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The and data; analyzed R.J.B. and A.R.R. research; hrfr edt hr nety uain nteeshared these in ancestry. share to tend therefore x the exhibit exhibit 20% data these another in pattern; sites nucleotide the of 30% About that Pygmies— than history 1. and of Fig. model in San, different a the require would they interest—Melanesians, because great of tions (X (Y population “LWK.CHB,” population African as Eurasian the such that abbreviations Eura- means use which of study we identify also extremes To analyses, (CHB). We western Chinese different northern Africa. and and (CEU) West eastern Europeans sia: of the East (YRI) of from Yoruba (LWK) populations Luhuya the the and populations, Africa (15). 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Email: addressed. be should correspondence whom To eateto pdmooy DAdro acrCne,Houston, Center, Cancer Anderson MD Epidemiology, of Department h eneta ouainge ag n eaae into separated and groups. local large two isolated grew largely into Denisovans. population split the Neanderthal and then The Neanderthals its It the followed lineage. populations, that modern y regional 10,000 the the from early during separation the small archaic very study the that was to show lineage We method populations. Pleis- archaic statistical these Late of a history the develop during We interbreeding these tocene. from by derived populations DNA Pleis- carry Middle the in modern early Many lineage tocene. that modern populations the from human separated were Denisovans and Neanderthals Significance n e f1 ieptenfeunisi hw nFg 2A. 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ANTHROPOLOGY AB

Fig. 1. (A) Population tree representing an African population, X; a Eurasian population, Y; Neanderthals, N; and Denisovans, D. The model involves admixture, mN; time parameters, Ti; and population sizes, Ni.(B) Population tree with embedded gene tree. A mutation on the solid red branch would generate site pattern yn (shown in red at the base of the tree). One on the solid blue branch would generate ynd. Mutations on the dashed black branches would be ignored. “0” and “1” represent the ancestral and derived alleles.

ancestors generate the xy site pattern. Shared ancestry also mixture (mN ) and Neanderthal–Denisovan separation time explains the elevated frequency of nd. (TND ) appear in Fig. 4. The admixture estimates are 1–3%, in As noted above, our model of history (Fig. 1A) excludes gene broad agreement with previous results. Our results do not, how- flow from Denisovans into Eurasians. This is not a limitation of ever, support the view that East Asians carry more Neanderthal our method; it is motivated by the structure of the datasets under study. To see why, consider Fig. 2B. Note first that yn is more common than xn—Neanderthals share more derived alleles with A Europeans than with Africans. This suggests gene flow from Neanderthals into Europeans (9). More surprisingly, xd is more common than yd. The same pattern appears in all four combi- (YRI.CEU, YRI.CHB, LWK.CEU, and LWK.CHB) of African and Eurasian populations in our analysis. This pattern suggests gene flow from Denisovans into Africans, a possibility that we consider in Section S3. It also precludes any estimate of gene flow from Denisovans into Eurasians. For this , our base model includes no such term. The analysis proceeds in two stages: one to discover dependen- cies among parameters and a second one imposing constraints to cope with these dependencies. In stage 1, we fit an unconstrained model to the observed data and also to 50 bootstrap replicates. With the data in Fig. 2A, stage 1 revealed strong dependencies among several parameters (Fig. S1). For example, there is a pos- itive relationship between mN , the admixture fraction, and 2NN , the Neanderthal population size (Fig. 3). This relationship makes : If the Neanderthal population were large, then most intro- gressing Neanderthal genes would be distantly related to the Altai Neanderthal fossil. It would therefore take more admixture B to produce a given effect on the yn site pattern. On the other , if the Neanderthal population were small, a little admix- ture would have a larger effect. Such associations make estimation difficult, because points along the regression line have similar effects on the data. To reduce such issues, stage 2 of our analysis uses associations in the bootstrap data to impose constraints. Each constraint replaces one parameter with its regression on several others, as described in Section S1.4. Because this involves ignoring some of the sam- pling variation, we do not estimate confidence intervals for con- strained parameters. To calibrate the , we use published estimates Fig. 2. (A) Open circles show relative frequencies (horizontal axis) of of TXY and TXYND , as explained in Section S2. We assume a −8 nucleotide sites exhibiting each site pattern (vertical axis) in four popula- generation time of 29 y and a mutation rate of 1.1 × 10 per tions: X, YRI; Y, CEU; N, Neanderthal; and D, Denisovan. (B) Expanded view generation (16). of four site-pattern frequencies, showing 95% confidence intervals, esti- All four analyses—YRI.CEU, YRI.CHB, LWK.CEU, and mated by moving-blocks bootstrap, with 1,000 polymorphic nucleotide sites LWK.CHB—yield similar results. Estimates of Neanderthal ad- per block (13).

