Neanderthal genetics

{{main|Neanderthal genome project}}

File:Neanderthal DNA extraction.jpg extracting ancient DNA (2005 photograph)]]

Genetic studies on Neanderthal ancient DNA became possible in the late 1990s.{{cite journal | last1=Ovchinnikov | first1=Igor V. | last2=Götherström | first2=Anders | last3=Romanova | first3=Galina P. | last4=Kharitonov | first4=Vitaliy M. | last5=Lidén | first5=Kerstin | last6=Goodwin | first6=William | title=Molecular analysis of Neanderthal DNA from the northern Caucasus | journal=Nature | volume=404 | issue=6777 | year=2000 | pages=490–93 | pmid=10761915 | doi=10.1038/35006625| bibcode=2000Natur.404..490O | s2cid=3101375 }} 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.{{Cite news|title=Neanderthal genome project launches |url=http://www.nbcnews.com/id/13955661 |archive-url=https://web.archive.org/web/20130725193507/http://www.nbcnews.com/id/13955661 |url-status=dead |archive-date=July 25, 2013 |date=July 20, 2006 |access-date=August 22, 2006 |last1=Moulson |first1=Geir |last2=Associated Press |publisher=NBC News|author2-link=Associated Press }} They published the full sequence Neanderthal mitochondrial DNA (mtDNA) in 2008.{{cite journal | last1 = Green | first1 = RE | last2 = Malaspinas | first2 = AS | last3 = Krause | first3 = J | last4 = Briggs | first4 = Aw | last5 = Johnson | first5 = PL | last6 = Uhler | first6 = C | author6-link = Caroline Uhler| last7 = Meyer | first7 = M | last8 = Good | first8 = JM | last9 = Maricic | first9 = T | last10 = Stenzel | first10 = U | last11 = Prüfer | first11 = K | last12 = Siebauer | first12 = M | last13 = Burbano | first13 = HA | last14 = Ronan | first14 = M | last15 = Rothberg | first15 = JM | last16 = Egholm | first16 = M | last17 = Rudan | first17 = P | last18 = Brajković | first18 = D | last19 = Kućan | first19 = Z | last20 = Gusić | first20 = I | last21 = Wikström | first21 = M | last22 = Laakkonen | first22 = L | last23 = Kelso | first23 = J | last24 = Slatkin | first24 = M | last25 = Pääbo | first25 = S | year = 2008 | title = A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing | journal = Cell | volume = 134 | issue = 3| pages = 416–26 | doi = 10.1016/j.cell.2008.06.021 |pmid=18692465 | pmc=2602844}} Svante Pääbo noted that, "Contamination was indeed an issue," and they eventually realised that 11% of their mtDNA sample was modern human DNA.{{Cite journal|journal = Science |year = 2009 |issue = 5916|pages = 866–71 |doi = 10.1126/science.323.5916.866 |title =Tales of a Prehistoric Human Genome |author = Elizabeth Pennisi|author-link = Elizabeth Pennisi|volume = 323|pmid = 19213888|s2cid = 206584252 }}{{Cite journal| pmid = 19661919|title = The Neandertal genome and ancient DNA authenticity | journal = EMBO J. |year = 2009| volume = 28 |issue = 17| pages = 2494–502 |pmc = 2725275 | doi = 10.1038/emboj.2009.222 |vauthors=Green RE, Briggs AW, Krause J, Prüfer K, Burbano HA, Siebauer M, Lachmann M, Pääbo S }} 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.{{cn|date=February 2025}}

The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans. This was based on three specimens in Vindija Cave, Croatia, which contained almost 4% archaic DNA (allowing for near complete sequencing of the genome). However, there was approximately 1 error for every 200 letters (base pairs) based on the implausibly high mutation rate, probably due to the preservation of the sample. In 2012, British-American geneticist Graham Coop hypothesised that they instead found evidence of a different archaic human species interbreeding with modern humans, which was disproven in 2013 by the sequencing of a high-quality Neanderthal genome preserved in a 50,000 year old toe (phalanx) bone from Denisova Cave, Siberia.{{sfn|Reich|2018}}

A visualisation map of the reference modern-human containing the genome regions with high degree of similarity or with novelty according to a 50,000 year old Neanderthal from the Siberian Altai Mountains has been built by Pratas et al.{{cite book |doi=10.1007/978-3-319-58838-4_26 |chapter=Visualization of Distinct DNA Regions of the Modern Human Relatively to a Neanderthal Genome |title=Pattern Recognition and Image Analysis |series=Lecture Notes in Computer Science |year=2017 |last1=Pratas |first1=Diogo |last2=Hosseini |first2=Morteza |last3=Silva |first3=Raquel M. |last4=Pinho |first4=Armando J. |last5=Ferreira |first5=Paulo J. S. G. |volume=10255 |pages=235–242 |isbn=978-3-319-58837-7 }}

