Genetic studies on Neanderthal ancient DNA became possible in the late 1990s.[1] The Neanderthal genome project, established in 2006, presented the first fully sequenced Neanderthal genome in 2013.

Since 2005, evidence for substantial admixture of Neanderthal DNA in modern populations is accumulating.[2][3][4]

The divergence time between the Neanderthal and modern human lineages is estimated at between 750,000 and 400,000 years ago. The recent time is suggested by Endicott et al. (2010)[5] and Rieux et al. (2014).[6] A significantly deeper time of parallelism, combined with repeated early admixture events, was calculated by Rogers et al. (2017).[7]

Genome sequencing

In July 2006, the Max Planck Institute for Evolutionary Anthropology and 454 Life Sciences announced that they would sequence the Neanderthal genome over the next two years. It was hoped the comparison would expand understanding of Neanderthals, as well as the evolution of humans and human brains.[8]

In 2008 Richard E. Green et al. from Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, published the full sequence of Neanderthal mitochondrial DNA (mtDNA) and suggested "Neanderthals had a long-term effective population size smaller than that of modern humans."[9] In the same publication, it was disclosed by Svante Pääbo that in the previous work at the Max Planck Institute, "Contamination was indeed an issue," and they eventually realised that 11% of their sample was modern human DNA.[10][11] Since then, more of the preparation work has been done in clean areas and 4-base pair 'tags' have been added to the DNA as soon as it is extracted so the Neanderthal DNA can be identified.

Geneticist at the Max Planck Institute for Evolutionary Anthropology extracting ancient DNA (2005 photograph)

The project first sequenced the entire genome of a Neanderthal in 2013 by extracting it from the phalanx bone of a 50,000-year-old Siberian Neanderthal.[12]

Among the genes shown to differ between present-day humans and Neanderthals were RPTN, SPAG17, CAN15, TTF1, and PCD16.[13]

A visualisation map of the reference modern-human containing the genome regions with high degree of similarity or with novelty according to a Neanderthal of 50 ka[12] has been built by Pratas et al.[14]

Interbreeding with anatomically modern humans

Researchers addressed the question of possible interbreeding between Neanderthals and anatomically modern humans (AMH) from the early archaeogenetic studies of the 1990s. As late as 2006, no evidence for interbreeding was found.[15] As late as 2009, analysis of about one third of the full genome of the Altai individual showed "no sign of admixture". The variant of microcephalin common outside Africa, suggested[16] to be of Neanderthal origin and responsible for rapid brain growth in humans, was not found in Neanderthals; nor was a very old MAPT variant found primarily in Europeans.[10] However, more recent studies have concluded that gene flow between Neanderthals and AMH occurred multiple times over thousands of years.[17]

Positive evidence for admixture was first published in May 2010.[13] Neanderthal-inherited genetic material is found in all non- Sub Saharan African populations and was initially reported to comprise 1 to 4 percent of the genome.[13] This fraction was refined to 1.5 to 2.1 percent.[12] Further analyses have found that Neanderthal gene flow is even detectable in African populations, suggesting that some variants obtained from Neanderthals posed a survival advantage.[17]

Approximately 20 percent of Neanderthal DNA survives in modern humans; however, a single human has an average of around 2% Neanderthal DNA overall with some countries and backgrounds having a maximum of 3% per human.[18] Modern human genes involved in making keratin, a protein constituent of skin, hair, and nails, contain high levels of introgression. For example, the genes of approximately 66% of East Asians contain a POUF23L variant introgressed from Neanderthals, while 70% of Europeans possess an introgressed allele of BNC2. Neanderthal variants affect the risk of developing several diseases, including lupus, biliary cirrhosis, Crohn's disease, type 2 diabetes, and SARS-CoV-2.[18][19][20] The allele of MC1R linked to red hair in Neanderthals is not found in Europeans, but is present in Taiwanese Aborigines at a frequency of 70% and at moderately high frequencies in other East Asian populations; hence, there is no evidence Neanderthals had red hair.[21] While interbreeding is viewed as the most parsimonious interpretation of these genetic findings, the 2010 research of five present-day humans from different parts of the world does not rule out an alternative scenario, in which the source population of several non-African modern humans was more closely related than other Africans to Neanderthals because of ancient genetic divisions within early Hominoids.[13][22]

Le Moustier Neanderthal skull reconstruction, Neues Museum Berlin[23]

