scholar]
  3. 3.
    Banerjee N, Polushina T, Bettella F, Giddaluru S, Steen VM et al. 2018. Recently evolved human-specific methylated regions are enriched in schizophrenia signals. BMC Evol. Biol. 18:63
    [Google Scholar]
  4. 4.
    Batyrev D, Lapid E, Carmel L, Meshorer E. 2020. Predicted archaic 3D genome organization reveals genes related to head and spinal cord separating modern from archaic humans. Cells 9:48
    [Google Scholar]
  5. 5.
    Berens AJ, Cooper TL, Lachance J. 2017. The genomic health of ancient hominins. Hum. Biol. 89:7–19
    [Google Scholar]
  6. 6.
    Bokelmann L, Hajdinjak M, Peyrégne S, Brace S, Essel E et al. 2019. A genetic analysis of the Gibraltar Neanderthals. PNAS 116:15610–15
    [Google Scholar]
  7. 7.
    Bomba L, Walter K, Soranzo N. 2017. The impact of rare and low-frequency genetic variants in common disease. Genome Biol. 18:77
    [Google Scholar]
  8. 8.
    Boyle EA, Li YI, Pritchard JK. 2017. An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–86
    [Google Scholar]
  9. 9.
    Brawand D, Soumillon M, Necsulea A, Julien P, Csárdi G et al. 2011. The evolution of gene expression levels in mammalian organs. Nature 478:343–48
    [Google Scholar]
  10. 10.
    Brown S, Massilani D, Kozlikin MB, Shunkov MV, Derevianko AP et al. 2021. The earliest Denisovans and their cultural adaptation. Nat. Ecol. Evol. 6:28–35
    [Google Scholar]
  11. 11.
    Browning SR, Browning BL, Zhou Y, Tucci S, Akey JM. 2018. Analysis of human sequence data reveals two pulses of archaic Denisovan admixture. Cell 173:53–61.e9
    [Google Scholar]
  12. 12.
    Bustamante CD, De La Vega FM, Burchard EG 2011. Genomics for the world. Nature 475:163–65
    [Google Scholar]
  13. 13.
    Cáceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L et al. 2003. Elevated gene expression levels distinguish human from non-human primate brains. PNAS 100:13030–35
    [Google Scholar]
  14. 14.
    Castellano S, Parra G, Sánchez-Quinto FA, Racimo F, Kuhlwilm M et al. 2014. Patterns of coding variation in the complete exomes of three Neandertals. PNAS 111:6666–71
    [Google Scholar]
  15. 15.
    Cerqueira CCS, Paixão-Côrtes VR, Zambra FMB, Salzano FM, Hünemeier T, Bortolini M-C. 2012. Predicting Homo pigmentation phenotype through genomic data: from Neanderthal to James Watson. Am. J. Hum. Biol. 24:705–9
    [Google Scholar]
  16. 16.
    Chen F, Welker F, Shen C-C, Bailey SE, Bergmann I et al. 2019. A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau. Nature 569:409–12
    [Google Scholar]
  17. 17.
    Chen J, Swofford R, Johnson J, Cummings BB, Rogel N et al. 2019. A quantitative framework for characterizing the evolutionary history of mammalian gene expression. Genome Res. 29:53–63
    [Google Scholar]
  18. 18.
    Chen L, Wolf AB, Fu W, Li L, Akey JM. 2020. Identifying and interpreting apparent Neanderthal ancestry in African individuals. Cell 180:677–87.e16
    [Google Scholar]
  19. 19.
    Chintalapati M, Dannemann M, Prüfer K. 2017. Using the Neandertal genome to study the evolution of small insertions and deletions in modern humans. BMC Evol. Biol. 17:179
    [Google Scholar]
  20. 20.
    Choin J, Mendoza-Revilla J, Arauna LR, Cuadros-Espinoza S, Cassar O et al. 2021. Genomic insights into population history and biological adaptation in Oceania. Nature 592:583–89
    [Google Scholar]
  21. 21.
    Colbran LL, Gamazon ER, Zhou D, Evans P, Cox NJ, Capra JA. 2019. Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences. Nat. Ecol. Evol. 3:1598–1606
    [Google Scholar]
  22. 22.