Neanderthal genomes sequenced include those from Denisova Cave{{Cite journal |last=Prüfer |first=Kay |last2=de Filippo |first2=Cesare |last3=Grote |first3=Steffi |last4=Mafessoni |first4=Fabrizio |last5=Korlević |first5=Petra |last6=Hajdinjak |first6=Mateja |last7=Vernot |first7=Benjamin |last8=Skov |first8=Laurits |last9=Hsieh |first9=Pinghsun |last10=Peyrégne |first10=Stéphane |last11=Reher |first11=David |last12=Hopfe |first12=Charlotte |last13=Nagel |first13=Sarah |last14=Maricic |first14=Tomislav |last15=Fu |first15=Qiaomei |date=2017-11-03 |title=A high-coverage Neandertal genome from Vindija Cave in Croatia |url=https://www.science.org/doi/10.1126/science.aao1887 |journal=Science |language=en |volume=358 |issue=6363 |pages=655–658 |doi=10.1126/science.aao1887 |issn=0036-8075 |pmc=6185897 |pmid=28982794}}{{Cite journal |last=Zavala |first=Elena I. |last2=Jacobs |first2=Zenobia |last3=Vernot |first3=Benjamin |last4=Shunkov |first4=Michael V. |last5=Kozlikin |first5=Maxim B. |last6=Derevianko |first6=Anatoly P. |last7=Essel |first7=Elena |last8=de Fillipo |first8=Cesare |last9=Nagel |first9=Sarah |last10=Richter |first10=Julia |last11=Romagné |first11=Frédéric |last12=Schmidt |first12=Anna |last13=Li |first13=Bo |last14=O’Gorman |first14=Kieran |last15=Slon |first15=Viviane |date=July 2021 |title=Pleistocene sediment DNA reveals hominin and faunal turnovers at Denisova Cave |url=https://www.nature.com/articles/s41586-021-03675-0 |journal=Nature |language=en |volume=595 |issue=7867 |pages=399–403 |doi=10.1038/s41586-021-03675-0 |issn=1476-4687 |pmc=8277575 |pmid=34163072}} including an offspring of a Neanderthal and a Denisovan,{{Cite journal |last=Slon |first=Viviane |last2=Mafessoni |first2=Fabrizio |last3=Vernot |first3=Benjamin |last4=de Filippo |first4=Cesare |last5=Grote |first5=Steffi |last6=Viola |first6=Bence |last7=Hajdinjak |first7=Mateja |last8=Peyrégne |first8=Stéphane |last9=Nagel |first9=Sarah |last10=Brown |first10=Samantha |last11=Douka |first11=Katerina |last12=Higham |first12=Tom |last13=Kozlikin |first13=Maxim B. |last14=Shunkov |first14=Michael V. |last15=Derevianko |first15=Anatoly P. |date=September 2018 |title=The genome of the offspring of a Neanderthal mother and a Denisovan father |url=https://www.nature.com/articles/s41586-018-0455-x |journal=Nature |language=en |volume=561 |issue=7721 |pages=113–116 |doi=10.1038/s41586-018-0455-x |issn=1476-4687 |pmc=6130845 |pmid=30135579}} from Chagyrskaya Cave,{{Cite journal |last=Mafessoni |first=Fabrizio |last2=Grote |first2=Steffi |last3=de Filippo |first3=Cesare |last4=Slon |first4=Viviane |last5=Kolobova |first5=Kseniya A. |last6=Viola |first6=Bence |last7=Markin |first7=Sergey V. |last8=Chintalapati |first8=Manjusha |last9=Peyrégne |first9=Stephane |last10=Skov |first10=Laurits |last11=Skoglund |first11=Pontus |last12=Krivoshapkin |first12=Andrey I. |last13=Derevianko |first13=Anatoly P. |last14=Meyer |first14=Matthias |last15=Kelso |first15=Janet |date=2020-06-30 |title=A high-coverage Neandertal genome from Chagyrskaya Cave |url=https://pnas.org/doi/full/10.1073/pnas.2004944117 |journal=Proceedings of the National Academy of Sciences |language=en |volume=117 |issue=26 |pages=15132–15136 |doi=10.1073/pnas.2004944117 |issn=0027-8424 |pmc=7334501 |pmid=32546518}} from Vindija Cave,{{Cite journal |last=Hajdinjak |first=Mateja |last2=Fu |first2=Qiaomei |last3=Hübner |first3=Alexander |last4=Petr |first4=Martin |last5=Mafessoni |first5=Fabrizio |last6=Grote |first6=Steffi |last7=Skoglund |first7=Pontus |last8=Narasimham |first8=Vagheesh |last9=Rougier |first9=Hélène |last10=Crevecoeur |first10=Isabelle |last11=Semal |first11=Patrick |last12=Soressi |first12=Marie |last13=Talamo |first13=Sahra |last14=Hublin |first14=Jean-Jacques |last15=Gušić |first15=Ivan |date=March 2018 |title=Reconstructing the genetic history of late Neanderthals |url=https://www.nature.com/articles/nature26151 |journal=Nature |language=en |volume=555 |issue=7698 |pages=652–656 |doi=10.1038/nature26151 |issn=1476-4687 |pmc=6485383 |pmid=29562232}} Mezmaiskaya cave, Les Cottés cave, Goyet Caves and Spy Cave, Hohlenstein-Stadel and Scladina caves{{Cite journal |last=Peyrégne |first=Stéphane |last2=Slon |first2=Viviane |last3=Mafessoni |first3=Fabrizio |last4=de Filippo |first4=Cesare |last5=Hajdinjak |first5=Mateja |last6=Nagel |first6=Sarah |last7=Nickel |first7=Birgit |last8=Essel |first8=Elena |last9=Le Cabec |first9=Adeline |last10=Wehrberger |first10=Kurt |last11=Conard |first11=Nicholas J. |last12=Kind |first12=Claus Joachim |last13=Posth |first13=Cosimo |last14=Krause |first14=Johannes |last15=Abrams |first15=Grégory |date=June 2019 |title=Nuclear DNA from two early Neanderthals reveals 80,000 years of genetic continuity in Europe |url=https://www.science.org/doi/10.1126/sciadv.aaw5873 |journal=Science Advances |language=en |volume=5 |issue=6 |doi=10.1126/sciadv.aaw5873 |issn=2375-2548 |pmc=6594762 |pmid=31249872}} Galería de las Estatuas{{Cite journal |last=Vernot |first=Benjamin |last2=Zavala |first2=Elena I. |last3=Gómez-Olivencia |first3=Asier |last4=Jacobs |first4=Zenobia |last5=Slon |first5=Viviane |last6=Mafessoni |first6=Fabrizio |last7=Romagné |first7=Frédéric |last8=Pearson |first8=Alice |last9=Petr |first9=Martin |last10=Sala |first10=Nohemi |last11=Pablos |first11=Adrián |last12=Aranburu |first12=Arantza |last13=de Castro |first13=José María Bermúdez |last14=Carbonell |first14=Eudald |last15=Li |first15=Bo |date=2021-05-07 |title=Unearthing Neanderthal population history using nuclear and mitochondrial DNA from cave sediments |url=https://www.science.org/doi/10.1126/science.abf1667 |journal=Science |language=en |volume=372 |issue=6542 |doi=10.1126/science.abf1667 |issn=0036-8075}} and Gibraltar.{{Cite journal |last=Bokelmann |first=Lukas |last2=Hajdinjak |first2=Mateja |last3=Peyrégne |first3=Stéphane |last4=Brace |first4=Selina |last5=Essel |first5=Elena |last6=de Filippo |first6=Cesare |last7=Glocke |first7=Isabelle |last8=Grote |first8=Steffi |last9=Mafessoni |first9=Fabrizio |last10=Nagel |first10=Sarah |last11=Kelso |first11=Janet |last12=Prüfer |first12=Kay |last13=Vernot |first13=Benjamin |last14=Barnes |first14=Ian |last15=Pääbo |first15=Svante |date=2019-07-30 |title=A genetic analysis of the Gibraltar Neanderthals |url=https://pnas.org/doi/full/10.1073/pnas.1903984116 |journal=Proceedings of the National Academy of Sciences |language=en |volume=116 |issue=31 |pages=15610–15615 |doi=10.1073/pnas.1903984116 |issn=0027-8424 |pmc=6681707 |pmid=31308224}}

Genetic data has been used to test various hypotheses about Neanderthal evolution and identify the last common ancestor (LCA) of Neanderthals and modern humans. Numerous dates have been suggested, such as 538–315,{{cite journal |first=C. |last=Stringer |year=2012 |title=The status of Homo heidelbergensis (Schoetensack 1908) |journal=Evolutionary Anthropology |volume=21 |issue=3 |pages=101–107|doi=10.1002/evan.21311 |pmid=22718477 |s2cid=205826399 |doi-access=free}} 553–321,{{cite journal |first1=A. W. |last1=Briggs |first2=J. M. |last2=Good |first3=R. E. |last3=Green |year=2009 |title=Targeted retrieval and analysis of five Neandertal mtDNA genomes |journal=Science |volume=325 |issue=5,938 |pages=318–321 |doi=10.1126/science.1174462 |pmid=19608918 |url=http://pdfs.semanticscholar.org/db3e/13246f66ddcaf0d6920fca4e7688ccc9a636.pdf |archive-url=https://web.archive.org/web/20190307185255/http://pdfs.semanticscholar.org/db3e/13246f66ddcaf0d6920fca4e7688ccc9a636.pdf |url-status=dead |archive-date=March 7, 2019 |bibcode=2009Sci...325..318B |s2cid=7117454}} 565–503,{{Cite journal |doi=10.1038/nature26151 |issn=1476-4687 |volume=555 |issue=7698 |pages=652–656 |last1=Hajdinjak |first1=M. |last2=Fu |first2=Q. |last3=Hübner |first3=A. |display-authors=3 |last4=Petr |first4=Martin |last5=Mafessoni |first5=Fabrizio |last6=Grote |first6=Steffi |last7=Skoglund |first7=Pontus |last8=Narasimham |first8=Vagheesh |last9=Rougier |first9=Hélène |last10=Crevecoeur |first10=Isabelle |last11=Semal |first11=Patrick |last12=Soressi |first12=Marie |last13=Talamo |first13=Sahra |last14=Hublin |first14=Jean-Jacques |last15=Gušić |first15=Ivan |last16=Kućan |first16=Željko |last17=Rudan |first17=Pavao |last18=Golovanova |first18=Liubov V. |last19=Doronichev |first19=Vladimir B. |last20=Posth |first20=Cosimo |last21=Krause |first21=Johannes |last22=Korlević |first22=Petra |last23=Nagel |first23=Sarah |last24=Nickel |first24=Birgit |last25=Slatkin |first25=Montgomery |last26=Patterson |first26=Nick |last27=Reich |first27=David |last28=Prüfer |first28=Kay |last29=Meyer |first29=Matthias |last30=Pääbo |first30=Svante |last31=Kelso |first31=Janet |title=Reconstructing the genetic history of late Neanderthals |journal=Nature |date=March 1, 2018 |pmid=29562232 |pmc=6485383 |bibcode=2018Natur.555..652H}} 654–475,{{cite journal |first1=P. |last1=Endicott |first2=S. Y. W. |last2=Ho |author3-link=Chris Stringer |first3=C. |last3=Stringer |year=2010 |title=Using genetic evidence to evaluate four palaeoanthropological hypotheses for the timing of Neanderthal and modern human origins |journal=Journal of Human Evolution |volume=59 |issue=1 |pages=87–95 |url=http://materiais.dbio.uevora.pt/MA/Artigos/The_timing_of_Neanderthal_and_modern_human_origins.pdf |doi=10.1016/j.jhevol.2010.04.005|pmid=20510437|bibcode=2010JHumE..59...87E }} 690–550,{{cite journal |last1=Krings |first1=M. |last2=Stone |first2=A. |last3=Schmitz |first3=R. W. |last4=Krainitzki |first4=H. |last5=Stoneking |first5=M. |last6=Pääbo |first6=S. |author-link6=Svante Pääbo|title=Neandertal DNA sequences and the origin of modern humans |journal=Cell |year= 1997 |volume=90 |issue=1 |pages=19–30 |doi=10.1016/s0092-8674(00)80310-4 |pmid=9230299 |hdl=11858/00-001M-0000-0025-0960-8 |s2cid=13581775 |hdl-access=free}} 765–550,{{cite journal |first1=M. |last1=Meyer |first2=J. |last2=Arsuaga |first3=C.|last3=de Filippo |first4=S. |last4=Nagel |title=Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins |journal=Nature |volume=531 |issue=7595 |pages=504–507 |year=2016 |doi=10.1038/nature17405 |pmid=26976447 |bibcode=2016Natur.531..504M |s2cid=4467094}} 741–317,{{cite journal |last1=Krings |first1=M. |last2=Geisert |first2=H. |last3=Schmitz |first3=R. W. |last4=Krainitzki |first4=H. |last5=Pääbo |first5=S. |author-link5=Svante Pääbo |title=DNA sequence of the mitochondrial hypervariable region II from the Neandertal type specimen |journal=Proceedings of the National Academy of Sciences |year=1999 |volume=96 |issue=10 |pages=5581–5585 |doi=10.1073/pnas.96.10.5581 |pmid=10318927 |pmc=21903 |bibcode=1999PNAS...96.5581K|doi-access=free }} and 800–520,000 years ago;{{cite journal |first1=R. E. |last1=Green |first2=A. S. |last2=Malaspinas |first3=J. |last3=Krause |first4=A. W. |last4=Briggs |display-authors=etal |year=2008 |title=A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing |journal=Cell |volume=134 |issue=3 |pages=416–426 |doi=10.1016/j.cell.2008.06.021 |pmc=2602844 |pmid=18692465}} and a dental analysis concluded before 800,000 years ago.{{cite journal |first=A. |last=Gómez-Robles |year=2019 |title=Dental evolutionary rates and its implications for the Neanderthal–modern human divergence |journal=Science Advances |volume=5 |issue=5 |page=eaaw1268 |doi=10.1126/sciadv.aaw1268 |pmid=31106274 |pmc=6520022 |bibcode=2019SciA....5.1268G}}