Research since 2010 refined the picture of interbreeding between Neanderthals, Denisovans, and anatomically modern humans. Interbreeding appears asymmetrically among the ancestors of modern-day humans, and this may explain differing frequencies of Neanderthal-specific DNA in the genomes of modern humans. Vernot and Akey (2015) concluded the greater quantity of Neanderthal-specific DNA in the genomes of individuals of East Asian descent (compared with those of European descent) cannot be explained by differences in selection.[24] They suggest "two additional demographic models, involving either a second pulse of Neanderthal gene flow into the ancestors of East Asians or a dilution of Neanderthal lineages in Europeans by admixture with an unknown ancestral population" are parsimonious with their data.[24]

Kim and Lohmueller (2015) reached similar conclusions:

" According to some researchers, the greater proportion of Neanderthal ancestry in East Asians than in Europeans or West Asians is due to purifying selection is less effective at removing the so-called 'weakly-deleterious' Neanderthal alleles from East Asian populations. Computer simulations of a broad range of models of selection and demography indicate this hypothesis cannot account for the higher proportion of Neanderthal ancestry in East Asians than in Europeans. Instead, complex demographic scenarios, likely involving multiple pulses of Neanderthal admixture, are required to explain the data."[25]

Khrameeva et al. (2014), a German-Russian-Chinese collaboration, compiled an elementary Neanderthal genome based on the Altai individual and three Vindjia individuals. This was compared to a consensus chimpanzee genome as the out-group and to the genome of eleven modern populations (three African, three East Asian, three European). Beyond confirming a greater similarity to the Neanderthal genome in several non-Africans than in Africans, the study also found a difference in the distribution of Neanderthal-derived sites between Europeans and East Asians, suggesting recent evolutionary pressures. Asian populations showed clustering in functional groups related to immune and haematopoietic pathways, while Europeans showed clustering in functional groups related to the lipid catabolic process.[26]

Kuhlwilm et al. (2016) presented evidence for AMH admixture to Neanderthals at roughly 100,000 years ago.[27]

At minimum, research indicates three episodes of interbreeding. The first occurred with some modern humans. The second occurred after the ancestral Melanesians branched; these people seem to have bred with Denisovans. The third involved Neanderthals and the ancestors of East Asians only.[28][29][30]

2016 research indicates some Neanderthal males might not have viable male offspring with some AMH females. This could explain the reason why no modern man has a Neanderthal Y chromosome.[31]

2018 research indicates interbreeding between Neanderthals and modern humans led to the exposure of each species to unfamiliar viruses. Later on, the exchange of genes granted resistance to those viruses, too.[32]

On July 3, 2020, scientists reported finding a major genetic risk factor of the COVID-19 virus was inherited from archaic Neanderthals 60,000 years ago.[19][20][33] It is estimated that 16% of people in Europe and 50% of people in south Asia have the particular sequence on chromosome III,[34] with 63% of Bangladeshis having these gene sequences. North Africans sub Saharan Africans, West Asians and East Asians feature the presence of the chromosome in very negligible amounts.[35]

In December 2023, scientists reported that genes inherited by modern humans from Neanderthals and Denisovans may biologically influence the daily routine of modern humans, including the ability for some humans to wake earlier than others.[36]

Epigenetics

Complete DNA methylation maps for Neanderthal and Denisovan individuals were reconstructed in 2014.[37] Differential activity of HOX cluster genes lie behind many of the anatomical differences between Neanderthals and modern humans, especially in regards to limb morphology. In general, Neanderthals possessed shorter limbs with curved bones.[37][38]