    Conrad B, Antonarakis SE. 2007. Gene duplication: a drive for phenotypic diversity and cause of human disease. Annu. Rev. Genom. Hum. Genet. 8:17–35
    [Google Scholar]
  23. 23.
    Coppo L, Mishra P, Siefert N, Holmgren A, Pääbo S, Zeberg H. 2022. A substitution in the glutathione reductase lowers electron leakage and inflammation in modern humans. Sci. Adv. 8:eabm1148
    [Google Scholar]
  24. 24.
    Dannemann M, Andrés AM, Kelso J. 2016. Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human Toll-like receptors. Am. J. Hum. Genet. 98:22–33
    [Google Scholar]
  25. 25.
    Dannemann M, Gallego Romero I. 2022. Harnessing pluripotent stem cells as models to decipher human evolution. FEBS J 289:29923010
    [Google Scholar]
  26. 26.
    Dannemann M, He Z, Heide C, Vernot B, Sidow L et al. 2020. Human stem cell resources are an inroad to Neandertal DNA functions. Stem Cell Rep 15:214–25
    [Google Scholar]
  27. 27.
    Dannemann M, Kelso J. 2017. The contribution of Neanderthals to phenotypic variation in modern humans. Am. J. Hum. Genet. 101:578–89
    [Google Scholar]
  28. 28.
    Dannemann M, Prüfer K, Kelso J. 2017. Functional implications of Neandertal introgression in modern humans. Genome Biol 18:61
    [Google Scholar]
  29. 29.
    Dannemann M, Racimo F. 2018. Something old, something borrowed: admixture and adaptation in human evolution. Curr. Opin. Genet. Dev. 53:1–8
    [Google Scholar]
  30. 30.
    Deschamps M, Laval G, Fagny M, Itan Y, Abel L et al. 2016. Genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes. Am. J. Hum. Genet. 98:5–21
    [Google Scholar]
  31. 31.
    Dolgova O, Lao O. 2018. Evolutionary and medical consequences of archaic introgression into modern human genomes. Genes 9:358
    [Google Scholar]
  32. 32.
    Douka K, Slon V, Jacobs Z, Ramsey CB, Shunkov MV et al. 2019. Age estimates for hominin fossils and the onset of the Upper Palaeolithic at Denisova Cave. Nature 565:640–44
    [Google Scholar]
  33. 33.
    ENCODE Proj. Consort. 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74
    [Google Scholar]
  34. 34.
    Feuk L, Carson AR, Scherer SW. 2006. Structural variation in the human genome. Nat. Rev. Genet. 7:85–97
    [Google Scholar]
  35. 35.
    Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y et al. 2015. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47:1228–35
    [Google Scholar]
  36. 36.
    Flanagan JM 2015. Epigenome-wide association studies (EWAS): past, present, and future. Cancer Epigenetics: Risk Assessment, Diagnosis, Treatment, and Prognosis M Verma 51–63 New York: Springer
    [Google Scholar]
  37. 37.
    Gasperini M, Tome JM, Shendure J. 2020. Towards a comprehensive catalogue of validated and target-linked human enhancers. Nat. Rev. Genet. 21:292–310
    [Google Scholar]
  38. 38.
    Gokcumen O. 2020. Archaic hominin introgression into modern human genomes. Am. J. Phys. Anthropol. 171:Suppl. 7060–73
    [Google Scholar]
  39. 39.
    Gokhman D, Lavi E, Prüfer K, Fraga MF, Riancho JA et al. 2014. Reconstructing the DNA methylation maps of the Neandertal and the Denisovan. Science 344:523–27
    [Google Scholar]
  40. 40.
    Gokhman D, Mishol N, de Manuel M, de Juan D, Shuqrun J et al. 2019. Reconstructing Denisovan anatomy using DNA methylation maps. Cell 179:180–92.e10
    [Google Scholar]
  41. 41.
    Gokhman D, Nissim-Rafinia M, Agranat-Tamir L, Housman G, García-Pérez R et al. 2020. Differential DNA methylation of vocal and facial anatomy genes in modern humans. Nat. Commun. 11:1189
    [Google Scholar]
  42. 42.
