Selection against archaic hominin genetic variation in regulatory regions

Neanderthal ancestry is depleted in regions of the genome with annotated molecular functions, and this depletion is strongest in annotated brain and testis regulatory regions.

“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 regions27–29.”

These findings fully recapitulate previously reported observations in Europeans.

“Interestingly, these findings fully recapitulate previously reported observations in Europeans [11, 12].”

Previous studies of regions with Neanderthal ancestry found depletion for evidence of background selection and functional annotations, such as genes and gene regulatory elements active in specific tissues.

“First, previous studies of regions with Neanderthal ancestry found depletion for evidence of background selection and functional annotations, such as genes and gene regulatory elements active in specific tissues18,19,27,29.”

Introgressed archaic DNA has mainly been deleterious and actively removed from coding sequences and conserved non-coding elements.

“beyond general agreement that introgressed archaic DNA has mainly been deleterious and actively removed from coding sequences and conserved non-coding elements [8, 12–14]”

Neanderthal aSNPs are strongly enriched within elements active within blood & immune T cells and mesenchymal cells both in Papuans and Europeans.

“with Neanderthal aSNPs strongly enriched within elements active within blood & immune T cells and mesenchymal cells both in Papuans and Europeans, replicating previously reported observations [11, 12].”

Admixture with Neanderthals might have similar consequences even across distantly related human populations.

“In addition, admixture with Neanderthals might have similar consequences even across distantly related human populations, with Neanderthal aSNPs strongly enriched within elements active within blood & immune T cells and mesenchymal cells both in Papuans and Europeans, replicating previously reported observations [11, 12].”

Introgressed variants are depleted in regulatory elements and eQTL generally.

“Given the previously observed depletion for introgressed variants in regulatory elements and eQTL (Petr et al. 2019; Rinker et al. 2020; Telis et al. 2020)”

The depletion in cognitive traits suggests that the previously observed strong depletion for Neanderthal alleles in regulatory regions active in the brain may be due to effects on brain-related complex traits.

“The depletion in cognitive traits suggests that the previously observed strong depletion for Neanderthal alleles in regulatory regions active in the brain may be due to effects on brain-related complex traits5,28,29.”

Neanderthal and Denisovan variants preferentially affect enhancers in a tissue-specific manner, with highly pleiotropic elements depleted of archaic variation.

“both Neanderthal and Denisovan variants seem to preferentially affect enhancers in a tissue-specific manner, with highly pleiotropic elements being depleted of archaic variation [12].”

aSNPs are depleted in highly pleiotropic enhancers, likely as a consequence of their potential to perturb gene expression across multiple tissues.

“Similar findings have been recently reported for highly pleiotropic enhancers, where aSNPs are depleted likely as a consequence of their potential to perturb gene expression across multiple tissues [12].”

Applying the approach to Neanderthal aSNPs segregating within present-day West Eurasians replicates most of the findings, as well as previously reported signals including a depletion of Neanderthal variants within enhancer-like elements.

“Applying our approach to Neanderthal aSNPs segregating within present-day West Eurasians [31] replicates most of our findings, as well as previously reported signals including a depletion of Neanderthal variants within enhancer-like elements [12].”

aSNPs from both archaic ancestries are in excess within quiescent chromatin.

“An exception to this trend was an excess of aSNPs from both archaic ancestries that fell within quiescent chromatin (Quies pDeni = 1.5 ⋅ 10−15), as previously reported by [12].”