The Contribution of Ancient Hominin Genomes from Siberia to Our

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<ul><li><p>ISSN 10193316, Herald of the Russian Academy of Sciences, 2015, Vol. 85, No. 5, pp. 392396. Pleiades Publishing, Ltd., 2015.Original Russian Text S. Pbo, 2015, published in Vestnik Rossiiskoi Akademii Nauk, 2015, Vol. 85, No. 10, pp. 879884.</p><p>392</p><p>1 The human genome is contained in chromosomesthat are present in almost every cell in our bodies. It iscomposed of approximately 3.2 billion nucleotides.When cells replicate to form germ cells that will contribute to the next generation, mutations occur. As aresult of these mutations, about 50 to 200 new substitutions exist in every new individual that is born. Thesesubstitutions accumulate in the genome over time tothe extent that roughly one nucleotide in a thousanddiffers between two human genomes today, whereasroughly one nucleotide in a hundred differs between ahuman and a chimpanzee genome. In addition, duplicated DNA sequences differ both between individualsand between species.</p><p>Each particular nucleotide site in the genome hasits own history that could, in principle, be traced backthrough past generations. Such a history can bedepicted in the form of a tree showing common ancestors shared with the same site seen in other individualstoday. However, in reality, it is impossible to trace thehistory of a single nucleotide site. Therefore, one generally traces the average history of a segment of thegenome, or the entire genome, and depicts that in theform of a tree that thus represents an average picture ofhow most sites in the DNA segments or genomeswhose nucleotide sequences have been determined arerelated.</p><p>Until recently, it was only possible to determineDNA sequences and whole genome sequences frompresentday individuals from which DNA can be isolated in good condition from fresh tissues, such asblood. To evolutionary scientists, this is somewhatfrustrating because it represents an indirect way tostudy the past: one studies DNA sequences that existtoday, uses the best models we have for how mutationsaccumulate, and estimates what common ancestors in</p><p>1 The text was submitted by the author in English.</p><p>the past may have looked like. This is frustratingbecause what we have are estimates subject to manyuncertainties, for example, as a result of the mutational models used. For over 30 years, our laboratoryhas worked on methods to overcome this time trapby going back in time and retrieving DNA sequencesfrom archaeological and paleontological remains.This is possible only on rare occasions when wellpreserved tissues can be found. Direct ancestors ofpresentday organisms are also almost never available.However, this approach, nevertheless, opens up newpossibilities in that it allows DNA sequences from pastpopulations and extinct species to be determined.</p><p>Of particular interest to us is the closest extinct relative of all presentday humans: the Neanderthals.This robust form of hominins emerged in Europe andwestern Asia approximately 300000 to 400000 yearsago and disappeared between 30000 and 40000 yearsago. The debate concerning the relationships betweenNeanderthals and modern humans, and about whathappened when they met, lasted for decades. One ideawas that modern humans replaced Neanderthals without interbreeding, in which case the Neanderthal contribution to presentday human genetic variationwould be zero. Another idea was that Neanderthalswere the direct ancestors of Europeans. In this case,the Neanderthal genetic contribution to presentdaypeople in Europe would approach 100%. Obviously, alllevels of contribution between 0 and 100% are alsopossible, and different levels of Neanderthal contribution to presentday Europeans have been argued for onthe basis of archaeological and paleontological data.</p><p>We got the first chance to test these hypothesesdirectly in the mid1990s, when we were allowed toanalyze the Neanderthal bones that had been discovered in the Neandertal Valley in Germany in 1856 andgave its name to this hominin group. At the time, wewere able to draw on over ten years of experience withthe development of techniques to extract and amplifysmall amounts of DNA from ancient remains of cavebears, mammoths, and other late Pleistocene mammals [1]. We focused on the mitochondrial DNA(mtDNA), because every cell contains hundreds or</p><p>DOI: 10.1134/S1019331615050081</p><p>The Contribution of Ancient Hominin Genomes from Siberiato Our Understanding of Human Evolution1</p><p>S. Pbo*</p><p>* Svante Pbo is a professor and director of the Department ofEvolutionary Genetics, Max Planck Institute for EvolutionaryAnthropology, Leipzig,</p><p>Papers by Laureates of the 2014 Lomonosov GrandGold Medal of the Russian Academy of Sciences</p></li><li><p>HERALD OF THE RUSSIAN ACADEMY OF SCIENCES Vol. 85 No. 5 2015</p><p>THE CONTRIBUTION OF ANCIENT HOMININ GENOMES FROM SIBERIA 393</p><p>even thousands of mtDNA copies, making it easier toretrieve mtDNA than any particular part of thenuclear genome. We reconstructed