    Gómez-Olivencia A, Arlegi M, Barash A, Stock JT, Been E. 2017. The Neandertal vertebral column 2: the lumbar spine. J. Hum. Evol. 106:84–101
    [Google Scholar]
  43. 43.
    Gower G, Picazo PI, Fumagalli M, Racimo F. 2021. Detecting adaptive introgression in human evolution using convolutional neural networks. eLife 10:e64669
    [Google Scholar]
  44. 44.
    Green RE, Krause J, Briggs AW, Maricic T, Stenzel U et al. 2010. A draft sequence of the Neandertal genome. Science 328:710–22
    [Google Scholar]
  45. 45.
    GTex Consort. 2020. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369:1318–30
    [Google Scholar]
  46. 46.
    Gunz P, Tilot AK, Wittfeld K, Teumer A, Shapland CY et al. 2019. Neandertal introgression sheds light on modern human endocranial globularity. Curr. Biol. 29:120–27.e5
    [Google Scholar]
  47. 47.
    Hajdinjak M, Fu Q, Hübner A, Petr M, Mafessoni F et al. 2018. Reconstructing the genetic history of late Neanderthals. Nature 555:652–56
    [Google Scholar]
  48. 48.
    Harris K, Nielsen R. 2016. The genetic cost of Neanderthal introgression. Genetics 203:881–91
    [Google Scholar]
  49. 49.
    Hernandez RD, Uricchio LH, Hartman K, Ye C, Dahl A, Zaitlen N. 2019. Ultrarare variants drive substantial cis heritability of human gene expression. Nat. Genet. 51:1349–55
    [Google Scholar]
  50. 50.
    Hofreiter M, Serre D, Poinar HN, Kuch M, Pääbo S. 2001. Ancient DNA. Nat. Rev. Genet. 2:353–59
    [Google Scholar]
  51. 51.
    Hsieh P, Vollger MR, Dang V, Porubsky D, Baker C et al. 2019. Adaptive archaic introgression of copy number variants and the discovery of previously unknown human genes. Science 366:eaax2083
    [Google Scholar]
  52. 52.
    Huerta-Sánchez E, Jin X, Asan BZ, Peter BM, Vinckenbosch N et al. 2014. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 512:194–97
    [Google Scholar]
  53. 53.
    Irving-Pease EK, Muktupavela R, Dannemann M, Racimo F. 2021. Quantitative human paleogenetics: What can ancient DNA tell us about complex trait evolution?. Front. Genet. 12:703541
    [Google Scholar]
  54. 54.
    Jacobs GS, Hudjashov G, Saag L, Kusuma P, Darusallam CC et al. 2019. Multiple deeply divergent Denisovan ancestries in Papuans. Cell 177:1010–21.e32
    [Google Scholar]
  55. 55.
    Jacobs Z, Li B, Shunkov MV, Kozlikin MB, Bolikhovskaya NS et al. 2019. Timing of archaic hominin occupation of Denisova Cave in southern Siberia. Nature 565:594–99
    [Google Scholar]
  56. 56.
    Jennings R, Finlayson C, Fa D, Finlayson G. 2011. Southern Iberia as a refuge for the last Neanderthal populations. J. Biogeogr. 38:1873–85
    [Google Scholar]
  57. 57.
    Juric I, Aeschbacher S, Coop G. 2016. The strength of selection against Neanderthal introgression. PLOS Genet. 12:e1006340
    [Google Scholar]
  58. 58.
    Kaler AS, Purcell LC. 2019. Estimation of a significance threshold for genome-wide association studies. BMC Genom. 20:618
    [Google Scholar]
  59. 59.
    Khaitovich P, Muetzel B, She X, Lachmann M, Hellmann I et al. 2004. Regional patterns of gene expression in human and chimpanzee brains. Genome Res. 14:1462–73
    [Google Scholar]
  60. 60.
    Kim BY, Lohmueller KE. 2015. Selection and reduced population size cannot explain higher amounts of Neandertal ancestry in East Asian than in European human populations. Am. J. Hum. Genet. 96:454–61
    [Google Scholar]
  61. 61.