The date of around 250,000 years ago cites "H. helmei" as being the LCA, and the split is associated with the Levallois technique of making stone tools. The date of about 400,000 years ago uses H. heidelbergensis as the LCA. Estimates of 600,000 years ago assume that "H. rhodesiensis" was the LCA, which split off into a modern human lineage and a Neanderthal/H. heidelbergensis lineage. 800,000 years ago has H. antecessor as the LCA, but different variations of this model would push the date back to 1 million years ago. A 2020 analysis of H. antecessor enamel proteomes suggests that H. antecessor is related but not a direct ancestor.{{cite journal |first=F. |last=Welker |display-authors=et al. |title=The dental proteome of Homo antecessor |journal=Nature |year=2020 |volume=580 |issue=7802 |pages=235–238 |doi=10.1038/s41586-020-2153-8 |pmid=32269345 |pmc=7582224 |bibcode=2020Natur.580..235W |s2cid=214736611}}

Neanderthals and Denisovans are more closely related to each other than they are to modern humans, meaning the Neanderthal/Denisovan split occurred after their split with modern humans.{{cite journal |first=K. |last=Prüfer |display-authors=etal |year=2014 |title=The complete genome sequence of a Neanderthal from the Altai Mountains |journal=Nature |volume=505 |issue=7481 |pages=43–49|doi=10.1038/nature12886 |pmid=24352235 |pmc=4031459 |bibcode=2014Natur.505...43P}}{{cite journal |first1=S. |last1=Sawyer |first2=G. |last2=Renaud |first3=B. |last3=Viola |first4=J. J. |last4=Hublin |year=2015 |title=Nuclear and mitochondrial DNA sequences from two Denisovan individuals |journal=Proceedings of the National Academy of Sciences |volume=112 |issue=51 |pages=15696–15700 |doi=10.1073/pnas.1519905112 |pmc=4697428 |pmid=26630009 |bibcode=2015PNAS..11215696S|doi-access=free }} Before splitting, Neanderthal/Denisovans (or "Neandersovans") migrating out of Africa into Europe apparently interbred with an unidentified "superarchaic" human species who were already present there; these superarchaics were the descendants of a very early migration out of Africa around 1.9 mya.{{cite journal |first1=A. R. |last1=Rogers |first2=N. S. |last2=Harris |first3=A. A. |last3=Achenbach |year=2020 |title=Neanderthal-Denisovan ancestors interbred with a distantly related hominin |journal=Science Advances |volume=6 |issue=8 |page=eaay5483 |doi=10.1126/sciadv.aay5483 |pmid=32128408 |pmc=7032934 |bibcode=2020SciA....6.5483R}} Assuming a mutation rate of 1 × 10⁻⁹ or 0.5 × 10⁻⁹ per base pair (bp) per year, the Neanderthal/Denisovan split occurred around either 236,000–190,000 or 473,000–381,000 years ago, respectively. Using 1.1 × 10⁻⁸ per generation with a new generation every 29 years, the time is 744,000 years ago. Using 5 × 10⁻¹⁰ nucleotide sites per year, it is 616,000 years ago. Using the latter dates, the split had likely already occurred by the time Neanderthal ancestors spread out across Europe.{{cite journal |first1=A. R. |last1=Rogers |first2=R. J. |last2=Bohlender |first3=C. D. |last3=Huff |title=Early history of Neanderthals and Denisovans |journal=Proceedings of the National Academy of Sciences |volume=114 |issue=37 |year=2017 |pages=9859–9863 |doi=10.1073/pnas.1706426114 |pmid=28784789 |pmc=5604018|bibcode=2017PNAS..114.9859R |doi-access=free }}

Like modern humans, Neanderthals probably descended from a very small population with an effective population—the number of individuals who can bear or father children—of 3,000 to 12,000 approximately. Genetic data suggests that Neanderthals maintained this very low population, proliferating weakly harmful genes due to the reduced effectivity of natural selection.{{cite journal |first1=F. |last1=Mafessoni |first2=K. |last2=Prüfer |title=Better support for a small effective population size of Neandertals and a long shared history of Neandertals and Denisovans |journal=Proceedings of the National Academy of Sciences |volume=114 |issue=48 |year=2017 |pages=10256–10257 |doi=10.1073/pnas.1716918114 |pmid=29138326 |pmc=5715791|bibcode=2017PNAS..11410256M |doi-access=free }}

Various studies, using mtDNA analysis, yield varying effective populations,{{cite journal |first1=J. |last1=Bocquet-Appel |first2=A. |last2=Degioanni |year=2013 |title=Neanderthal demographic estimates |journal=Current Anthropology |volume=54 |pages=202–214 |doi=10.1086/673725 |s2cid=85090309}} such as about 1,000 to 5,000; 5,000 to 9,000 remaining constant;{{cite journal |last1=Lalueza-Fox |first1=C. |last2=Sampietro |first2=M. L. |last3=Caramelli |first3=D. |last4=Puder |first4=Y. |year=2013 |title=Neandertal evolutionary genetics: mitochondrial DNA data from the iberian peninsula |journal=Molecular Biology and Evolution |volume=22 |issue=4 |pages=1077–1081 |doi=10.1093/molbev/msi094 |pmid=15689531 |doi-access=free}} or 3,000 to 25,000 steadily increasing until 52,000 years ago before declining until extinction.{{cite journal |first1=V. |last1=Fabre |first2=S. |last2=Condemi |first3=A. |last3=Degioanni |year=2009 |title=Genetic evidence of geographical groups among Neanderthals |journal=PLOS ONE |volume=4 |issue=4 |pages=e5151 |doi=10.1371/journal.pone.0005151 |pmc=2664900 |pmid=19367332 |bibcode=2009PLoSO...4.5151F|doi-access=free }} Archaeological evidence suggests that the modern human population at the time of the Neanderthal/modern human transition was ten times higher.{{cite journal |first1=P. |last1=Mellars |first2=J. C. |last2=French |year=2011 |title=Tenfold population increase in Western Europe at the Neandertal-to-modern human transition |journal=Science |volume=333 |issue=6042 |pages=623–627 |doi=10.1126/science.1206930 |pmid=21798948 |bibcode=2011Sci...333..623M |s2cid=28256970}} Neanderthals may have been at a demographic disadvantage due to a lower fertility rate, a higher infant mortality rate, or a combination of the two.{{cite journal |first=E. |last=Trinkaus |author-link=Erik Trinkaus |year=2011 |title=Late Pleistocene adult mortality patterns and modern human establishment |journal=Proceedings of the National Academy of Sciences |volume=108 |issue=4 |pages=1267–1271 |doi=10.1073/pnas.1018700108 |pmc=3029716 |pmid=21220336 |bibcode=2011PNAS..108.1267T|doi-access=free }} Estimates giving a total population in the higher tens of thousands are contested.