2 of 5 | www.pnas.org/cgi/doi/10.1073/pnas.1706426114 Rogers et al. Downloaded by guest on October 3, 2021 Downloaded by guest on October 3, 2021 pcfiainerrt xli h arwcndneitrasof intervals invoke confidence not narrow parameters. need the these explain we to that error imply specification distributions small. narrow is of These simulations in spreads our the row. intervals that in interesting confidence bias is the the it that Thus, of suggesting 5, those and to 4 Figs. similar are widths simula- Nonetheless, these distributions. Our sampling therefore of error. widths may the specification and underestimate disequilibrium estima- of linkage our ignores absence how algorithm simu- the show tion each 6) in (Fig. from behaves set data parameters tor one resulting by estimated The implied dataset. then lated model and the estimates under of datasets in 50 described simulated is We which legosim, program simulation narrow the to zero. at applies the boundary also against for concern intervals replicates, same confidence bootstrap The esti- boundary. from all same pushing those by including effects such mates, produce can error confidence Specification the Furthermore, for differ. intervals barely parameters these that of requires 1A) (Fig. model analysis. YRI.CEU the their by and implied moderns, as Neanderthals, ancestors, of size population effective of eaain u eut ml eaieylreNadrhlpopu- Neanderthal with large lation, relatively a imply results our Neanderthal–Denisovan separation, the Following intervals. confidence row point of 4, Our estimates small. very Fig. apparently was in the population events, archaic intervals separation ancestral two the confidence between interval confi- narrow the During high the Lower. with from estimated moderns. judging is from dence, time archaics separation of this separation Furthermore, the after about ago—only generations generations 300 25,600 to close are Denisovans, and intervals confidence broad Asian of the estimates East by our the hidden by surrounding but hand, documented real, other be biases the may the On excess of (10). arti- Bohlender or an and be (17) Rogers may bias view ascertainment This of 17–21). fact 14, (12, Europeans than DNA 2. Fig. in as are Data 3. Fig. oese al. et Rogers ots hs“onaycmrsin yohss eue our used we hypothesis, “boundary-compression” this test To Our model? misspecified a of artifacts be results these Could l siae of estimates All oaito fetmtsof estimates of Covariation 2N 2N T ND ntetn fthousands. of tens the in ND r xrml—ehp implausibly—narrow. extremely—perhaps are ag rmaot10t bu ,0,wt nar- with 1,000, about to 100 about from range T ND 2N h eaaintm fNeanderthals of time separation the , ND m T hs siae r ls othe to close are estimates whose , m N ND N . n 2N and < T XYND i.S3 Fig. N T cosbosrpreplicates. bootstrap across ND e u estimates our Yet . and rpstehistory the graphs 2N eto S1.5. Section ND r nar- are htaekono upce,adteeoisosmyhave may omissions these and suspected, or known are that along lie that values 3. parameter Fig. line. between regression in choose the seen to association difficult 5). the is reflects and It distributions this 4 sampling Presumably (Figs. broad bias. exhibit They data and they parameters. real 6), other (Fig. in the simulations intervals In of those confidence as broad behaved exhibit as not are on based are intervals analysis. confidence the of and 2 estimates stage point boot- All moving-blocks 50 replicates. on strap based intervals confidence 95% show lines zontal (T time separation Denisovan 4. Fig. nevl r ae nsae1. stage 2N on for based interval are intervals Confidence analysis. the of 2 5. Fig. mt eea om fgn flow gene of forms several omits 1A) (Fig. model base Our of estimates that show also simulations These ouainsz siae.Alpitetmtsaebsdo stage on based are estimates point All estimates. size Population siae fNadrhlamxue(m admixture Neanderthal of Estimates ND .Tevria ie(Lower line vertical The ). XYND NSEryEdition Early PNAS sbsdo tg ;other 2; stage on based is N n h Neanderthal– the and ) shows ) m N T and XYND | Hori- . 2N f5 of 3 N