    King M-C, Wilson AC. 1975. Evolution at two levels in humans and chimpanzees. Science 188:107–16
    [Google Scholar]
  62. 62.
    Kuhlwilm M, Boeckx C. 2019. A catalog of single nucleotide changes distinguishing modern humans from archaic hominins. Sci. Rep. 9:8463
    [Google Scholar]
  63. 63.
    Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A et al. 2015. Integrative analysis of 111 reference human epigenomes. Nature 518:317–30
    [Google Scholar]
  64. 64.
    Larena M, McKenna J, Sanchez-Quinto F, Bernhardsson C, Ebeo C et al. 2021. Philippine Ayta possess the highest level of Denisovan ancestry in the world. Curr. Biol. 31:4219–30.e10
    [Google Scholar]
  65. 65.
    Lazaridis I, Nadel D, Rollefson G, Merrett DC, Rohland N et al. 2016. Genomic insights into the origin of farming in the ancient Near East. Nature 536:419–24
    [Google Scholar]
  66. 66.
    Leakey MG, Spoor F, Dean MC, Feibel CS, Antón SC et al. 2012. New fossils from Koobi Fora in northern Kenya confirm taxonomic diversity in early Homo. Nature 488:201–4
    [Google Scholar]
  67. 67.
    Li Z-Y, Wu X-J, Zhou L-P, Liu W, Gao X et al. 2017. Late Pleistocene archaic human crania from Xuchang, China. Science 355:969–72
    [Google Scholar]
  68. 68.
    Lin Y-L, Pavlidis P, Karakoc E, Ajay J, Gokcumen O 2015. The evolution and functional impact of human deletion variants shared with archaic hominin genomes. Mol. Biol. Evol. 32:1008–19
    [Google Scholar]
  69. 69.
    Liu Y, Mao X, Krause J, Fu Q. 2021. Insights into human history from the first decade of ancient human genomics. Science 373:1479–84
    [Google Scholar]
  70. 70.
    Mafessoni F, Grote S, de Filippo C, Slon V, Kolobova KA et al. 2020. A high-coverage Neandertal genome from Chagyrskaya Cave. PNAS 117:15132–36
    [Google Scholar]
  71. 71.
    Marciniak S, Perry GH. 2017. Harnessing ancient genomes to study the history of human adaptation. Nat. Rev. Genet. 18:659–74
    [Google Scholar]
  72. 72.
    Maricic T, Helmbrecht N, Riesenberg S, Macak D, Kanis P et al. 2021. Comment on “Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment. .” Science 374:eabi6060
    [Google Scholar]
  73. 73.
    Martin AR, Gignoux CR, Walters RK, Wojcik GL, Neale BM et al. 2017. Human demographic history impacts genetic risk prediction across diverse populations. Am. J. Hum. Genet. 100:635–49
    [Google Scholar]
  74. 74.
    Mathieson I. 2021. The omnigenic model and polygenic prediction of complex traits. Am. J. Hum. Genet. 108:1558–63
    [Google Scholar]
  75. 75.
    Mathov Y, Batyrev D, Meshorer E, Carmel L 2020. Harnessing epigenetics to study human evolution. Curr. Opin. Genet. Dev. 62:23–29
    [Google Scholar]
  76. 76.
    McArthur E, Rinker DC, Capra JA. 2021. Quantifying the contribution of Neanderthal introgression to the heritability of complex traits. Nat. Commun. 12:4481
    [Google Scholar]
  77. 77.
    McCoy RC, Wakefield J, Akey JM. 2017. Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression. Cell 168:916–27.e12
    [Google Scholar]
  78. 78.
    Meyer M, Arsuaga J-L, de Filippo C, Nagel S, Aximu-Petri A et al. 2016. Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins. Nature 531:504–7
    [Google Scholar]
  79. 79.
    Meyer M, Fu Q, Aximu-Petri A, Glocke I, Nickel B et al. 2014. A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature 505:403–6
    [Google Scholar]
  80. 80.
    Meyer M, Kircher M, Gansauge M-T, Li H, Racimo F et al. 2012. A high-coverage genome sequence from an archaic Denisovan individual. Science 338:222–26
    [Google Scholar]
  81. 81.