See also

References

  1. ↑ Ovchinnikov, Igor V.; Götherström, Anders; Romanova, Galina P.; Kharitonov, Vitaliy M.; Lidén, Kerstin; Goodwin, William (2000). "Molecular analysis of Neanderthal DNA from the northern Caucasus". Nature. 404 (6777): 490–93. Bibcode:2000Natur.404..490O. doi:10.1038/35006625. PMID 10761915. S2CID 3101375.
  2. ↑ Sánchez-Quinto, Federico; Botigué, Laura R.; Civit, Sergi; Arenas, Conxita; Ávila-Arcos, María C.; Bustamante, Carlos D.; Comas, David; Lalueza-Fox, Carles (17 October 2012). "North African Populations Carry the Signature of Admixture with Neandertals". PLOS ONE. 7 (10): e47765. Bibcode:2012PLoSO...747765S. doi:10.1371/journal.pone.0047765. PMC 3474783. PMID 23082212.
  3. ↑ Fu, Qiaomei; Li, Heng; Moorjani, Priya; Jay, Flora; Slepchenko, Sergey M.; Bondarev, Aleksei A.; Johnson, Philip L. F.; Aximu-Petri, Ayinuer; Prüfer, Kay; de Filippo, Cesare; Meyer, Matthias; Zwyns, Nicolas; Salazar-García, Domingo C.; Kuzmin, Yaroslav V.; Keates, Susan G.; Kosintsev, Pavel A.; Razhev, Dmitry I.; Richards, Michael P.; Peristov, Nikolai V.; Lachmann, Michael; Douka, Katerina; Higham, Thomas F. G.; Slatkin, Montgomery; Hublin, Jean-Jacques; Reich, David; Kelso, Janet; Viola, T. Bence; Pääbo, Svante (October 2014). "Genome sequence of a 45,000-year-old modern human from western Siberia". Nature. 514 (7523): 445–449. Bibcode:2014Natur.514..445F. doi:10.1038/nature13810. PMC 4753769. PMID 25341783.
  4. ↑ Brahic, Catherine (3 February 2014). "Humanity's forgotten return to Africa revealed in DNA". New Scientist.
  5. ↑ Endicott, Phillip; Ho, Simon Y.W.; Stringer, Chris (July 2010). "Using genetic evidence to evaluate four palaeoanthropological hypotheses for the timing of Neanderthal and modern human origins". Journal of Human Evolution. 59 (1): 87–95. doi:10.1016/j.jhevol.2010.04.005. PMID 20510437. S2CID 223433.
  6. ↑ 295–498 ka. A. Rieux (2014). "Improved calibration of the human mitochondrial clock using ancient genomes". Molecular Biology and Evolution. 31 (10): 2780–92. doi:10.1093/molbev/msu222. PMC 4166928. PMID 25100861.
  7. ↑ Rogers, Alan R.; Bohlender, Ryan J.; Huff, Chad D. (12 September 2017). "Early history of Neanderthals and Denisovans". Proceedings of the National Academy of Sciences. 114 (37): 9859–9863. Bibcode:2017PNAS..114.9859R. doi:10.1073/pnas.1706426114. PMC 5604018. PMID 28784789.; see also: Jordana Cepelewicz, Genetics Spills Secrets From Neanderthals' Lost History, Quanta Magazine, 18 September 2017. "The dating of that schism between the Neanderthals and the Denisovans is surprising because previous research pegged it as much more recent: a 2016 study, for instance, set it at only 450,000 years ago. An earlier separation means we should expect to find many more fossils of both eventually. It also changes the interpretation of some fossils. Take the large-brained hominid bones belonging to a species called Homo heidelbergensis, which lived in Europe and Asia around 600,000 years ago. Paleoanthropologists disagreed about how they relate to other human groups, some positing they were ancestors of both modern humans and Neanderthals, others claim they were a non-ancestral species replaced by the Neanderthals in their spread across Europe."
  8. ↑ Moulson, Geir; Associated Press (July 20, 2006). "Neanderthal genome project launches". NBC News. Retrieved August 22, 2006.
  9. ↑ Green, RE; Malaspinas, AS; Krause, J; Briggs, Aw; Johnson, PL; Uhler, C; Meyer, M; Good, JM; Maricic, T; Stenzel, U; Prüfer, K; Siebauer, M; Burbano, HA; Ronan, M; Rothberg, JM; Egholm, M; Rudan, P; Brajković, D; Kućan, Z; Gusić, I; Wikström, M; Laakkonen, L; Kelso, J; Slatkin, M; Pääbo, S (2008). "A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing". Cell. 134 (3): 416–26. doi:10.1016/j.cell.2008.06.021. PMC 2602844. PMID 18692465.
