Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals

Abstract

Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.

Fig. 1.. Melanesian genomic variation in a global context.

(A) Locations of the 159 geographically diverse populations studied. Information about the Melanesian individuals sequenced (blue triangles) is shown in the inset. (B) PCA of Melanesian genomes in the context of present-day worldwide genetic diversity. (C) Modern human variation projected onto the top two eigenvectors defined by PCA of the Altai Neandertal, Denisovan, and chimpanzee genome (14). Population means were plotted for each of the 11 Melanesian populations and each population of the global data set. (D) Estimates of Denisovan ancestry in Oceanic populations estimated from an f4 statistic (14). The 11 Melanesian populations are highlighted by the light blue box.

Fig. 2.. Identifying Neandertal and Denisovan sequences in modern human genomes.

(A) Bivariate archaic match P value distributions for simulations of nonintrogressed sequences, Esan in Nigeria, Europeans, and Melanesians. Null simulations and Esan show no skew in Neandertal or Denisovan match P values toward zero, Europeans show only a skew of Neandertal match P values toward zero, and Melanesians exhibit both Neandertal and Denisovan match P values skewed toward zero. (B) Amount of archaic introgressed sequences identified in each population. (Inset) Amount of Neandertal, Denisovan, and ambiguous (Neandertal or Denisovan) introgressed sequences for each Melanesian individual. (C) Schematic representation of introgressed haplotypes in an intronic portion of the GRM7 locus in Melanesian individuals illustrating mosaic patterns of archaic ancestry.

Fig. 3.. Identifying shared and unique pulses of Neandertal admixture among human populations.

(A) Schematics of two simulated introgression models and patterns of reciprocal match probabilities. Contour plots are fit to the scatter plot of reciprocal match probabilities calculated from analyzing all pairwise combinations of individuals between two populations. (Left) Gene flow occurs into the common ancestor of Population 1 and Population 2, and reciprocal match probabilities fall along the diagonal as predicted by theory (binomial test, P > 0.05) (14). Right, Population 2 receives additional admixture shifting reciprocal match probabilities above the diagonal (binomial test, P < 0.05). (B) Reciprocal match probabilities of Neandertal sequences in modern human populations, consistent with additional Neandertal admixture into East Asians versus Europeans, and into Europeans, East Asians, and South Asians versus Melanesians. (C) Simplified schematic of admixture history consistent with the data.

Fig. 4.. Maps of archaic admixture reveal signatures of purifying and positive selection.

(A) Proportion of windows significantly depleted of Neandertal introgression in Europeans and East Asians (dashed line) versus what is expected in neutral demographic models (95% confidence interval in gray). (B) Distribution of Neandertal and Denisovan sequences across chromosome 7 in Melanesians (MEL), East Asians (EAS), South Asians (SAS), and Europeans (EUR), and then summed across all populations (ALL). Masked regions are shown as gray vertical lines. An 11.1-Mb region significantly depleted of Denisovan and Neandertal ancestry in all populations is shown in light pink. (C) The frequency of archaic haplotypes in Melanesians versus Europeans. The red line indicates the 99th percentile defined by neutral coalescent simulations. Notable genes are labeled. (D) Visual representation of a high-frequency haplotype encompassing GBP4 and GBP7. Rows indicate individual haplotypes, and columns denote variants that tag the introgressed haplotype (14). Alleles are colored according to whether they are ancestral (white), derived variants that match both archaic genomes (blue), derived variants that match one archaic genome (dark gray), or derived but do not match either archaic genome (light gray). Archaic sequences are represented above, with black denoting derived variants. Missense, untranslated region (UTR), and putative regulatory variants (14) are highlighted with red boxes.