Functional implications of Neandertal introgression in modern humans

Abstract

Background: Admixture between early modern humans and Neandertals approximately 50,000-60,000 years ago has resulted in 1.5-4% Neandertal ancestry in the genomes of present-day non-Africans. Evidence is accumulating that some of these archaic alleles are advantageous for modern humans, while others are deleterious; however, the major mechanism by which these archaic alleles act has not been fully explored.

Results: Here we assess the contributions of introgressed non-synonymous and regulatory variants to modern human protein and gene expression variation. We show that gene expression changes are more often associated with Neandertal ancestry than expected, and that the introgressed non-synonymous variants tend to have less predicted functional effect on modern human proteins than mutations that arose on the human lineage. Conversely, introgressed alleles contribute proportionally more to expression variation than non-introgressed alleles.

Conclusions: Our results suggest that the major influence of Neandertal introgressed alleles is through their effects on gene regulation.

Keywords: Gene expression regulation; Human evolution; Neandertal introgression; Protein sequence variation.

Fig. 1

Functional impact of Neandertal non-synonymous alleles. Left: Average PolyPhen2 scores for archaic non-synonymous alleles in East Asians, South Asians, and Europeans (red squares). These averages are compared to averaged Polyphen2 scores for 1000 frequency matched sets of non-archaic non-synonymous alleles (yellow, orange, and brown violin plots). Polyphen2 scores range from 0–1 with higher scores associated with increased deleteriousness. Right: Average SIFT scores for archaic non-synonymous alleles in East Asians, South Asians, and Europeans (red squares). These averages are compared to averaged SIFT scores for 1000 frequency matched sets of non-archaic non-synonymous alleles (yellow, orange, and brown violin plots). SIFT scores range from 0–1 with lower scores associated with increased deleteriousness

Fig. 2

Enrichment of significant GEA archaic loci compared to non-archaic loci across all tissues. Each violin plot shows the distribution of the ratio between the number of significant archaic GEAs and 1000 samples of significant non-archaic GEAs for all archaic loci (blue), the subset of archaic loci with a Neandertal allele frequency <5% (dark blue), and the subset of archaic loci with a Neandertal allele frequency ≥5% (light blue)

Fig. 3

Direction of change for alleles showing significant frequency changes in recent modern human history. Left: The percentage of archaic alleles showing association with differential expression in at least one tissue that increase in frequency, and comparison to two sets of frequency matched alleles: (i) archaic alleles not associated with differential expression; and (ii) non-archaic alleles that are associated with differential expression. Right: The percentage of non-synonymous archaic alleles that increase in frequency compared to (i) synonymous archaic alleles and (ii) frequency-matched, non-synonymous non-archaic alleles

Fig. 4

Global frequency distribution of archaic alleles at the OAS gene cluster and differential expression for OAS3. The frequency of the archaic locus (orange) spanning the OAS gene cluster in present-day human populations from the 1000 Genomes phase III (light blue) and Simons Genome Diversity Project (dark blue) datasets are shown in the upper panel. The sizes of the pie charts are proportional to the number of individuals in each population. The lower panel shows the genotype-dependence of expression (log-transformed read counts) of OAS3 in pancreas (left) and fibroblasts (right). The expression distributions for both homozygote and the heterozygote states are shown as box plots and expression in each individual is plotted as a black square. The Spearman correlation coefficient and the corresponding P value for both tissues are shown above each graph. The introgressed Neandertal allele is the “A” (chr12:113366899)