Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations

Abstract

Neanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes. Here we demonstrate that introgressed sequences reintroduced thousands of ancestral alleles that were lost in Eurasian populations prior to introgression. Our simulations and variant effect predictions argue that these reintroduced alleles (RAs) are more likely to be tolerated by modern humans than introgressed Neanderthal-derived alleles (NDAs) due to their distinct evolutionary histories. Consistent with this, we show enrichment for RAs and depletion for NDAs on introgressed haplotypes with expression quantitative trait loci (eQTL) and phenotype associations. Analysis of available cross-population eQTLs and massively parallel reporter assay (MPRA) data show that RAs commonly influence gene expression independent of linked NDAs. We further validate these independent effects for one RA in vitro . Finally, we demonstrate that NDAs are depleted for regulatory activity compared to RAs, while RAs have activity levels similar to non-introgressed variants. In summary, our study reveals that Neanderthal introgression reintroduced thousands of lost ancestral variants with gene regulatory activity and that these RAs were more tolerated than NDAs. Thus, RAs and their distinct evolutionary histories must be considered when evaluating the effects of introgression. ONE SENTENCE SUMMARY Neanderthal interbreeding with anatomically modern humans restored thousands of ancient alleles that were previously lost in Eurasian populations.

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

“…The largest set included all variants with evidence of introgression in any Eurasian population according to Sprime 36 ( N = 900,902, Methods); this set will be referred to as “introgressed variants” throughout the manuscript. This set includes not only high-confidence Neanderthal-origin introgressed variants, but also ancestral alleles lost in Africans that were reintroduced to Eurasians through archaic introgression 5 , variants with origins in other archaic hominins, such as Denisovans, and possibly variants tightly linked to introgressed haplotypes that arose in Eurasians shortly after introgression. The most stringent and high-confidence sets include Neanderthal-introgressed alleles that are observed in Europeans and explicitly match either the Altai genome ( N = 138,774) or the Vindija genome ( N = 167,927, see Methods); these sets will be referred to as “Altai-matching” and “Vindija-matching” introgressed variants, respectively.…”

“…As a result, nearly all Eurasians have ~2% Neanderthal ancestry resulting from interbreeding events that occurred shortly after their ancestors left Africa 1 , 2 . Analyses of available genome-wide association studies and large-scale biobank data revealed that alleles of Neanderthal ancestry are associated with diverse traits in modern Eurasians 1 , 3 – 5 . However, due to limited phenotype data and technical challenges quantifying the associations between archaic alleles and traits 5 , 6 , previous studies have not comprehensively characterized the genome-wide influence of Neanderthal introgression on modern human diseases and traits.…”

“…Second, Neanderthal ancestry is depleted in regions of the genome with annotated molecular functions (e.g., genes and gene regulatory elements), and this depletion is strongest in annotated brain and testis regulatory regions 27 – 29 . Furthermore, the remaining alleles of Neanderthal ancestry—i.e., introgressed alleles that were maintained by either selection or drift since admixture—are predicted to be less likely to modify protein and regulatory functions than matched sets of alleles that arose on the human lineage, suggesting that functional introgressed variants were less tolerated 5 , 30 . Finally, the majority of archaic alleles that are strongly associated with disease in single-locus tests are risk-increasing in the context of modern human populations 3 .…”

The influence of evolutionary history on human health and disease

“…However, some of these associations may be influenced by linked non-Neanderthal alleles 140 . For example, in addition to alleles of Neanderthal origin, introgression also reintroduced ancestral alleles that were lost in modern Eurasian populations prior to interbreeding (for example, in the out-of-Africa bottleneck) 141 . Some introgressed alleles may have initially lessened adverse effects from migration to northern climates, dietary changes and introduction to novel pathogens 117 , 142 , 143 .…”

A signature of Neanderthal introgression on molecular mechanisms of environmental responses

“…Nevertheless, we provide a proof of concept that applying computational and experimental functional genomics approaches enables researchers to assay the gene regulatory function of archaic alleles in modern human cells. Recently, MPRA data have been used to show that ancestral alleles reintroduced by Neanderthal introgression have activity levels similar to non-introgressed variants, while Neanderthal derived alleles are depleted for regulatory activity compared to reintroduced ancestral alleles [57]. Interestingly, in the dataset we considered, all functionally validated Neanderthal alleles led to increased gene expression.…”