ANTHROPOLOGY m exchanged mates only rarely. In such a population, the effec- N tive size of the global population can be large, even if each local 0.00 0.01 0.02 0.03 0.04 population is small (25). A sample from a single subpopulation Admixture Fraction would show a misleading signal of gradual , even if the true population were constant (26). Furthermore, Tnd there is direct evidence of large genetic differences among Nean- 0 10000 20000 TXYND derthal populations (22, 27). Finally, the rich and widespread Generations fossil record of Neanderthals is hard to reconcile with the view that their global population was tiny. We suggest that previous 2NXYND research has documented the small size of local Neanderthal populations, whereas our own findings document the large effec- 2NXY tive size of the metapopulation that contributed genes to modern humans. 2NND This interpretation implies that at least some of the Nean- 2NN derthals who contributed to the modern gene pool were distant relatives of the Altai Neanderthal. On the other hand, there is 0 20000 40000 60000 also evidence of gene flow from moderns into the Altai Nean- Haploid Population Size (2N) derthal (28). This suggests contact between modern humans and at least two groups of Neanderthals: one that was ancestral to the Fig. 6. Marginal sampling distributions of legofit estimates, based on 50 simulated datasets. Simulation parameters (shown as red crosses) equal the Altai fossil and one or more others whose relationship to Altai estimates from the YRI.CEU analysis in Figs. 4 and 5. was distant. As discussed above, our results also disagree with previous esti- mates of the Neanderthal–Denisovan separation time. On the introduced bias. We therefore fitted four alternative models, as other hand, Meyer et al. (29) show that 430 ky-old fossils from described in Section S3. None of these explains the surprising fea- Sima de los Huesos, Spain are more closely related to Nean- tures of our estimates. We have found no way to explain these derthals than to Denisovans. This implies an early separation of features as artifacts of a misspecified model. the two archaic lineages. Our own estimate—25,660 generations, Our estimate of the Neanderthal–Denisovan separation time or 744 ky—is earlier still. It is consistent with the results of Meyer is surprisingly old. The most recent whole- estimate of et al. (29) but not with those of Prufer¨ et al. (14), as discussed this parameter is 381 kya (ref. 14, table S12.2), which cor- above. The cause of this discrepancy is unclear. Prufer¨ et al. responds to 502 kya or 17,318 generations under our molec- use the pairwise sequentially Markovian coalescent (PSMC) ular clock. To determine the cause of this inconsistency, we method (30), which may give biased estimates of separation times fitted a model in which TND is fixed at 17,318 generations. in subdivided populations (ref. 26, p. 6). The red crosses in Fig. 7 show the difference between fitted Our results shed light on the large-brained hominins who and observed site-pattern frequencies under this constrained appear in Europe early in the Middle Pleistocene. Various au- model. The constrained model predicts too much nd but too thors have suggested that these were African immigrants (1, 2). little xnd and ynd. The predicted points lie well outside the This story is consistent with genetic estimates of the separation confidence intervals. This, along with the smaller discrepan- time of archaics and moderns (14). Our own results imply that, cies seen elsewhere in Fig. 7, refutes the hypothesis that Nean- by the time these hominins show up in European archaeological derthals and Denisovans separated as recently as 17,318 gener- ations ago. Our estimate of 2NND is also surprising, because it implies a previously unsuspected bottleneck among the ancestors of Nean- derthals and Denisovans. To explore the cause of this result, we fitted a model in which 2NND was constrained to equal a larger of 10,000. The blue circles in Fig. 7 show the errors implied by this constraint. The constrained model predicts too much nd and yd but too little xnd and ynd, and many of the points lie out- side the confidence intervals. The data are not consistent with a large value of 2NND . Our own date estimates inherit the uncertainty of the molec- ular clock. Using the YRI.CEU data, our point estimate of the Neanderthal–Denisovan separation time is 744 kya. Many authors prefer a higher mutation rate of 5×10−10 per nucleotide site per . Under this clock, our estimate becomes 616 kya. Discussion These results contradict current views about Neanderthal pop- ulation history. For example, Prufer¨ et al. (14) estimate that the Neanderthal population was very small—declining toward . This view receives additional support from research showing elevated frequencies of nonsynonymous (and presum- ably deleterious) mutations among Neanderthals (22–24). This abundance of deleterious alleles implies that drift was strong and Fig. 7. Poor fit of two constrained models. Horizontal axis shows devia- thus that population size was small. Yet our estimate of Nean- tion of fitted from observed site-pattern frequencies under two constraints: derthal population size is large—in the tens of thousands. 2NND = 10,000 (blue circles) and TND = 17, 318 generations (red crosses). To reconcile these views, we suggest that the Neanderthal Horizontal bars show 95% confidence intervals. Both analyses use the population consisted of many small subpopulations, which YRI.CEU data.