    Miga KH, Wang T. 2021. The need for a human pangenome reference sequence. Annu. Rev. Genom. Hum. Genet. 22:81–102
    [Google Scholar]
  82. 82.
    Moore JE, Purcaro MJ, Pratt HE, Epstein CB, Shoresh N et al. 2020. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583:699–710
    [Google Scholar]
  83. 83.
    Mostafavi H, Harpak A, Agarwal I, Conley D, Pritchard JK, Przeworski M. 2020. Variable prediction accuracy of polygenic scores within an ancestry group. eLife 9:e48376
    [Google Scholar]
  84. 84.
    Narasimhan VM, Patterson N, Moorjani P, Rohland N, Bernardos R et al. 2019. The formation of human populations in South and Central Asia. Science 365:eaat7487
    [Google Scholar]
  85. 85.
    Nurk S, Koren S, Rhie A, Rautiainen M, Bzikadze AV et al. 2021. The complete sequence of a human genome. bioRxiv 2021.05.26.445798. https://doi.org/10.1101/2021.05.26.445798
    [Crossref]
  86. 86.
    Petr M, Hajdinjak M, Fu Q, Essel E, Rougier H et al. 2020. The evolutionary history of Neanderthal and Denisovan Y chromosomes. Science 369:1653–56
    [Google Scholar]
  87. 87.
    Petr M, Pääbo S, Kelso J, Vernot B. 2019. Limits of long-term selection against Neandertal introgression. PNAS 116:1639–44
    [Google Scholar]
  88. 88.
    Peyrégne S, Slon V, Mafessoni F, de Filippo C, Hajdinjak M et al. 2019. Nuclear DNA from two early Neandertals reveals 80,000 years of genetic continuity in Europe. Sci. Adv. 5:eaaw5873
    [Google Scholar]
  89. 89.
    Popejoy AB, Fullerton SM. 2016. Genomics is failing on diversity. Nature 538:161–64
    [Google Scholar]
  90. 90.
    Posth C, Nägele K, Colleran H, Valentin F, Bedford S et al. 2018. Language continuity despite population replacement in Remote Oceania. Nat. Ecol. Evol. 2:731–40
    [Google Scholar]
  91. 91.
    Posth C, Wißing C, Kitagawa K, Pagani L, van Holstein L et al. 2017. Deeply divergent archaic mitochondrial genome provides lower time boundary for African gene flow into Neanderthals. Nat. Commun. 8:16046
    [Google Scholar]
  92. 92.
    Prado-Martinez J, Sudmant PH, Kidd JM, Li H, Kelley JL et al. 2013. Great ape genetic diversity and population history. Nature 499:471–75
    [Google Scholar]
  93. 93.
    Prang TC, Ramirez K, Grabowski M, Williams SA. 2021. Ardipithecus hand provides evidence that humans and chimpanzees evolved from an ancestor with suspensory adaptations. Sci. Adv. 7:eabf2474
    [Google Scholar]
  94. 94.
    Prüfer K, de Filippo C, Grote S, Mafessoni F, Korlević P et al. 2017. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science 358:655–58
    [Google Scholar]
  95. 95.
    Prüfer K, Racimo F, Patterson N, Jay F, Sankararaman S et al. 2014. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505:43–49
    [Google Scholar]
  96. 96.
    Racimo F, Sankararaman S, Nielsen R, Huerta-Sánchez E. 2015. Evidence for archaic adaptive introgression in humans. Nat. Rev. Genet. 16:359–71
    [Google Scholar]
  97. 97.
    Reich D, Green RE, Kircher M, Krause J, Patterson N et al. 2010. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468:1053–60
    [Google Scholar]
  98. 98.
    Rinker DC, Simonti CN, McArthur E, Shaw D, Hodges E, Capra JA. 2020. Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations. Nat. Ecol. Evol. 4:1332–41
    [Google Scholar]
  99. 99.
    Rogers AR, Harris NS, Achenbach AA. 2020. Neanderthal-Denisovan ancestors interbred with a distantly related hominin. Sci. Adv. 6:eaay5483
    [Google Scholar]
  100. 100.
    Rotival M, Quintana-Murci L. 2020. Functional consequences of archaic introgression and their impact on fitness. Genome Biol 21:3
    [Google Scholar]
  101. 101.
