Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

Abstract

11 12 Background: Nearly all Eurasians have ~2% Neanderthal ancestry due to several events of 13 inbreeding between anatomically modern humans and archaic hominins. Previous studies 14 characterizing the legacy of Neanderthal ancestry in modern Eurasians have identified 15 examples of both adaptive and deleterious effects of admixture. However, we lack a 16 comprehensive understanding of the genome-wide influence of Neanderthal introgression on 17 modern human diseases and traits. 18 Results: We integrate recent maps of Neanderthal ancestry with well-powered association 19 studies for more than 400 diverse traits to estimate heritability enrichment patterns in regions of 20 the human genome tolerant of Neanderthal ancestry and in introgressed Neanderthal variants 21 themselves. First, we find that variants in regions tolerant of Neanderthal ancestry are depleted 22 131We find three exceptions to this complex trait heritability depletion; sunburn (1.16x, P = 132 0.3), skin color (1.21x, P = 0.4), and tanning (1.25x, P = 0.4) are not depleted among regions 133 that retain Neanderthal ancestry (Fig. 1B). These three traits are genetically correlated with 134 magnitudes between r = 0.55 and 0.86. Several previous hypotheses suggest that the 135 introgression of Neanderthal alleles related to hair and skin pigmentation could have provided 136 non-African AMHs with adaptive benefits as they moved to higher latitudes. 3,4,17,18 The 137 exceptions to the overall depletion we observe for skin traits suggest that regions of the human 138 genome involved in skin pigmentation were more tolerant of Neanderthal introgression than 139 regions of the genome associated with other traits. 140 141

The influence of evolutionary history on human health and disease

“…Large-scale sequencing efforts, in combination with analysis of clinical biobanks and improved computational methods, have revealed the potential impacts of introgressed DNA on modern human genomes. Several recent studies link regions of archaic admixture in modern populations with a range of diseases, including immunological, neuropsychiatric and dermatological phenotypes 102 , 132 – 139 . This demonstrates the functional impact of introgressed sequence on disease risk in non-African humans today.…”

Long-range regulatory effects of Neandertal DNA in modern humans

“…Based on the fossil record previous studies presented evidence for differences in skeletal features and fat distribution between Neandertals and modern humans [56]. Furthermore, it has repeatedly been shown that introgressed Neandertal DNA significantly influences skin and hair traits [5][6][7]. Some of these studies have also demonstrated that Neandertal DNA showed an over-proportional number of associations with behavioral traits such as sleep [5][6][7]57], which are partially controlled by hormones produced in the thyroid.…”

“…Several studies have used information from genome-wide association studies to link archaic DNA to their potential phenotypic effects. These studies have shown that Neandertal DNA significantly influences skin and hair traits, immunity and behavioral phenotypes [5][6][7][8]. Many of the phenotype-associated archaic variants have been associated with regulatory effects as well, including several instances of Neandertal DNA with additional evidence for local adaptation [9,10].…”

Our Tangled Family Tree: New Genomic Methods Offer Insight into the Legacy of Archaic Admixture

“…Multiple studies have used large genotypic data sets with phenotypic data, such as electronic health records to link archaic alleles with specific traits, and have identified Neanderthal alleles associated with traits including neurological phenotypes, height, blood coagulation and inflammation, chronotype, and skin and hair pigmentation ( Simonti et al 2016 ; Dannemann and Kelso 2017 ; Prüfer et al 2017 ). More recently, ( McArthur et al 2020 ) used an approach based on associating genome-wide trait heritability with Neanderthal ancestry to identify impacts of Neanderthal introgression on hair and skin, autoimmunity, chronotype, bone density, lung capacity, and menopause age. Although many associations between archaic alleles and phenotypes have been discovered, recent re-analysis has found that many of these associations are actually due to nonarchaic variants in linkage with archaic haplotypes ( Skov et al 2020 ).…”