Low population caused a low genetic diversity and probably inbreeding, which reduced the population's ability to filter out harmful mutations (inbreeding depression). It is unclear how this affected a single Neanderthal's genetic burden and, thus, if this caused a higher rate of birth defects than in contemporary modern humans (Cro-Magnons).{{cite journal |first1=F. |last1=Sánchez-Quinto |first2=C. |last2=Lalueza-Fox |year=2015 |title=Almost 20 years of Neanderthal palaeogenetics: adaptation, admixture, diversity, demography and extinction |journal=Philosophical Transactions of the Royal Society B |volume=370 |issue=1660 |page=20130374 |doi=10.1098/rstb.2013.0374 |pmc=4275882 |pmid=25487326}} If it did, it could have contributed to the extinction of the species (mutational meltdown).{{cite journal |first1=L. |last1=Ríos |first2=T. L. |last2=Kivell |first3=C. |last3=Lalueza-Fox |first4=A. |last4=Estalrrich |year=2019 |title=Skeletal anomalies in the Neandertal family of El Sidrón (Spain) support a role of inbreeding in Neandertal extinction |journal=Scientific Reports |volume=9 |issue=1 |page=1697 |doi=10.1038/s41598-019-38571-1 |pmc=6368597 |pmid=30737446 |bibcode=2019NatSR...9.1697R}}

File:Neanderthal genetic subgroups.png

Genetic analysis indicates there were at least three distinct geographical groups: Western Europe, the Mediterranean coast, and east of the Caucasus, with some migration among these regions.{{cite journal |first1=V. |last1=Fabre |first2=S. |last2=Condemi |first3=A. |last3=Degioanni |year=2009 |title=Genetic evidence of geographical groups among Neanderthals |journal=PLOS ONE |volume=4 |issue=4 |pages=e5151 |doi=10.1371/journal.pone.0005151 |pmc=2664900 |pmid=19367332 |bibcode=2009PLoSO...4.5151F|doi-access=free }} Over long periods of time, there is evidence of large-scale cross-continental migration. Early specimens from Mezmaiskaya Cave in the Caucasus and Denisova Cave in the Siberian Altai Mountains differ genetically from Western European Neanderthals, whereas later specimens from these caves both have genetic profiles more similar to Western European Neanderthals than to the earlier specimens from the same locations. These suggest large-scale population replacement over time.{{cite journal |last1=Peyrégne |first1=S. |last2=Slon |first2=V. |last3=Mafessoni |first3=F. |display-authors=et al. |title=Nuclear DNA from two early Neandertals reveals 80 ka of genetic continuity in Europe |journal=Science Advances |volume=5 |number=6 |page=eaaw5873 |year=2019 |doi=10.1126/sciadv.aaw5873 |pmid=31249872 |pmc=6594762 |bibcode=2019SciA....5.5873P}}{{cite journal |author-first1=M. |author-last1=Hajdinjak |author-first2=Q. |author-last2=Fu |author-first3=A. |author-last3=Hübner |year=2018 |title=Reconstructing the genetic history of late Neanderthals |journal=Nature |volume=555 |issue=7698 |pages=652–656 |doi=10.1038/nature26151 |pmid=29562232 |pmc=6485383 |bibcode=2018Natur.555..652H}}

{{Main|Interbreeding between archaic and modern humans}}

===Interbreeding with modern humans===

File:Map of western Eurasia showing areas and estimated dates of possible Neandertal–modern human hybridization (in red) based on fossil samples from indicated sites.jpg

The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans.{{cite journal |doi= 10.1126/science.1188021 |title= A Draft Sequence of the Neanderthal Genome |year= 2010 |last1= Green |first1= Richard E. |last2= Krause |first2= Johannes |last3= Briggs |first3= Adrian W. |last4= Maricic |first4= Tomislav |last5= Stenzel |first5= Udo |last6= Kircher |first6= Martin |last7= Patterson |first7= Nick |last8= Li |first8= Heng |last9= Zhai |first9= Weiwei |last10= Fritz |first10= Markus Hsi-Yang |last11= Hansen |first11= Nancy F. |last12= Durand |first12= Eric Y. |last13= Malaspinas |first13= Anna-Sapfo |last14= Jensen |first14= Jeffrey D. |last15= Marques-Bonet |first15= Tomas |last16= Alkan |first16= Can |last17= Prüfer |first17= Kay |last18= Meyer |first18= Matthias |last19= Burbano |first19= Hernán A. |last20= Good |first20= Jeffrey M. |last21= Schultz |first21= Rigo |last22= Aximu-Petri |first22= Ayinuer |last23= Butthof |first23= Anne |last24= Höber |first24= Barbara |last25= Höffner |first25= Barbara |last26= Siegemund |first26= Madlen |last27= Weihmann |first27= Antje |last28= Nusbaum |first28= Chad |last29= Lander |first29= Eric S. |last30= Russ |first30= Carsten |journal= Science |volume= 328 |issue= 5979 |pages= 710–22 |pmid= 20448178 |bibcode= 2010Sci...328..710G |pmc= 5100745}}{{cite journal |last1=Sankararaman |first1=S. |last2=Patterson |first2=N. |last3=Li |first3=H. |last4=Pääbo |first4=S. |author-link4=Svante Pääbo |last5=Reich |first5=D |last6=Akey |first6=J. M. |title=The date of interbreeding between Neandertals and modern humans |journal=PLOS Genetics |year=2012 |volume=8 |issue=10 |page=e1002947 |doi=10.1371/journal.pgen.1002947 |pmid=23055938 |pmc=3464203 |bibcode=2012arXiv1208.2238S |arxiv=1208.2238 |doi-access=free }}{{cite journal |last1=Yang |first1=M. A. |last2=Malaspinas |first2=A. S. |last3=Durand |first3=E. Y. |last4=Slatkin |first4=M. |title=Ancient structure in Africa unlikely to explain Neanderthal and non-African genetic similarity |journal=Molecular Biology and Evolution |year=2012 |volume=29 |issue=10 |pages=2,987–2,995 |doi=10.1093/molbev/mss117 |pmid=22513287 |pmc=3457770}}{{cite journal |last1=Sánchez-Quinto |first1=F. |last2=Botigué |first2=L. R. |last3=Civit |first3=S. |last4=Arenas |first4=C. |last5=Ávila-Arcos |first5=M. C. |last6=Bustamante |first6=C. D. |last7=Comas |first7=D. |last8=Lalueza-Fox |first8=C. |last9=Caramelli |first9=D.|title=North African populations carry the signature of admixture with Neandertals |journal=PLOS ONE |year= 2012 |volume=7 |issue=10 |pages=e47765 |doi=10.1371/journal.pone.0047765 |pmid=23082212 |pmc=3474783 |bibcode=2012PLoSO...747765S|doi-access=free }} The genomes of all studied modern populations contain Neanderthal DNA.{{cite journal |last1=Sankararaman |first1=S.|last2=Mallick |first2=S. |last3=Dannemann |first3=M. |last4=Prüfer |first4=K. |last5=Kelso |first5=J. |last6=Pääbo |first6=S. |author-link6=Svante Pääbo |last7=Patterson |first7=N. |last8=Reich |first8=D. |title=The genomic landscape of Neanderthal ancestry in present-day humans |journal=Nature |year= 2014 |volume=507 |issue=7492 |pages=354–357 |doi=10.1038/nature12961 |pmid=24476815 |pmc=4072735 |bibcode=2014Natur.507..354S}}{{cite journal |doi=10.1093/molbev/msr024 |title=An X-linked haplotype of Neandertal origin is present among all non-African populations |year=2011 |last1=Yotova |first1=V. |last2=Lefebvre |first2=J.-F. |last3=Moreau |first3=C. |display-authors=3 |last4=Gbeha |first4=E. |last5=Hovhannesyan |first5=K. |last6=Bourgeois |first6=S. |last7=Bédarida |first7=S. |last8=Azevedo |first8=L. |last9=Amorim |first9=A. |last10=Sarkisian |first10=T. |last11=Avogbe |first11=P. H. |last12=Chabi |first12=N. |last13=Dicko |first13=M. H. |last14=Kou' Santa Amouzou |first14=E. S. |last15=Sanni |first15=A. |last16=Roberts-Thomson |first16=J. |last17=Boettcher |first17=B. |last18=Scott |first18=R. J. |last19=Labuda |first19=D. |journal=Molecular Biology and Evolution |volume=28 |issue=7 |pages=1957–1962 |pmid=21266489 |doi-access=free}}{{cite journal |last1=Fu |first1=Q. |last2=Li |first2=H. |last3=Moorjani |first3=P. |display-authors=3 |last4=Jay |first4=F. |last5=Slepchenko |first5=S. M. |last6=Bondarev |first6=A. A. |last7=Johnson |first7=P. L. F. |last8=Aximu-Petri |first8=A. |last9=Prüfer |first9=K. |last10=de Filippo |first10=C. |last11=Meyer |first11=M. |last12=Zwyns |first12=Ni. |last13=Salazar-García |first13=D. C. |last14=Kuzmin |first14=Y. V. |last15=Keates |first15=S. G. |last16=Kosintsev |first16=P. A. |last17=Razhev |first17=D. I. |last18=Richards |first18=M. P. |last19=Peristov |first19=N. V. |last20=Lachmann |first20=M. |last21=Douka |first21=K. |last22=Higham |first22=T. F. G. |last23=Slatkin |first23=M. |last24=Hublin |first24=J.-J. |last25=Reich |first25=D. |last26=Kelso |first26=J. |last27=Viola |first27=T. B. |last28=Pääbo |first28=S. |author-link28=Svante Pääbo |title=Genome sequence of a 45,000-year-old modern human from western Siberia |journal=Nature |year= 2014 |volume=514 |issue=7523 |pages=445–449 |doi=10.1038/nature13810 |pmid=25341783 |pmc=4753769 |bibcode=2014Natur.514..445F}} In all, approximately 20% of the Neanderthal genome appears to have survived in the modern human gene pool.{{cite journal |title=Resurrecting surviving Neandertal lineages from modern human genomes |journal=Science |volume=343 |issue=6174 |pages=1017–1021 |year=2014 |bibcode=2014Sci...343.1017V |last1=Vernot |first1=B. |last2=Akey |first2=J. M. |doi=10.1126/science.1245938 |pmid=24476670 |s2cid=23003860|doi-access=free }}

