To study the impact of the Denisovan and Neanderthal admixture events simultaneously, we developed methods that allow us to distinguish these two sources of archaic ancestry. We applied these methods to the Simons Genome Diversity Project (SGDP) dataset: 257 high-quality genomes from 120 non-African populations, including 20 Oceanian individuals from populations known to have high Denisovan admixture (unpublished data; Supplemental Experimental Procedures , “Data Processing”).

1 Reich D.

Green R.E.

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Jay F.

Sankararaman S.

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Heinze A.

Renaud G.

Sudmant P.H.

de Filippo C.

et al. The complete genome sequence of a Neanderthal from the Altai Mountains.

7 Wall J.D.

Yang M.A.

Jay F.

Kim S.K.

Durand E.Y.

Stevison L.S.

Gignoux C.

Woerner A.

Hammer M.F.

Slatkin M. Higher levels of neanderthal ancestry in East Asians than in Europeans.

8 Meyer M.

Kircher M.

Gansauge M.T.

Li H.

Racimo F.

Mallick S.

Schraiber J.G.

Jay F.

Prüfer K.

de Filippo C.

et al. A high-coverage genome sequence from an archaic Denisovan individual.

9 Vernot B.

Akey J.M. Complex history of admixture between modern humans and Neandertals.

10 Skoglund P.

Jakobsson M. Archaic human ancestry in East Asia.

11 Reich D.

Patterson N.

Kircher M.

Delfin F.

Nandineni M.R.

Pugach I.

Ko A.M.

Ko Y.C.

Jinam T.A.

Phipps M.E.

et al. Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania.

12 Huerta-Sánchez E.

Jin X.

Asan

Bianba Z.

Peter B.M.

Vinckenbosch N.

Liang Y.

Yi X.

He M.

Somel M.

et al. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.

13 Jeong C.

Alkorta-Aranburu G.

Basnyat B.

Neupane M.

Witonsky D.B.

Pritchard J.K.

Beall C.M.

Di Rienzo A. Admixture facilitates genetic adaptations to high altitude in Tibet.

6 Prüfer K.

Racimo F.

Patterson N.

Jay F.

Sankararaman S.

Sawyer S.

Heinze A.

Renaud G.

Sudmant P.H.

de Filippo C.

et al. The complete genome sequence of a Neanderthal from the Altai Mountains.

Pearson

Figure 2 Variation in Denisovan Ancestry Proportion Show full caption (A) Proportion of the genome inferred to be Denisovan in ancestry in diverse non-Africans. The color scale is not linear to allow saturation of the high Denisova proportions in Oceania (bright red) and better visualization of the peak of Denisova proportion in South Asia. (B) Proportion of the genome confidently inferred to be Denisovan in ancestry in mainland Eurasians plotted against the rate of allele sharing of each sample with non-West Eurasians as measured by an f 4 statistic. Error bars (1 SE) were obtained from a block jackknife. The Denisovan ancestry estimates in South Asians are systematically above expectation (fitted trend line) (p = 0.0013). See also Table S3

Table 1 Genome-wide Estimates of Archaic Ancestry Population Individuals Neanderthal Ancestry (%) Denisovan Ancestry (%) Autosomes X Autosomes X America 29 1.37 ± 0.11 0.26 ± 0.18 0.05 ± 0.01 0.00 ± 0.00 Central Asia 27 1.40 ± 0.12 0.23 ± 0.18 0.05 ± 0.01 0.00 ± 0.00 East Asia 50 1.39 ± 0.11 0.32 ± 0.28 0.06 ± 0.02 0.00 ± 0.01 Oceania 26 1.54 ± 0.12 0.42 ± 0.36 0.85 ± 0.43 0.18 ± 0.17 South Asia 48 1.19 ± 0.11 0.40 ± 0.26 0.06 ± 0.03 0.01 ± 0.03 West Eurasia 77 1.06 ± 0.12 0.18 ± 0.19 0.02 ± 0.01 0.00 ± 0.00 7 Wall J.D.

Yang M.A.

Jay F.

Kim S.K.

Durand E.Y.