    Saitou M, Resendez S, Pradhan AJ, Wu F, Lie NC et al. 2021. Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor. Sci. Adv. 7:eabi4476
    [Google Scholar]
  102. 102.
    Sams AJ, Dumaine A, Nédélec Y, Yotova V, Alfieri C et al. 2016. Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans. Genome Biol 17:246
    [Google Scholar]
  103. 103.
    Sánchez-Quinto F, Botigué LR, Civit S, Arenas C, Ávila-Arcos MC et al. 2012. North African populations carry the signature of admixture with Neandertals. PLOS ONE 7:e47765
    [Google Scholar]
  104. 104.
    Sankararaman S, Mallick S, Dannemann M, Prüfer K, Kelso J et al. 2014. The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507:354–57
    [Google Scholar]
  105. 105.
    Sankararaman S, Mallick S, Patterson N, Reich D. 2016. The combined landscape of Denisovan and Neanderthal ancestry in present-day humans. Curr. Biol. 26:1241–47
    [Google Scholar]
  106. 106.
    Sawyer S, Renaud G, Viola B, Hublin J-J, Gansauge M-T et al. 2015. Nuclear and mitochondrial DNA sequences from two Denisovan individuals. PNAS 112:15696–700
    [Google Scholar]
  107. 107.
    Scally A, Dutheil JY, Hillier LW, Jordan GE, Goodhead I et al. 2012. Insights into hominid evolution from the gorilla genome sequence. Nature 483:169–75
    [Google Scholar]
  108. 108.
    Seguin-Orlando A, Gamba C, Sarkissian CD, Ermini L, Louvel G et al. 2015. Pros and cons of methylation-based enrichment methods for ancient DNA. Sci. Rep. 5:11826
    [Google Scholar]
  109. 109.
    Silvert M, Quintana-Murci L, Rotival M. 2019. Impact and evolutionary determinants of Neanderthal introgression on transcriptional and post-transcriptional regulation. Am. J. Hum. Genet. 104:1241–50
    [Google Scholar]
  110. 110.
    Simonti CN, Vernot B, Bastarache L, Bottinger E, Carrell DS et al. 2016. The phenotypic legacy of admixture between modern humans and Neandertals. Science 351:737–41
    [Google Scholar]
  111. 111.
    Sirugo G, Williams SM, Tishkoff SA. 2019. The missing diversity in human genetic studies. Cell 177:26–31
    [Google Scholar]
  112. 112.
    Sivakumaran S, Agakov F, Theodoratou E, Prendergast JG, Zgaga L et al. 2011. Abundant pleiotropy in human complex diseases and traits. Am. J. Hum. Genet. 89:607–18
    [Google Scholar]
  113. 113.
    Skoglund P, Mathieson I. 2018. Ancient genomics of modern humans: the first decade. Annu. Rev. Genom. Hum. Genet. 19:381–404
    [Google Scholar]
  114. 114.
    Skov L, Macià MC, Sveinbjörnsson G, Mafessoni F, Lucotte EA et al. 2020. The nature of Neanderthal introgression revealed by 27,566 Icelandic genomes. Nature 582:78–83
    [Google Scholar]
  115. 115.
    Slatkin M, Racimo F. 2016. Ancient DNA and human history. PNAS 113:6380–87
    [Google Scholar]
  116. 116.
    Slon V, Mafessoni F, Vernot B, de Filippo C, Grote S et al. 2018. The genome of the offspring of a Neanderthal mother and a Denisovan father. Nature 561:113–16
    [Google Scholar]
  117. 117.
    Slon V, Viola B, Renaud G, Gansauge M-T, Benazzi S et al. 2017. A fourth Denisovan individual. Sci. Adv. 3:e1700186
    [Google Scholar]
  118. 118.
    Smith ZD, Meissner A. 2013. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14:204–20
    [Google Scholar]
  119. 119.
    Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW. 2013. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14:483–95
    [Google Scholar]
  120. 120.
    Telis N, Aguilar R, Harris K. 2020. Selection against archaic hominin genetic variation in regulatory regions. Nat. Ecol. Evol. 4:1558–66
    [Google Scholar]
  121. 121.