Various estimates exist for the proportion, such as 1–4% or 3.4–7.9% in modern Eurasians,{{cite journal |arxiv=1307.8263 |title=Maximum likelihood evidence for Neandertal admixture in Eurasian populations from three genomes |first1=K. |last1=Lohse |first2=L. A. F. |last2=Frantz |journal=Populations and Evolution |bibcode=2013arXiv1307.8263L |volume=1307 |year=2013 |page=8263}} or 1.8–2.4% in modern Europeans and 2.3–2.6% in modern East Asians.{{cite journal |last1=Prüfer |first1=K. |last2=de Filippo |first2=C. |last3=Grote | first3=S. |last4=Mafessoni |first4=F. |last5=Korlević |first5=P. |last6=Hajdinjak |first6=M. |title=A high-coverage Neandertal genome from Vindija Cave in Croatia |journal=Science |year=2017 |doi=10.1126/science.aao1887 |pmid=28982794 |pmc=6185897 |display-authors=etal |volume=358 |issue=6363 |pages=655–658 |bibcode=2017Sci...358..655P}} Pre-agricultural Europeans appear to have had similar, or slightly higher, percentages to modern East Asians. The percentage may have decreased in Europeans due to dilution with a group of people which had split off before Neanderthal introgression.{{sfn|Reich|2018}} Typically, studies have reported finding no significant levels of Neanderthal DNA in Sub-Saharan Africans, but a 2020 study detected 0.3-0.5% in the genomes of five African sample populations, likely the result of Eurasians back-migrating and interbreeding with Africans.{{cite journal |first1=L. |last1=Chen |first2=A. B. |last2=Wolf |first3=W. |last3=Fu |first4=J. M. |last4=Akey |year=2020 |title=Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals |journal=Cell |volume=180 |issue=4 |pages=677–687.e16 |doi=10.1016/j.cell.2020.01.012 |pmid=32004458 |s2cid=210955842|doi-access=free }}

While a large portion of surviving introgression appears to be non-coding ("junk") DNA with few biological functions, some Neanderthal-derived genes seem to have functional implications.{{sfn|Reich|2018}}

Due to their small population and resulting reduced effectivity of natural selection, Neanderthals accumulated several weakly harmful mutations, which were introduced to and slowly selected out of the much larger modern human population; the initial hybridised population may have experienced up to a 94% reduction in fitness compared to contemporary humans. By this measure, Neanderthals may have substantially increased in fitness.{{cite journal |first1=I. |last1=Juric |first2=S. |last2=Aeschbacher |first3=G. |last3=Coop |year=2016 |title=The strength of selection against Neanderthal introgression |journal=PLOS Genetics |volume=12 |issue=11 |pages=e1006340 |doi=10.1371/journal.pgen.1006340 |pmid=27824859 |pmc=5100956 |doi-access=free }} A 2017 study focusing on archaic genes in Turkey found associations with coeliac disease, malaria severity and Costello syndrome.{{cite journal |first1=R. O. |last1=Taskent |first2=N. D. |last2=Alioglu |first3=E. |last3=Fer |display-authors=et al. |year=2017 |title=Variation and functional impact of Neanderthal ancestry in Western Asia |journal=Genome Biology and Evolution |volume=9 |issue=12 |pages=3516–3624 |doi=10.1093/gbe/evx216 |pmc=5751057 |pmid=29040546}}

Nonetheless, some genes may have helped modern humans adapt to the environment. The putatively Neanderthal Val92Met variant of the MC1R gene may be weakly associated with red hair and UV radiation sensitivity.{{cite journal |last1=Zorina-Lichtenwalter |first1=K. |last2=Lichtenwalter |first2=R. N. |last3=Zaykin |first3=D. V. |display-authors=et al. |title=A study in scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect |journal=Human Molecular Genetics |year= 2019 |volume=28 |issue=12 |pages=2093–2106 |doi=10.1093/hmg/ddz018 |pmid=30657907 |pmc=6548228 |doi-access=free}} This variant is primarily found in East Asian populations (especially Taiwanese indigenous peoples) rather than Europeans.{{cite journal |last1=Ding |first1=Q. |last2=Hu |first2=Y. |last3=Xu |first3=S. |last4=Wang |first4=C.-C. |last5=Li |first5=H. |last6=Zhang |first6=R. |last7=Yan |first7=S. |last8=Wang |first8=J. |last9=Jin |first9=L.|title=Neanderthal origin of the haplotypes carrying the functional variant Val92Met in the MC1R in modern humans |journal=Molecular Biology and Evolution |year= 2014 |volume=31 |issue=8 |pages=1994–2003 |doi=10.1093/molbev/msu180 |pmid=24916031 |doi-access=free}} "We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (~5%), moderate in continental East Asians (~30%), and high in Taiwanese aborigines (60–70%)." Different modern human populations seem to have maintained certain Neanderthal-derived genes due to local evolutionary pressures; for instance, Asian populations showed clustering in functional groups related to complement and haematopoietic pathways,

while Europeans showed clustering in functional groups related to the lipid catabolic process.

"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."

{{cite journal | doi = 10.1038/ncomms4584 | volume= 5 | title= Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans | year= 2014 | journal= Nature Communications | last1 = Khrameeva | first1 = Ekaterina E. | last2 = Bozek | first2 = Katarzyna | last3 = He | first3 = Liu | last4 = Yan | first4 = Zheng | last5 = Jiang | first5 = Xi | last6 = Wei | first6 = Yuning | last7 = Tang | first7 = Kun | last8 = Gelfand | first8 = Mikhail S. | last9 = Prufer | first9 = Kay | last10 = Kelso | first10 = Janet | last11 = Paabo | first11 = Svante | last12 = Giavalisco | first12 = Patrick | last13 = Lachmann | first13 = Michael | last14 = Khaitovich | first14 = Philipp | page= 3584 | pmid = 24690587 | pmc = 3988804 | bibcode = 2014NatCo...5.3584K}}.

