Impact and Evolutionary Determinants of Neanderthal Introgression on Transcriptional and Post-Transcriptional Regulation

Abstract

Archaic admixture is increasingly recognized as an important source of diversity in modern humans, and Neanderthal haplotypes cover 1%-3% of the genome of present-day Eurasians. Recent work has shown that archaic introgression has contributed to human phenotypic diversity, mostly through the regulation of gene expression. Yet the mechanisms through which archaic variants alter gene expression and the forces driving the introgression landscape at regulatory regions remain elusive. Here, we explored the impact of archaic introgression on transcriptional and post-transcriptional regulation. We focused on promoters and enhancers across 127 different tissues as well as on microRNA (miRNA)-mediated regulation. Although miRNAs themselves harbor few archaic variants, we found that some of these variants may have a strong impact on miRNA-mediated gene regulation. Enhancers were by far the regulatory elements most affected by archaic introgression: up to one-third of the tissues we tested presented significant enrichments. Specifically, we found strong enrichments of archaic variants in adipose-related tissues and primary T cells, even after accounting for various genomic and evolutionary confounders such as recombination rate and background selection. Interestingly, we identified signatures of adaptive introgression at enhancers of some key regulators of adipogenesis, raising the interesting hypothesis of a possible adaptation of early Eurasians to colder climates. Collectively, this study sheds new light on the mechanisms through which archaic admixture has impacted gene regulation in Eurasians and, more generally, increases our understanding of the contribution of Neanderthals to the regulation of acquired immunity and adipose homeostasis in modern humans.

Denisovan introgression has shaped the immune system of present-day Papuans

“…Nevertheless, out of the substantial number of archaic variants still segregating within present-day populations, a large fraction still falls within genomic regions that show strong evidence of functional activity. Studies conducted primarily on Neanderthal introgressed DNA have suggested a non-negligible contribution to gene expression variation in modern humans [7, 8, 17], with repeated examples of Neanderthal archaic variants falling within regulatory elements or the seed region of mature micro-RNAs predicted to affect transcriptional and post-transcriptional regulatory processes [7, 43].…”

“…At the genomic level, these introgressed archaic alleles are mostly observed outside protein-coding sequences, distributed over non-functional and regulatory regions [7, 8]. Enhancers, in particular, are amongst the top targeted elements of introgression.…”

Admixture has obscured signals of historical hard sweeps in humans

“…In addition, six of the eight sweeps with either a single gene or a single biological process are Ancestral West Eurasian (>35kya), and are either involved in lipid metabolism (two sweeps) or with nervous tissue maintenance (four sweeps) (Material and Methods), both of which have been associated with adaptation to cold environments (Brandefelt et al, 2011;Daló et al, 2007;Nedergaard and Cannon, 2018). A potential association with cold adaptation is interesting as this has been identified as a likely important factor as Anatomically Modern Humans (AMH) first moved into Eurasian environments (Silvert et al, 2019) -which were around 5°C cooler than those of their northern African origins at 55-50kya (Brandefelt et al, 2011) (Material and Methods).…”

Functional consequences of archaic introgression and their impact on fitness

“…For example, Dannemann et al have shown that non-synonymous archaic alleles that segregate today in the human population tend to be less deleterious than non-synonymous alleles that segregate at similar frequency on non-archaic haplotypes [4]. Furthermore, archaic introgression appears to be less pronounced in regions of functional relevance such as promoters or protein-coding regions, with respect to other elements such as enhancers [5, 6]. Given their larger size across the genome, enhancers are then the functional elements that carry the largest number of Neanderthal alleles [6].…”

“…Furthermore, archaic introgression appears to be less pronounced in regions of functional relevance such as promoters or protein-coding regions, with respect to other elements such as enhancers [5, 6]. Given their larger size across the genome, enhancers are then the functional elements that carry the largest number of Neanderthal alleles [6]. It is therefore expected that a significant fraction of the phenotypic impact of Neanderthal introgression is mediated by changes in enhancer activity.…”