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D, archaic Reich of estimators 11. in Bias (2015) RJ Bohlender AR, Rogers 10. h eneta ouainge ag n rgetdinto metapopulation fragmented Neanderthal and The groups. large local grew isolated largely population Denisovans, Neanderthal Neanderthal– from mod- separating the the the After interval, small. left was intervening lineage ancestors only the Denisovan their During separated after lineage. Denisovans generations ern hundred and few Neanderthals a that appears It the of most Conclusions produced at in of and number time, small the offspring. of a some , Nonethe- least one (26). at least that size indicate effective flow results in gene our reduction in less, a increase numbers as an masquerade disproportionate population, than structured may have a smaller In also few children. is of a size much if Effective been size size. have census average may size its the effective than If its 109–111). smaller size, pp. 31, in (ref. varied possibilities population other also are there but oese al. et Rogers between interval have the may throughout population small The Denisovans. been and Neanderthals to argues tral who 5), kya. (4, an 500–600 over began Hublin Europe, that in with interval gradually emerged agrees de features than Sima Neanderthal also Neanderthals that at to It hominins similar Denisovans. the more that to genetically show were who agrees Huesos (29), This los al. Denisovans. et from Meyer separated with already had they sites, .GenR,e l 21)Adatsqec fteNadra genome. Neandertal the of sequence draft Indian A Reconstructing (2010) (2009) al. L et Singh RE, AL, Green Price four N, 9. evaluate Patterson to K, Thangaraj evidence D, genetic Reich Using 8. (2010) C Stringer SYW, Ho humans. modern P, of evolution Endicott the and 7. 3 Mode (1997) MM Lahr R, Foley Nean- the 6. of evolution the and paleogeography, changes, Climatic (1998) JJ Neandertals. Homo of Hublin of origin The role 5. (2009) The JJ Pleistocene: Hublin Middle the 4. in evolution Human (1998) GP Rightmire 3. origins. (2009) human RG modern Klein and 2. , Anatomy, (1995) RG Klein 1. eetmt ml fetv iei h ouainances- population the in size effective small a estimate We c USA Sci history. population human of reconstruction genomes. human 1,092 from variation genetic . Altai 225–248. pp York), New dence. individual. . in Biol 710–722. history. population human modern and Neanderthal origins. of timing the for hypotheses palaeoanthropological J K, Archaeol Camb Aoki T, Akazawa 295–310. eds pp York), Asia, New Western Press, in (Plenum O Humans Bar-Yosef Modern and Neandertals dertals. heidelbergensis. Ed. 3rd Chicago), Press, Chicago 9:167–198. frK ta.(04 h opeegnm euneo eneta rmthe from Neanderthal a of sequence genome complete The (2014) al. et K, ufer ¨ 100:63–78. d eaeR ilr (, L Billard R, LePage eds Bootstrap, the of “Limits” the Exploring 108:18301–18306. u Evol Hum J h ua aer ua ilgcladClua Origins Cultural and Biological Human Career: Human The vlAtrplIse esRev News Issues Anthropol Evol Nature 7:3–36. 468:1053–1060. 338:222–226. Nature 59:87–95. 505:43–49. 461:489–494. rcNt cdSiUSA Sci Acad Natl Proc a e Genet Rev Nat Nature 6:218–227. 491:56–65. T 15:149–162. ND 106:16022–16027. and ol Prehist World J rcNt Acad Natl Proc Science ho Popul Theor T XYND Ui of (Univ 328: , 0 iH ubnR(01 neec fhmnpplto itr rmidvda whole- (1970) individual M from Kimura JF, history Crow population human 31. of Inference de (2011) Sima R Pleistocene Durbin Middle H, the Li from sequences 30. DNA Nuclear (2016) al. Eastern et into M, humans modern Meyer early from 29. flow gene Ancient (2016) al. et M, Kuhlwilm 28. of importance the On Dal (2016) L 27. Chikhi S, Boitard S, Grusea W, Rodriguez O, Mazet coalescence and diversity, 26. genetic size, introgression. population Effective Neanderthal (1993) of N Takahata cost M, Nei genetic The 25. (2016) Neanderthal R against Nielsen selection K, of of strength Harris The exomes 24. (2016) complete G the Coop in S, Aeschbacher variation I, coding Juric of 23. Patterns (2014) al. et and humans S, modern Castellano between in admixture 22. of ancestry history Neanderthal Complex (2015) of J landscape Akey in B, genomic than Vernot The Asians 21. East (2014) in al. ancestry et Neanderthal S, of Sankararaman levels 20. Higher (2013) al. into et dispersals JD, human modern Wall first the 19. and admixture Denisova (2011) al. et D, Reich 18. 