the most variablepart of the mtDNA and estimated phylogenetic treesto reconstruct the history of the mtDNAs of Neanderthals and presentday people. In contrast to thenuclear genome, the mtDNA is inherited as one singleunit from mothers to offspring without recombinationso a phylogenetic tree for mtDNA reflects not theaverage history but the exact maternal lineages thatrelate the mtDNA analyzed. </p><p>On the one hand, these trees showed what wasalready known: that the mtDNAs of all people inhabiting the Earth today trace their ancestry back to acommon ancestor about 100000200000 years ago.But they also showed that the mtDNA lineage of theNeanderthal type specimen went much further back intime and shared a common ancestor with presentdaymtDNAs on the order of half a million years ago [2].Subsequently, we and others have determined severalother Neanderthal mtDNA sequences. They all falltogether outside the variation of the mtDNAs ofpresentday people. Thus, in 1997, it was clear that forthe mtDNA, the complete replacement model held:no person today carries an mtDNA derived from aNeanderthal.</p><p>However, the mtDNA represents only a tiny part ofour total genome. The full picture of our genetic history can only be obtained by studying the nucleargenome. In the early years of this millennium, itbecame feasible to consider sequencing genomes fromancient organisms thanks to new techniques that madeit possible to sequence millions of DNA moleculesrapidly and inexpensively. We were fortunate to receivefunding from the Max Planck Society for a fiveyeareffort to improve the technique of extraction of DNAfrom ancient bones and to make DNA libraries thatcould be used for highthroughput DNA sequencing.We also analyzed a large number of bones from manysites in Europe to find those bones that contained thelargest relative proportion of Neanderthal DNA. </p><p>We settled on a site in Croatia, from which we usedthree bones from different Neanderthal individualsand sequenced more than one billion short DNA fragments extracted from the bones. We developed computer algorithms to match these short DNA sequencesto the human genome while accounting for errorsinduced by chemical process that have affected themover tens of thousands of years. Only a few percent ofall sequences were derived from the Neanderthal individuals. Nevertheless, in 2010 we were able to presentabout 3 billion nucleotides of Neanderthal DNA thathad been mapped to the human genome. Togetherthese DNA fragments covered about 55% of the partsof the Neanderthal genome to which short fragmentscan be mapped [3]. This was enough to ask if any</p><p>genetic interaction had occurred when modernhumans encountered Neanderthals.</p><p>If Neanderthals had made no genetic contributionto modern humans, the Neanderthal genome wouldbe equally far from Africans, Europeans, and anyother presentday populations. In contrast, if presentday Europeans carried DNA that they had inheritedfrom Neanderthals, European genomes would carryfewer differences from Neanderthals than Africangenomes, since Neanderthals were never in Africa;therefore, they would not be expected to have contributed to genomes there. To test this, we sequenced thegenomes of five presentday people and identified thepositions where two of these differed from each other.We then asked how often at these positions the Neanderthal genome carried the variant seen in onepresentday person and how often it carried the variantseen in the other presentday person. This approach ofcounting matches to pairs of presentday genomes wasnecessary since the quality of the Neanderthal genomewas so low that we could not trust sequence variantsthat were seen only in the Neanderthal genome andnot in one of the presentday genomes. When we compared two African genomes in this way, the Neanderthal genome matched variants in the two genomesequally often. This is to be expected since there was noreason to expect that Neanderthals would have contributed DNA to the ancestors of any of the Africans.Intriguingly, when we compared a European and anAfrican to the Neanderthal genome, we detected statistically significantly greater matching to the European genome, suggesting that Neanderthals had contributed DNA to the ancestor of the Europeans. Evenmore surprising was that, when we compared a personfrom China to an African and a person from PapuaNew Guinea to an African, we always found that thenonAfrican matched the Neanderthal genome moreoften than the African genome. This was surprising tous since Neanderthals had probably never been inChina and surely never in New Guinea. How couldthis be?