The genomic landscape of Neanderthal ancestry in present-day humans

Abstract

Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.

Figure 1. Maps of Neandertal ancestry

(a) Individual maps: We show the marginal probability of Neandertal ancestry for 1 European American, 1 East Asian and 1 sub-Saharan African phased genome across chromosome 9. (b) Population maps: We show the average of the inferred proportion of Neandertal ancestry in Europeans (above axis) and East Asians (below axis) in non-overlapping 100 kb windows on chromosome 9.

Figure 2. Functionally important regions are deficient in Neandertal ancestry

We plot the median of the proportion of Neandertal ancestry (the average over the marginal probability of Neandertal ancestry assigned to each individual allele at a SNP) within quintiles of a B-statistic that measures proximity to functionally important regions (1-low, 5-high). We show results on the autosomes and chromosome X, and in Europeans and East Asians.

Extended Data Figure 1. Three features used in the Conditional Random Field for predicting Neandertal ancestry

Feature 1: Patterns of variation at a single SNP. Sites where a panel of sub-Saharan Africans carries the ancestral allele and where the sequenced Neandertal and the test haplotype carry the derived allele are likely to be derived from Neandertal gene flow. Feature 2: Haplotype divergence patterns. Genomic segments where the divergence of the test haplotype to the sequenced Neandertal is low while the divergence to a panel of sub-Saharan Africans is high are likely to be introgressed. Feature 3: we search for segments that have a length consistent with what is expected from the Neandertal-into-modern human gene flow 2,000 generations ago, corresponding to a size of about 0.05cM = (100cM/Morgan)/(2000 generations).

Extended Data Figure 2. Map of Neandertal ancestry in 1000 Genomes European and East Asian populations

For each chromosome, we plot the fraction of alleles confidently inferred to be of Neandertal origin (probability > 90%) in non-overlapping 1 Mb windows. We label 10 Mb scale windows that are deficient in Neandertal ancestry (e1–e9, a1–a17) (SI 8).

Extended Data Figure 3. Tiling path from confidently inferred Neandertal haplotypes

a, Example tiling path at the BNC2 locus on chromosome 9 in Europeans. Red denotes confident Neandertal haplotypes. Blue denotes the resulting tiling path. We identified Neandertal haplotypes by scanning for runs of consecutive SNPs along a haplotype with a marginal probability > 90% and requiring the haplotypes to be at least 0.02 cM long. b, Distribution of contig lengths obtained by constructing a tiling path across confidently inferred Neandertal haplotypes. On merging Neandertal haplotypes in each of the 1000 Genomes European and East Asian populations, we reconstructed 4,437 Neandertal contigs with median length 129 kb.