Some genes related to the immune system appear to have been affected by introgression, which may have aided migration,{{cite journal |first1=L. |last1=Ségurel |first2=L. |last2=Quintana-Murci |year=2014 |title=Preserving immune diversity through ancient inheritance and admixture |journal=Current Opinion in Immunology |volume=30 |pages=79–84 |doi=10.1016/j.coi.2014.08.002 |pmid=25190608}} such as OAS1,{{cite journal |first1=F. L. |last1=Mendez |first2=J. C. |last2=Watkins |first3=M. F. |last3=Hammer |year=2013 |title=Neandertal origin of genetic variation at the cluster of OAS immunity genes |journal=Molecular Biology and Evolution |volume=30 |issue=4 |pages=798–801 |doi=10.1093/molbev/mst004 |pmid=23315957 |s2cid=2839679 |url=http://pdfs.semanticscholar.org/4960/a4cb348c36a636721213898bce2c4fd99e4e.pdf |archive-url=https://web.archive.org/web/20190223155415/http://pdfs.semanticscholar.org/4960/a4cb348c36a636721213898bce2c4fd99e4e.pdf |url-status=dead |archive-date=February 23, 2019}} STAT2,{{cite journal |first1=F. L. |last1=Mendez |first2=J. C. |last2=Watkins |first3=M. F. |last3=Hammer |title=A haplotype at STAT2 introgressed from Neanderthals and serves as a candidate of positive selection in Papua New Guinea |journal=American Journal of Human Genetics |volume=91 |issue=2 |year=2012 |pages=265–274 |doi=10.1016/j.ajhg.2012.06.015 |pmc=3415544 |pmid=22883142}} TLR6, TLR1, TLR10,{{cite journal |first1=M. |last1=Dannemann |first2=A. A. |last2=Andrés |first3=J. |last3=Kelso |year=2016 |title=Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human toll-like receptors |journal=American Journal of Human Genetics |volume=98 |issue=1 |pages=22–33 |doi=10.1016/j.ajhg.2015.11.015 |pmc=4716682 |pmid=26748514}} and several related to immune response.{{cite journal |first1=Y. |last1=Nédélec |first2=J. |last2=Sanz |first3=G. |last3=Baharian |display-authors=et al. |year=2016 |title=Genetic ancestry and natural selection drive population differences in immune responses to pathogens |journal=Cell |volume=167 |issue=3 |pages=657–669 |doi=10.1016/j.cell.2016.09.025 |pmid=27768889 |doi-access=free}}{{efn|OAS1 and STAT2 both are associated with fighting viral inflections (interferons), and the listed toll-like receptors (TLRs) allow cells to identify bacterial, fungal, or parasitic pathogens. African origin is also correlated with a stronger inflammatory response.}} Of the inherited Neanderthal genome, 25% in modern Europeans and 32% in modern East Asians may be related to viral immunity.{{cite journal |first1=D. |last1=Enard |first2=D. A. |last2=Petrov |year=2018 |title=Evidence that RNA viruses drove of adaptive introgression between Neanderthals and modern humans |journal=Cell |volume=175 |issue=2 |pages=360–371 |doi=10.1016/j.cell.2018.08.034 |pmc=6176737 |pmid=30290142}}

Neanderthal genes have also been implicated in the structure and function of the brain,{{efn|Higher levels of Neanderthal-derived genes are associated with an occipital and parietal bone shape reminiscent to that of Neanderthals, as well as modifications to the visual cortex and the intraparietal sulcus (associated with visual processing).{{cite journal |first1=M. D. |last1=Gregory |first2=J. S. |last2=Kippenhan |first3=D. P. |last3=Eisenberg |display-authors=et al. |year=2017 |title=Neanderthal-derived genetic variation shapes modern human cranium and brain |journal=Scientific Reports |volume=7 |issue=1 |page=6308 |doi=10.1038/s41598-017-06587-0 |pmid=28740249 |pmc=5524936 |bibcode=2017NatSR...7.6308G}}}} keratin filaments, sugar metabolism, muscle contraction, body fat distribution, enamel thickness and oocyte meiosis.{{cite journal |first1=O. |last1=Dolgova |first2=O. |last2=Lao |year=2018 |title=Evolutionary and medical consequences of archaic introgression into modern human genomes |journal=Genes |volume=9 |issue=7 |page=358 |doi=10.3390/genes9070358 |pmc=6070777 |pmid=30022013 |doi-access=free}}

Neanderthal mtDNA (which is passed on from mother to child) is absent in modern humans.{{cite journal |last1=Luo |first1=S. |last2=Valencia |first2=C. A. |last3=Zhang |first3=J. |last4=Lee |first4=N.-C. |last5=Slone |first5=J. |last6=Gui |first6=B. |last7=Wang |first7=X.|last8=Li |first8=Z.|last9=Dell |first9=S. |last10=Brown |first10=J. |last11=Chen |first11=S. M.|last12=Chien |first12=Y.-H. |last13=Hwu |first13=W.-L. |last14=Fan |first14=P.-C.|last15=Wong |first15=L.-J. |last16=Atwal |first16=P. S. |last17=Huang |first17=T.|title=Biparental inheritance of mitochondrial DNA in humans |journal=Proceedings of the National Academy of Sciences |year=2018 |volume=115 |issue=51 |pages=13039–13044 |doi=10.1073/pnas.1810946115 |pmid=30478036 |pmc=6304937|bibcode=2018PNAS..11513039L |doi-access=free }} This is evidence that interbreeding occurred mainly between Neanderthal males and modern human females.{{cite book | last=Papini | first=M. | title=Comparative Psychology: Evolution and Development of Brain and Behavior, 3rd Edition | publisher=Taylor & Francis | year=2020 | isbn=978-1-000-17770-1 | url=https://books.google.com/books?id=hvj3DwAAQBAJ&pg=PT619 | access-date=March 28, 2024 | page=619 |quote="There is evidence of somewhat selective interbreeding. mtDNA from Neanderthals is absent in modern humans. Because mtDNA is carried only by females, interbreeding may have occurred mainly between Neanderthal males and modern females (Krings, Stone, Schmitz, Krainitzki, Stoneking, & Pääbo, 1997). "}} According to Svante Pääbo, it is not clear that modern humans were socially dominant over Neanderthals, which may explain why the interbreeding occurred primarily between Neanderthal males and modern human females.{{cite book | last=Paabo | first=S. | title=Neanderthal Man: In Search of Lost Genomes | publisher=Basic Books | year=2014 | isbn=978-0-465-02083-6 | url=https://books.google.com/books?id=cguNAgAAQBAJ&pg=PA19 | access-date=March 28, 2024 | page=19}} Furthermore, even if Neanderthal women and modern human males did interbreed, Neanderthal mtDNA lineages may have gone extinct if women who carried them only gave birth to sons.

There is considerably less Neanderthal ancestry on the X-chromosome compared to the autosomal chromosomes, which similarly suggests that admixture with modern humans was primarily the result of mating between modern human females and Neanderthal males. Other authors have suggested that this may be due to negative selection against Neanderthal alleles, but these two proposals are not mutually exclusive.{{Cite journal |last1=Reilly |first1=Patrick F. |last2=Tjahjadi |first2=Audrey |last3=Miller |first3=Samantha L. |last4=Akey |first4=Joshua M. |last5=Tucci |first5=Serena |date=September 2022 |title=The contribution of Neanderthal introgression to modern human traits |journal=Current Biology |language=en |volume=32 |issue=18 |pages=R970–R983 |doi=10.1016/j.cub.2022.08.027 |pmc=9741939 |pmid=36167050|bibcode=2022CBio...32.R970R }} A 2023 study confirmed that the low level of Neanderthal ancestry on the X-chromosomes is best explained by sex bias in the admixture events, and these authors also found evidence for negative selection on archaic genes.{{cite journal | last1=Chevy | first1=Elizabeth T. | last2=Huerta-Sánchez | first2=Emilia | last3=Ramachandran | first3=Sohini | title=Integrating sex-bias into studies of archaic introgression on chromosome X | journal=PLOS Genetics | volume=19 | issue=8 | date=August 14, 2023 | issn=1553-7404 | pmid=37578977 | pmc=10449224 | doi=10.1371/journal.pgen.1010399 | doi-access=free | page=e1010399 |quote= We have shown that the observed low level of archaic coverage on chromosome X could be explained merely by a reduction in the effect of heterosis and sex-biases in the introgression events, without involving a more complex model with hybrid incompatibilities. Our work also suggests that negative selection was likely acting on archaic variants, and provides an appropriate set of null models for evaluating positive selection on introgressed segments on chromosome X.}}

