The genomic landscape of Neanderthal ancestry in present-day humans

Genomic studies have shown thatNeanderthals interbredwithmodern humans,andthatnon-Africanstodayare theproductsof thismixture. The antiquity ofNeanderthal gene flow intomodernhumansmeans thatgenomic regions thatderive fromNeanderthals inanyonehuman todayareusually less thanahundredkilobases 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 toadapt tonon-Africanenvironments.We identifymultiple Neanderthal-derived alleles that confer risk for disease, suggesting thatNeanderthal alleles continue to shape humanbiology.Anunexpected finding is that regionswith reducedNeanderthal 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 causeddecreased fertility inmaleswhenmoved to amodern human genetic background. To search systematically for Neanderthal haplotypes, we developed a method based on a conditional random field (CRF) that combines information from three features of genetic variation that are informative of Neanderthal ancestry (Supplementary Information section 1 and Extended Data Fig. 1). The first is the allelic pattern at a single nucleotide polymorphism (SNP): if a non-African individual carries a derived allele seen in Neanderthals but absent from the west-African Yoruba from Ibadan, Nigeria (YRI), the allele is likely to originate from Neanderthals. The second is high sequence divergence of the nonAfrican haplotype to all YRI haplotypes but low divergence to Neanderthal. The third is a haplotype length consistent with interbreeding 37–86-thousand years ago. We trained the CRF using simulations, and established its robustness to deviations from the assumed demography (Supplementary Information section 2). We screened for Neanderthal haplotypes in the 1000 Genomes Project Phase 1 (1KG) data, using the Altai Neanderthal genome of 52-fold average coverage to determine alleles present inNeanderthals, a six-primate consensus to determine ancestral alleles, and 176 YRI genomes as a reference panel assumed to harbour no Neanderthal ancestry (Fig. 1a). Table 1 reports the mean and standard deviation across individuals of the fraction of their ancestry confidently inferred to be Neanderthal (probability. 90%). Figure 1b and Extended Data Fig. 2 plot the fraction of European (n5 758) and east-Asian (n5 572) haplotypes that descend from Neanderthals at each genomic location (Supplementary Information section 3). We created a tiling path of inferred Neanderthal haplotypes that spans 1.1 gigabases (Gb) over 4,437 contigs (Supplementary Information section 4), thus filling in gaps in the Neanderthal sequence over a number of repetitive regions that cannot be reconstructed from short ancient DNA fragments (Extended Data Fig. 3). Four features of theNeanderthal introgressionmap suggest that it is producing reasonable results. First, when we infer Neanderthal ancestry using low-coverage data from Croatian Neanderthals we obtain correlated inferences (Spearman rank correlationr 5 0.88 inEuropeans; Supplementary Information section 3). Second, in the African Luhya inWebuye, Kenya (LWK), the proportion of the genome inferred to be Neanderthal is 0.08%, an order of magnitude smaller than in nonAfrican populations (Table 1). Third, the proportion of the genome with confidently inferredNeanderthal ancestry has amean of 1.38% in east-Asian and 1.15% in European populations (Table 1), consistent with previous reports ofmoreNeanderthal ancestry in east-Asian than