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  11. ↑ Green RE, Briggs AW, Krause J, Prüfer K, Burbano HA, Siebauer M, Lachmann M, Pääbo S (2009). "The Neandertal genome and ancient DNA authenticity". EMBO J. 28 (17): 2494–502. doi:10.1038/emboj.2009.222. PMC 2725275. PMID 19661919.
  12. 1 2 3 K. Prüfer; et al. (2014). "The complete genome sequence of a Neanderthal from the Altai Mountains". Nature. 505 (7481): 43–49. Bibcode:2014Natur.505...43P. doi:10.1038/nature12886. PMC 4031459. PMID 24352235.
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  14. ↑ Pratas, Diogo; Hosseini, Morteza; Silva, Raquel M.; Pinho, Armando J.; Ferreira, Paulo J. S. G. (2017). "Visualization of Distinct DNA Regions of the Modern Human Relatively to a Neanderthal Genome". Pattern Recognition and Image Analysis. Lecture Notes in Computer Science. Vol. 10255. pp. 235–242. doi:10.1007/978-3-319-58838-4_26. ISBN 978-3-319-58837-7.
  15. ↑ "Neanderthal Genome Sequencing Yields Surprising Results And Opens A New Door To Future Studies" (Press release). Lawrence Berkeley National Laboratory. November 16, 2006. Retrieved May 31, 2009.
  16. ↑ Evans PD, Mekel-Bobrov N, Vallender EJ, Hudson RR, Lahn BT (November 2006). "Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage". Proceedings of the National Academy of Sciences of the United States of America. 103 (48): 18178–83.
  17. 1 2 Chen, Lu; Wolf, Aaron B.; Fu, Wenqing; Li, Liming; Akey, Joshua M. (20 February 2020). "Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals". Cell. 180 (4): 677–687.e16. doi:10.1016/j.cell.2020.01.012. PMID 32004458. S2CID 210955842.
  18. 1 2 "Surprise! 20 Percent of Neanderthal Genome Lives On in Modern Humans, Scientists Find". National Geographic. 29 January 2014. Archived from the original on March 9, 2021. Retrieved October 7, 2016.
  19. 1 2 Zimmer, Carl (4 July 2020). "DNA Linked to Covid-19 Was Inherited From Neanderthals, Study Finds - The stretch of six genes seems to increase the risk of severe illness from the coronavirus". The New York Times. Retrieved 5 July 2020.
  20. 1 2 Zeberg, Hugo; Pääbo, Svante (July 3, 2020). "The major genetic risk factor for severe COVID-19 is inherited from Neanderthals". bioRxiv. doi:10.1101/2020.07.03.186296. hdl:21.11116/0000-0006-AB4F-2. S2CID 220366134.
  21. ↑ Ding, Qiliang; Hu, Ya; Xu, Shuhua; Wang, Chuan-Chao; Li, Hui; Zhang, Ruyue; Yan, Shi; Wang, Jiucun; Jin, Li (August 2014). "Neanderthal Origin of the Haplotypes Carrying the Functional Variant Val92Met in the MC1R in Modern Humans". Molecular Biology and Evolution. 31 (8): 1994–2003. doi:10.1093/molbev/msu180. PMID 24916031.
  22. ↑ Lowery, Robert K.; Uribe, Gabriel; Jimenez, Eric B.; Weiss, Mark A.; Herrera, Kristian J.; Regueiro, Maria; Herrera, Rene J. (November 2013). "Neanderthal and Denisova genetic affinities with contemporary humans: Introgression versus common ancestral polymorphisms". Gene. 530 (1): 83–94. doi:10.1016/j.gene.2013.06.005. PMID 23872234.
  23. ↑ Bekker, Henk (23 October 2017). "Neues Museum in Berlin 1175".
  24. 1 2 Vernot, Benjamin; Akey, Joshua M (2015). "Complex History of Admixture between Modern Humans and Neanderthals". American Journal of Human Genetics. 96 (3): 454–61. doi:10.1016/j.ajhg.2015.01.006. PMC 4375686. PMID 25683119.
  25. ↑ Kim, BY; Lohmueller, KE (2015). "Selection and Reduced Population Size Cannot Explain Higher Amounts of Neanderthal Ancestry in East Asian than in European Human Populations". American Journal of Human Genetics. 96 (3): 448–53. doi:10.1016/j.ajhg.2014.12.029. PMC 4375557. PMID 25683122.