The lack of Neanderthal-derived Y-chromosomes in modern humans (which is passed on from father to son), has also inspired the suggestions that the hybrids that contributed ancestry to modern populations were predominantly females, or that the Neanderthal Y-chromosome was not compatible with modern humans and became extinct.{{sfn|Reich|2018}}{{cite journal |first1=F. L. |last1=Mendez |first2=G. D. |last2=Poznik |first3=S. |last3=Castellano |first4=C. D. |last4=Bustamante |year=2016 |title=The divergence of Neandertal and modern human Y chromosomes |journal=American Journal of Human Genetics |volume=98 |issue=4 |pages=728–734 |doi=10.1016/j.ajhg.2016.02.023 |pmc=4833433 |pmid=27058445}}

File:Homo sapiens sapiens, Oase, Rumänien (Daniela Hitzemann).jpg with around 7.3% Neanderthal DNA (from an ancestor 4–6 generations back)|alt=A dark-skinned man with black, shiny hair going down to his shoulders, a slight moustache, a goatee, brown eyes, weak eyebrows, wearing a tailored shirt and holding a long spear to support himself]]

The low percentages of Neanderthal DNA in all present-day populations indicate infrequent interbreeding,{{cite journal |first=S. |last=Pääbo |author-link=Svante Pääbo |title=The diverse origins of the human gene pool |journal=Nature Reviews Genetics |volume=16 |number=6 |pages=313–314 |year=2015 | doi=10.1038/nrg3954 |pmid=25982166 |s2cid=5628263}} unless interbreeding was more common with a different population of modern humans which did not contribute to the present day gene pool.{{sfn|Reich|2018}}

According to linkage disequilibrium mapping, the last Neanderthal gene flow into the modern human genome occurred 86–37,000 years ago, but most likely 65–47,000 years ago.{{cite journal |first1=S. |last1=Sankararaman |first2=N. |last2=Patterson |first3=H. |last3=Li |first4=S. |last4=Pääbo |author-link4=Svante Pääbo |first5=D. |last5=Reich |year=2012 |title=The date of interbreeding between Neandertals and modern humans |journal=PLOS Genetics |volume=8 |issue=10 |page=e1002947 |pmid=23055938 |pmc=3464203 |doi=10.1371/journal.pgen.1002947 |bibcode=2012arXiv1208.2238S |arxiv=1208.2238 |doi-access=free }}{{cite journal |first1=Leonardo N. M. |last1=Iasi |first2=Manjusha |last2=Chintalapati |first3=Laurits |last3=Skov |first4=Alba Bossoms |last4=Mesa |first5=Mateja |last5=Hajdinjak |first6=Benjamin M. |last6=Peter |first7=Priya |last7=Moorjani |year=2024 |title=Neanderthal ancestry through time: Insights from genomes of ancient and present-day humans |volume=386 |issue=6727 |journal=Science |doi=10.1126/science.adq3010 }} Neanderthals additionally came into genetic contact with modern humans during a more ancient modern humans dispersal out of Africa 250,000 years ago; this caused a 6% modern human ancestry in Neanderthal populations. Modern human mtDNA may have introgressed into Neanderthal populations possibly 268,000 to 413,000 years ago.{{cite journal |author1=Daniel Harris |author2=Alexander Platt |author3=Matthew E.B. Hansen |author4=Shaohua Fan |author5=Michael A. McQuillan |author6=Thomas Nyambo |author7=Sununguko Wata Mpoloka |author8=Gaonyadiwe George Mokone |author9=Gurja Belay |author10=Charles Fokunang |author11=Alfred K. Njamnshi |author12=Sarah A. Tishkoff |title=Diverse African genomes reveal selection on ancient modern human introgressions in Neanderthals |journal=Current Biology |date=2023 |volume=33 |issue=22 |pages=4905-4916.e5 |doi=10.1016/j.cub.2023.09.066 |url=https://www.sciencedirect.com/science/article/pii/S0960982223013155 |access-date=8 May 2024 |issn=0960-9822|pmc=10841429 }} There could have been another interbreeding episode with a population ancestral to East Asians.{{cite journal | year = 2015 | title = Selection and Reduced Population Size Cannot Explain Higher Amounts of Neanderthal Ancestry in East Asian than in European Human Populations | url= | journal = American Journal of Human Genetics | volume = 96 | issue = 3 | pages = 448–53 | doi = 10.1016/j.ajhg.2014.12.029 | pmid= 25683122 | pmc= 4375557 | last1 = Kim | first1 = BY | last2 = Lohmueller | first2 = KE}}

Interbreeding still occurred without contributing to the modern genome.{{sfn|Reich|2018}} The approximately 40,000-year-old modern human Oase 2 was found, in 2015, to have had 6–9% (point estimate 7.3%) Neanderthal DNA, indicating a Neanderthal ancestor up to four to six generations earlier, but this hybrid population does not appear to have made a substantial contribution to the genomes of later Europeans.{{cite journal |first1=Q. |last1=Fu |first2=M. |last2=Hajdinjak |first3=O. T. |last3= Moldovan |display-authors=3 |first4=S. |last4=Constantin |first5=S. |last5= Mallick |first6=Pontus |last6=Skoglund |first7=N. |last7=Patterson |first8=N. |last8=Rohland |first9=I. |last9=Lazaridis |first10=B. |last10=Nickel |first11=B. |last11=Viola |first12=Kay |last12=Prüfer |first13=M. |last13=Meyer |first14=J. |last14=Kelso |first15=D |last15=Reich |first16=S. |last16=Pääbo |author-link16=Svante Pääbo |title=An early modern human from Romania with a recent Neanderthal ancestor |journal=Nature |year=2015 |volume=524 |issue=7564 |pages=216–219 |doi=10.1038/nature14558 |pmid=26098372 |pmc=4537386 |bibcode=2015Natur.524..216F}} In 2016, the DNA of Neanderthals from Denisova Cave revealed evidence of interbreeding 100,000 years ago, and interbreeding with an earlier dispersal of H. sapiens may have occurred as early as 120,000 years ago in places such as the Levant.{{cite journal |last1=Kuhlwilm |first1=M. |title=Ancient gene flow from early modern humans into eastern Neanderthals |journal=Nature |year=2016 |volume=530 |issue=7591 |pages= 429–433 |doi=10.1038/nature16544 |pmid=26886800 |pmc=4933530 |bibcode=2016Natur.530..429K}} The earliest H. sapiens remains outside of Africa occur at Misliya Cave 194–177,000 years ago, and Skhul and Qafzeh 120–90,000 years ago.{{cite journal |first1=I. |last1=Hershkovitz |first2=G. W. |last2=Weber |first3=R. |last3=Quam |first4=M. |last4=Duval |first5=R. |last5=Grün |year=2018 |title=The earliest modern humans outside Africa |journal=Science |volume=359 |issue=6374 |pages=459 |doi=10.1126/science.aap8369 |pmid=29371468 |url=https://www.researchgate.net/publication/322706982 |bibcode=2018Sci...359..456H |hdl=10072/372670 |doi-access=free|hdl-access=free }} The Qafzeh humans lived at approximately the same time as the Neanderthals from the nearby Tabun Cave.{{cite journal |last1=McDermott |first1=F. |last2=Grün |first2=R. |last3=Stringer |first3=C. B. |author-link3=Chris Stringer|last4=Hawkesworth |first4=C. J. |title=Mass-spectrometric U-series dates for Israeli Neanderthal/early modern hominid sites |journal=Nature |year= 1993 |volume=363 |issue=6426 |pages=252–255 |doi=10.1038/363252a0 |pmid=8387643 |bibcode=1993Natur.363..252M |s2cid=4234812}} The Neanderthals of the German Hohlenstein-Stadel have deeply divergent mtDNA compared to more recent Neanderthals, possibly due to introgression of human mtDNA between 316,000 and 219,000 years ago, or simply because they were genetically isolated.{{cite journal |last1=Peyrégne |first1=S. |last2=Slon |first2=V. |last3=Mafessoni |first3=F. |display-authors=et al. |title=Nuclear DNA from two early Neandertals reveals 80 ka of genetic continuity in Europe |journal=Science Advances |volume=5 |number=6 |page=eaaw5873 |year=2019 |doi=10.1126/sciadv.aaw5873 |pmid=31249872 |pmc=6594762 |bibcode=2019SciA....5.5873P}} Whatever the case, these first interbreeding events have not left any trace in modern human genomes.{{cite journal |last1=Pagani |first1=L. |title=Genomic analyses inform on migration events during the peopling of Eurasia |journal=Nature |year= 2016 |volume=538 |issue=7624 |pages=238–242 |bibcode=2016Natur.538..238P |doi=10.1038/nature19792 |pmid=27654910 |pmc=5164938}}