    Torkamani A, Wineinger NE, Topol EJ. 2018. The personal and clinical utility of polygenic risk scores. Nat. Rev. Genet. 19:581–90
    [Google Scholar]
  122. 122.
    Trujillo CA, Rice ES, Schaefer NK, Chaim IA, Wheeler EC et al. 2021. Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment. Science 371:eaax2537
    [Google Scholar]
  123. 123.
    Ungar PS. 2011. Dental evidence for the diets of Plio-Pleistocene hominins. Am. J. Phys. Anthropol. 146:Suppl. 5347–62
    [Google Scholar]
  124. 124.
    Vernot B, Akey JM. 2014. Resurrecting surviving Neandertal lineages from modern human genomes. Science 343:1017–21
    [Google Scholar]
  125. 125.
    Vernot B, Akey JM. 2015. Complex history of admixture between modern humans and Neandertals. Am. J. Hum. Genet. 96:448–53
    [Google Scholar]
  126. 126.
    Vernot B, Tucci S, Kelso J, Schraiber JG, Wolf AB et al. 2016. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352:235–39
    [Google Scholar]
  127. 127.
    Vernot B, Zavala EI, Gómez-Olivencia A, Jacobs Z, Slon V et al. 2021. Unearthing Neanderthal population history using nuclear and mitochondrial DNA from cave sediments. Science 372:eabf1667
    [Google Scholar]
  128. 128.
    Villanea FA, Schraiber JG. 2019. Multiple episodes of interbreeding between Neanderthal and modern humans. Nat. Ecol. Evol. 3:39–44
    [Google Scholar]
  129. 129.
    Wall JD, Brandt DYC. 2016. Archaic admixture in human history. Curr. Opin. Genet. Dev. 41:93–97
    [Google Scholar]
  130. 130.
    Wang Q, Dhindsa RS, Carss K, Harper AR, Nag A et al. 2021. Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature 597:527–32
    [Google Scholar]
  131. 131.
    Wang S, Lachance J, Tishkoff SA, Hey J, Xing J. 2013. Apparent variation in Neanderthal admixture among African populations is consistent with gene flow from non-African populations. Genome Biol. Evol. 5:2075–81
    [Google Scholar]
  132. 132.
    Welker F, Ramos-Madrigal J, Gutenbrunner P, Mackie M, Tiwary S et al. 2020. The dental proteome of Homo antecessor. Nature 580:235–38
    [Google Scholar]
  133. 133.
    Wilkinson RD, Steiper ME, Soligo C, Martin RD, Yang Z, Tavaré S 2011. Dating primate divergences through an integrated analysis of palaeontological and molecular data. Syst. Biol. 60:16–31
    [Google Scholar]
  134. 134.
    Wolf AB, Akey JM. 2018. Outstanding questions in the study of archaic hominin admixture. PLOS Genet 14:e1007349
    [Google Scholar]
  135. 135.
    Wood B, Boyle EK. 2016. Hominin taxic diversity: fact or fantasy?. Am. J. Phys. Anthropol. 159:Suppl. 6137–78
    [Google Scholar]
  136. 136.
    Wood B, Harrison T. 2011. The evolutionary context of the first hominins. Nature 470:347–52
    [Google Scholar]
  137. 137.
    Zeberg H, Dannemann M, Sahlholm K, Tsuo K, Maricic T et al. 2020. A Neanderthal sodium channel increases pain sensitivity in present-day humans. Curr. Biol. 30:3465–69.e4
    [Google Scholar]
  138. 138.
    Zeberg H, Kelso J, Pääbo S. 2020. The Neandertal progesterone receptor. Mol. Biol. Evol. 37:2655–60
    [Google Scholar]
  139. 139.
    Zeberg H, Pääbo S. 2020. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature 587:610–12
    [Google Scholar]
  140. 140.
    Zeberg H, Pääbo S. 2021. A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. PNAS 118:e2026309118
    [Google Scholar]
  141. 141.
    Zhang C, Hansen MEB, Tishkoff SA. 2022. Advances in integrative African genomics. Trends Genet. 38:152–68
    [Google Scholar]
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