</p><p>The explanation that we suggested and that hassince been borne out by work in our own and othergroups was that Neanderthals met modern humansand mixed with them probably in the Middle East. Ifthese modern humans later became the ancestors ofeverybody that today lives outside Africa, these earlymodern humans can, so to speak, have carried withthem the Neanderthal genetic contribution also togeographical areas where Neanderthals never existed.As a result, between 1 and 2% of the genomes of everyperson whose roots are nonAfrican is of Neanderthalorigin. The Neanderthal component in the genomes ofpresentday people has since been dated by studies ofthe extent to which Neanderthallike DNA segmentshave been broken down to smaller pieces by recombination that happens in each generation [4]. It has also</p></li><li><p>394</p><p>HERALD OF THE RUSSIAN ACADEMY OF SCIENCES Vol. 85 No. 5 2015</p><p>PBO</p><p>been confirmed by subsequent studies of a modernhuman from about 40000 years ago who carried muchlarger segments of Neanderthal DNA than presentday people, since they lived much closer to the time ofmixture [5].</p><p>Of course, it is unlikely that mixing between Neanderthals and modern humans happened only in onepopulation and exclusively in the Middle East, but,given the data at hand in 2010, this was the simplestexplanation of our findings. Further insights werelargely limited by the comparatively low quality of theNeanderthal genome. This was to be changed thanksto our collaboration with Anatolii Panteleevich Derevyanko.</p><p>The excavations at Denisova Cave, led by Academician Derevyanko and Professor M.V. Shunkov ofthe Institute of Archaeology and Ethnography of theSiberian Branch of the Russian Academy of Scienceshave generated many fundamental and novel insightsinto human evolution. One of their crucial finds is ahominin toe bone discovered in 2010. When weapplied new, ultrasensitive methods that my laboratorydeveloped to extract DNA and produce DNA librariesto this bone, we were able to sequence almost 50foldmore endogenous DNA from this single small bonethan from the three bones from Croatia that had beenused to produce the first Neanderthal genome a fewyears earlier. This individual turned out to be a Neanderthal, and its genome was sequenced to a qualityhigher than most genomes determined from presentday living people [6].</p><p>Using such highquality genomic information, it ispossible to observe differences between the twogenomes that the individual inherited from her fatherand from her mother. One can thus gauge the extent ofvariation in the population where the parents of theindividual lived. One can also estimate how closelyrelated the mother and the father of the individualwere to each other. In the case of the Neanderthalfrom Denisova Cave, this yielded an unexpectedresult. The paternal and maternal genomes had longsegments of DNA that were identical. This means thatthe parents of this individual were closely related. Onecan estimate that they must have been related at thelevel of half siblings. When in the future further Neanderthal genomes are sequenced to the same high quality as the one from Denisova Cave, it will be interestingto see if this was an unusual situation among Neanderthals or if it reflects a social pattern typical of Neanderthals.</p><p>The high quality of the Neanderthal genome fromDenisova Cave can also be used to estimate what partsof the genomes of presentday people were inheritedfrom Neanderthals. This confirms that everybody outside SubSaharan Africa carries between 1 to 2% ofNeanderthal DNA. This proportion is slightly larger inEast Asia than in Europe, suggesting that additional</p><p>admixture between Neanderthals and modern humansmay have happened during the colonization of Asia[7]. To get a perspective on this, you may recall that weall have onehalf of our DNA from each of our parents, about 25% from each grandparent, about 12%from our great grandparents, and so on. From anancestor six generations back, we have, on average,inherited about 1.5% of our DNA. Thus, from thepoint of view of the total amount of DNA people todayhave inherited from Neanderthals, it is as if they had aNeanderthal ancestor six generations back. However,due to recombination that occurs when new germ cellsare formed in each generation, the Neanderthal DNAis distributed in much smaller fragments than theDNA you have inherited from your ancestors six generations back. You may also ask how much of the totalNeanderthal genome exists distributed among peopleliving today. This estimate is still very approximate, butit would seem that at least about 40% of the Neanderthal genome can be found in people today.</p><p>Amazingly, the highquality Neanderthal genomeis not the only great gift that Denisova Cave has giventhe world. In 2008 a tiny piece of the phalanx of a fifthfinger of a child was discovered in the East gallery ofthe cave. We were privileged to work on this find andwere happy to be able to generate first a low qualitygenome [8] and then, as our techniques improved, ahighquality genome from it. In this genome, eachposition in the part of the genome amenable to mapping short pieces of DNA was covered over 30 times[9]. When we compared this genome to othergenomes, we were surprised to find that it was neithera modern human nor a Neanderthal. It shared a common ancestor with Neanderthals, but this ancestralpopulation lived about four times further back in timethan the oldest ancestral population shared amongpresentday human populations....</p></li></ul>