5 akrrmnS atro ,L ,P H, history Li separation N, and Patterson S, size Sankararaman population human 35. Inferring (2014) R Durbin S, Schiffels 34. (1993) WS Cleveland 33. (2006) JA Lampinen RM, Storn K, Price 32. c lsfracacgnmswr onoddfrom downloaded were VCF genomes archaic denisova/VCF for files Vcf Methods and Materials years million a half foreshadowed than more been happened earlier. have which to one, The another seems populations. by regional diaspora into Eurasian pop- split modern a and experienced bottleneck then size and ulation population African an from arated fossil. Neanderthal than Altai larger the of much population was local humans the modern to genes contributed that iels a onoddfrom downloaded was list site inadaayi,dcso opbih rpeaaino h manuscript. the collec- of data preparation design, or study publish, in to role decision no analysis, Awards investigator: had and Institute (Principal tion funders Uni- Cancer The CA016672 the MD). and National Depinho, at PhD) by Ronald Chang, supported Shine Performance was (PI: High R.J.B. R25CA057730 for Utah. Ser- Center BCS of Award and the versity Foundation Seger, by Science Jon National and by Rogers, 1638840 supported Nala was Lokey, A.R.R. Tucci. Mitchell ena Chikhi, Lounes Cashdan, ACKNOWLEDGMENTS. missing with or errors, systematic with individual. context, samples any CpG all in a across data biallelic in are sites that exclude 1–22 and on SNPs only include hssoyi iia ota fmdr uain,woas sep- also who Eurasians, modern of that to similar is story This efitrstsuigteMap35 the using sites filter We ttsia ehd r ecie in described are methods Statistical eoesequences. genome hominins. Huesos los Neanderthals. West. the in replacement population and inference? for size evolution—Lessons population human ancestral and rates coalescence Instantaneous structured: populations. subdivided in time 203:881–891. introgression. Neandertals. three Neandertals. humans. present-day Europeans. . and Asia Southeast ewe enetl n oenhumans. modern and Neandertals between sequences. genome multiple from Optimization Global York). New Row, neta-leeclsaefo h eioagenome. Denisova the from are calls Ancestral-allele . nL ta.(02 ata eei unvri enetl:Cniut nteEast the in Continuity Neandertals: in turnover genetic Partial (2012) al. et L, en ´ n from and mJHmGenet Hum J Am LSGenet PLoS Nature rcNt cdSiUSA Sci Acad Natl Proc Nature 194:199–209. Srne,Berlin). (Springer, iulzn Data Visualizing Nature Nature 530:429–433. eaegaeu o omnsfo Elizabeth from comments for grateful are We cdna.eva.mpg.de/neandertal/altai/AltaiNeandertal/ nItouto oPplto eeisTheory Genetics Population to Introduction An 12:e1006340. 475:493–496. 531:504–507. 507:354–357. mJHmGenet Hum J Am 96:448–453. o Evol Mol J bioinf.eva.mpg.de/altai a Genet Nat a ¨ Heredity 0%ciei 1) h iiu filtered minimum The (14). criteria 100% b ,RihD(02 h aeo interbreeding of date The (2012) D Reich S, abo ¨ Hbr rs,Smi,NJ). Summit, Press, (Hobart ifrnilEouin rcia prahto Approach Practical A Evolution: Differential etosS1 Sections o ilEvol Biol Mol 111:6666–6671. 37:240–244. LSGenet PLoS 46:919–925. 116:362–371. 89:516–528. NSEryEdition Early PNAS and 29:1893–1897. 8:e1002947. S2. minimal cdna.eva.mpg.de/ filters Hre and (Harper | Genetics f5 of 5 We .

ANTHROPOLOGY