  26. ↑ "Specifically, genes in the LCP [lipid catabolic process] term had the greatest excess of NLS in populations of European descent, with an average NLS frequency of 20.8±2.6% versus 5.9±0.08% genome wide (two-sided t-test, P<0.0001, n=379 Europeans and n=246 Africans). Further, among examined out-of-Africa human populations, the excess of NLS [Neanderthal-like genomic sites] in LCP genes was only observed in individuals of European descent: the average NLS frequency in Asians is 6.7±0.7% in LCP genes versus 6.2±0.06% genome wide." Khrameeva, Ekaterina E.; Bozek, Katarzyna; He, Liu; Yan, Zheng; Jiang, Xi; Wei, Yuning; Tang, Kun; Gelfand, Mikhail S.; Prufer, Kay; Kelso, Janet; Paabo, Svante; Giavalisco, Patrick; Lachmann, Michael; Khaitovich, Philipp (2014). "Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans". Nature Communications. 5: 3584. Bibcode:2014NatCo...5.3584K. doi:10.1038/ncomms4584. PMC 3988804. PMID 24690587..
  27. ↑ Kuhlwilm, Martin; Gronau, Ilan; Hubisz, Melissa J.; de Filippo, Cesare; Prado-Martinez, Javier; Kircher, Martin; Fu, Qiaomei; Burbano, Hernán A.; Lalueza-Fox, Carles; Marco; Rosas, Antonio; Rudan, Pavao; Brajkovic, Dejana; Kucan, Željko; Gušic, Ivan; Marques-Bonet, Tomas; Andrés, Aida M.; Viola, Bence; Pääbo, Svante; Meyer, Matthias; Siepel, Adam; Castellano, Sergi (2016). "Ancient gene flow from early modern humans into Eastern Neanderthals". Nature. 530 (7591): 429–33. Bibcode:2016Natur.530..429K. doi:10.1038/nature16544. PMC 4933530. PMID 26886800.
  28. ↑ S. Sankararaman; S. Mallick; M. Dannemann; K. Prüfer; J. Kelso; N. Patterson; D. Reich (2014). "The landscape of Neanderthal ancestry in present-day humans". Nature. 507 (7492): 354–57. Bibcode:2014Natur.507..354S. doi:10.1038/nature12961. PMC 4072735. PMID 24476815.
  29. ↑ Sankararaman, Sriram; Mallick, Swapan; Patterson, Nick; Reich, David (2016). "The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans". Current Biology. 26 (9): 1241–47. doi:10.1016/j.cub.2016.03.037. PMC 4864120. PMID 27032491.
  30. ↑ "Neanderthals mated with modern humans much earlier than thought, study finds: First genetic evidence of modern human DNA in a Neanderthal individual". ScienceDaily. February 17, 2016. Retrieved March 6, 2016.
  31. ↑ Mendez, Fernando L.; et al. (April 7, 2016). "The Divergence of Neanderthal and Modern Human Y Chromosomes". The American Journal of Human Genetics. 98 (4): 728–34. doi:10.1016/j.ajhg.2016.02.023. PMC 4833433. PMID 27058445.
  32. ↑ Enard, David; Petrov, Dmitri A. (October 4, 2018). "Evidence that RNA Viruses Drove Adaptive Introgression between Neanderthals and Modern Humans". Cell. 175 (2): 360–371. doi:10.1016/j.cell.2018.08.034. PMC 6176737. PMID 30290142.
  33. ↑ "Neanderthal genes may be liability for Covid19 patients". Fairfax_AP. 1 October 2020.
  34. ↑ Zeberg, Hugo; Pääbo, Svante (30 September 2020). "The major genetic risk factor for severe COVID-19 is inherited from Neanderthals". Nature. 587 (7835): 610–612. Bibcode:2020Natur.587..610Z. doi:10.1038/s41586-020-2818-3. hdl:21.11116/0000-0007-0F26-F. PMID 32998156. [...] the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.
  35. ↑ Sample, Ian (30 September 2020). "Neanderthal genes increase risk of serious Covid-19, study claims". The Guardian.
  36. ↑ Zimmer, Carl (14 December 2023). "Morning Person? You Might Have Neanderthal Genes to Thank. - Hundreds of genetic variants carried by Neanderthals and Denisovans are shared by people who like to get up early". The New York Times. Archived from the original on 14 December 2023. Retrieved 14 December 2023.
  37. 1 2 Gokhman D, Lavi E, Prüfer K, Fraga MF, Riancho JA, Kelso J, Pääbo S, Meshorer E, Carmel L (2014). "Reconstructing the DNA methylation maps of the Neandertal and the Denisovan". Science. 344 (6183): 523–27. Bibcode:2014Sci...344..523G. doi:10.1126/science.1250368. PMID 24786081. S2CID 28665590.
  38. ↑ Tibayrenc, Michel; Ayala, Francisco J. (2016-09-12). On Human Nature: Biology, Psychology, Ethics, Politics, and Religion. ISBN 9780127999159.
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