Stevison L.S.

Gignoux C.

Woerner A.

Hammer M.F.

Slatkin M. Higher levels of neanderthal ancestry in East Asians than in Europeans. 8 Meyer M.

Kircher M.

Gansauge M.T.

Li H.

Racimo F.

Mallick S.

Schraiber J.G.

Jay F.

Prüfer K.

de Filippo C.

et al. A high-coverage genome sequence from an archaic Denisovan individual. We estimated the probability of Neanderthal and Denisovan ancestry for each phased genome in each population. We report the mean and SD of the proportion of confidently inferred archaic alleles (marginal probability >50%) across diploid individuals within each population. The highest point estimate of Neanderthal ancestry is in Oceania, and although this estimate is significantly higher than that in West Eurasia (Z = 3.9), consistent with previous reports [], it is not higher than that in East Asia (Z = 0.7). See also Table S2

For each individual, we inferred archaic ancestry segments across the autosomes (chromosomes 1–22) and chromosome X (our method did not allow us to test for archaic ancestry on chromosome Y because the archaic genomes are from females). Figure 2 A plots the estimates of the proportion of confidently inferred Denisovan ancestry on a map, and Table 1 tabulates the results for six population pools ( Table S2 tabulates the results for each population). Denisovan ancestry in Oceanians is greater than in other non-Africans [] ( Table 1 ). Both Neanderthal and Denisovan ancestry are greater in eastern non-Africans than in West Eurasians [] ( Supplemental Experimental Procedures , “Variation in the genome-wide proportions of archaic ancestry”; Table S3 ). We replicate previous findings of substantial Denisovan ancestry in New Guineans and Australians, as well as in populations that harbor admixtures of New Guinean ancestry []. However, we were surprised to detect a peak of Denisovan ancestry estimates in South Asians, both in the Himalayan region and in South and Central India ( Figure 2 A). The highest estimate is in Sherpas (0.10%), who have a Denisovan point estimate about one-tenth of that seen in Papuans (1.12%) ( Table S3 ). Although this is notable in light of the likely Denisovan origin of the EPAS1 allele that confers high-altitude adaptation in Tibetans [], EPAS1 is not sufficient to explain the observation as Sherpas have the highest point estimate even without chromosome 2, on which EPAS1 resides. To determine whether the peak of Denisovan ancestry in South Asia is significant, we tested whether the Denisovan ancestry proportion in diverse mainland Eurasians can be explained by differential proportions of non-West Eurasian ancestry (as it is already known that there is more Denisovan ancestry in East Eurasians than in West Eurasians []). For each Eurasian population X, we computed an allele frequency correlation statistic that is proportional to eastern non-African ancestry ( Figure 2 B; Supplemental Experimental Procedures , “Modeling the variation in Denisovan ancestry across populations”). We regressed the proportion of confidently inferred Denisovan ancestry against this statistic. Although the proportion of Denisovan ancestry in these populations is correlated with non-West Eurasian ancestry (ρ= 0.832, block jackknife p = 3.6 × 10for the correlation coefficient being non-zero), South Asian groups as a whole have significantly more Denisovan ancestry than expected (block jackknife Z score for residuals = 3.2, p = 0.0013 by a two-sided test for the null hypothesis that the Denisovan ancestry estimate in South Asians is predicted by their proportion of non-West Eurasian ancestry; Figure 2 B; Supplemental Experimental Procedures , “Modeling the variation in Denisovan ancestry across populations”). The signal remains significant (Z = 3.1) when we remove from the analysis five populations that have ancestry very different from the majority of South Asians (Tibetan, Sherpa, Hazara, Kusunda, and Onge); however, the signals are non-significant for Central Asians (Z = 1.2) and Native Americans (Z = 0.1). Taken together, the evidence of Denisovan admixture in modern humans could in theory be explained by a single Denisovan introgression into modern humans, followed by dilution to different extents in Oceanians, South Asians, and East Asians by people with less Denisovan ancestry. If dilution does not explain these patterns, however, a minimum of three distinct Denisovan introgressions into the ancestors of modern humans must have occurred.