File:Homo-Stammbaum, Version Stringer-en.svg's Homo family tree. The horizontal axis represents geographic location, and the vertical time in millions of years ago.{{efn|Homo floresiensis originated in an unknown location from unknown ancestors and reached remote parts of Indonesia. Homo erectus spread from Africa to western Asia, then east Asia and Indonesia; its presence in Europe is uncertain, but it gave rise to Homo antecessor, found in Spain. Homo heidelbergensis originated from Homo erectus in an unknown location and dispersed across Africa, southern Asia and southern Europe (other scientists interpret fossils, here named heidelbergensis, as late erectus). Modern humans spread from Africa to western Asia and then to Europe and southern Asia, eventually reaching Australia and the Americas. In addition to Neanderthals and Denisovans, a third gene flow of archaic Africa origin is indicated at the right.{{cite journal |doi=10.1038/485033a |bibcode=2012Natur.485...33S |pmid=22552077 |title=Evolution: what makes a modern human |year=2012 |journal=Nature |last1=Stringer |first1=C. |volume=485 |issue=7396 |pages=33–35 |s2cid=4420496 |doi-access=free}} The chart is missing superarchaic (which diverged from erectus 1.9 mya) introgression into Neanderthal/Denisovan common ancestor.}}]]

Based on nuclear DNA (nDNA), Neanderthals and Denisovans share a more recent last common ancestor (LCA) than to modern humans. However, Neanderthals and modern humans share a more recent mitochondrial LCA (observable by studying mtDNA) and Y chromosome LCA.{{Cite journal |last1=Petr |first1=Martin |last2=Hajdinjak |first2=Mateja |last3=Fu |first3=Qiaomei |last4=Essel |first4=Elena |last5=Rougier |first5=Hélène |last6=Crevecoeur |first6=Isabelle |last7=Semal |first7=Patrick |last8=Golovanova |first8=Liubov V. |last9=Doronichev |first9=Vladimir B. |last10=Lalueza-Fox |first10=Carles |last11=de la Rasilla |first11=Marco |last12=Rosas |first12=Antonio |last13=Shunkov |first13=Michael V. |last14=Kozlikin |first14=Maxim B. |last15=Derevianko |first15=Anatoli P. |date=September 25, 2020 |title=The evolutionary history of Neanderthal and Denisovan Y chromosomes |url=https://www.science.org/doi/10.1126/science.abb6460 |journal=Science |language=en |volume=369 |issue=6511 |pages=1653–1656 |doi=10.1126/science.abb6460 |pmid=32973032 |bibcode=2020Sci...369.1653P |hdl=21.11116/0000-0007-11C2-A |issn=0036-8075|hdl-access=free }} This likely resulted from an interbreeding event subsequent to the Neanderthal/Denisovan split. This involved either introgression coming from an unknown archaic human into Denisovans,{{cite journal |first1=F. |last1=Chen |first2=F. |last2=Welker |first3=C. |last3=Shen |year=2019 |title=A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau |journal=Nature |volume=569 |issue=7,756 |pages=409–412 |doi=10.1038/s41586-019-1139-x|pmid=31043746 |bibcode=2019Natur.569..409C |s2cid=141503768|url=https://kar.kent.ac.uk/74280/1/Xiahe_Main.pdf }}{{cite journal |first1=A. R. |last1=Rogers |first2=R. J. |last2=Bohlender |first3=C. D. |last3=Huff |title=Early history of Neanderthals and Denisovans |journal=Proceedings of the National Academy of Sciences |volume=114 |issue=37 |year=2017 |pages=9859–9863 |doi=10.1073/pnas.1706426114 |pmid=28784789 |pmc=5604018|bibcode=2017PNAS..114.9859R |doi-access=free }}{{cite journal |author-first1=M. |author-last1=Hajdinjak |author-first2=Q. |author-last2=Fu |author-first3=A. |author-last3=Hübner |year=2018 |title=Reconstructing the genetic history of late Neanderthals |journal=Nature |volume=555 |issue=7698 |pages=652–656 |doi=10.1038/nature26151 |pmid=29562232 |pmc=6485383 |bibcode=2018Natur.555..652H}} or introgression from an earlier unidentified modern human wave from Africa into Neanderthals.{{cite journal |first1=C. |last1=Posth |first2=C. |last2=Wißing |first3=K. |last3=Kitagawa |display-authors=et al. |title=Deeply divergent archaic mitochondrial genome provides lower time boundary for African gene flow into Neanderthals |journal=Nature Communications |volume=8 |page=16046 |year=2017 |doi=10.1038/ncomms16046| pmid=28675384 | pmc=5500885 | bibcode=2017NatCo...816046P}} Several Neanderthal-like fossils in Eurasia from a similar time period are often grouped into H. heidelbergensis, of which some may be relict populations of earlier humans, which could have interbred with Denisovans.{{cite journal |last1=Pääbo |first1=S.|author-link=Svante Pääbo |title=A mitochondrial genome sequence of a hominin from Sima de los Huesos |journal=Nature |volume=505 |year=2014 |issue=7483 |pages=403–406 |bibcode=2014Natur.505..403M |doi=10.1038/nature12788 |pmid=24305051 |s2cid=4456221 |url=https://eprints.ucm.es/27979/1/nature12788.pdf}} This is also used to explain an approximately 124,000-year-old German Neanderthal specimen with mtDNA that diverged from other Neanderthals (except for Sima de los Huesos) about 270,000 years ago, while its genomic DNA indicated divergence less than 150,000 years ago.

Sequencing of the genome of a Denisovan from Denisova Cave has shown that 17% of its genome derives from Neanderthals.{{cite journal |doi=10.1126/science.340.6134.799 |pmid=23687020 |title=More genomes from Denisova Cave show mixing of early human groups |journal=Science |volume=340 |issue=6134 |page=799 |year=2013 |last1=Pennisi |first1=E. |author-link=Elizabeth Pennisi |bibcode=2013Sci...340..799P}} This Neanderthal DNA more closely resembled that of a 120,000-year-old Neanderthal bone from the same cave than that of Neanderthals from Vindija Cave, Croatia, or Mezmaiskaya Cave in the Caucasus, suggesting that interbreeding was local.

For the 90,000-year-old Denisova 11, it was found that her father was a Denisovan related to more recent inhabitants of the region, and her mother a Neanderthal related to more recent European Neanderthals at Vindija Cave, Croatia. Given how few Denisovan bones are known, the discovery of a first-generation hybrid indicates interbreeding was very common between these species, and Neanderthal migration across Eurasia likely occurred sometime after 120,000 years ago.{{cite journal |author=Warren, Matthew |title=Mum's a Neanderthal, dad's a Denisovan: First discovery of an ancient-human hybrid |journal=Nature News |volume=560 |issue=7719 |pages=417–418 |year=2018 |doi= 10.1038/d41586-018-06004-0 |pmid=30135540 |bibcode=2018Natur.560..417W |doi-access=free}}

• Human evolutionary genetics
• Recent human evolution
• Accretion model of Neanderthal origins

{{notelist}}

{{reflist}}

• {{cite book |first=David |last=Reich |author-link=David Reich (geneticist) |year=2018 |chapter=Encounters with Neanderthals |title=Who we are and how we got here: ancient DNA and the new science of the human past |publisher=Oxford University Press |isbn=978-0-19-882125-0 |url={{google books |plainurl=yes |id=uLNSDwAAQBAJ |page=25}}}}

• Emily L. Casanova and F. Alex Feltus, "Neandertal DNA and the Human Mind", Scientific American, vol. 332, no. 2 (February 2025), pp. 42–47.

{{Homo neanderthalensis}}

{{Human genetics}}

Category:Ancient human genetic history

Category:Ancient DNA (human)

Genetics