A signature of Neanderthal introgression on molecular mechanisms of environmental responses

Abstract

Ancient human migrations led to the settlement of population groups in varied environmental contexts worldwide. The extent to which adaptation to local environments has shaped human genetic diversity is a longstanding question in human evolution. Recent studies have suggested that introgression of archaic alleles in the genome of modern humans may have contributed to adaptation to environmental pressures such as pathogen exposure. Functional genomic studies have demonstrated that variation in gene expression across individuals and in response to environmental perturbations is a main mechanism underlying complex trait variation. We considered gene expression response to \emph{in vitro} treatments as a molecular phenotype to identify genes and regulatory variants that may have played an important role in adaptations to local environments. We investigated if Neanderthal introgression in the human genome may contribute to the transcriptional response to environmental perturbations. To this end we used eQTLs for genes differentially expressed in a panel of 52 cellular environments, resulting from 5 cell types and 26 treatments, including hormones, vitamins, drugs, and environmental contaminants. We found that SNPs with introgressed Neanderthal alleles (N-SNPs) disrupt binding of transcription factors important for environmental responses, including ionizing radiation and hypoxia, and for glucose metabolism. We identified an enrichment for N-SNPs among eQTLs for genes differentially expressed in response to 8 treatments, including glucocorticoids, caffeine, and vitamin D. Using Massively Parallel Reporter Assays (MPRA) data, we validated the regulatory function of 21 introgressed Neanderthal variants in the human genome, corresponding to 8 eQTLs regulating 15 genes that respond to environmental perturbations. These findings expand the set of environments where archaic introgression may have contributed to adaptations to local environments in modern humans and provide experimental validation for the regulatory function of introgressed variants.

Leveraging massively parallel reporter assays for evolutionary questions

“…Finally, MPRAs have been used to understand the functional consequences of archaic admixture. Jagoda and colleagues [82] as well as Findley and colleagues [83] quantified the regulatory activity of variants introgressed from Neanderthals into the modern human gene pool. Both studies found that the in vitro activity of many of these variants was suggestive of causal effects on gene regulation.…”

Long-range regulatory effects of Neandertal DNA in modern humans

“…It remains challenging to computationally reconstruct regulatory mechanisms and therefore fully reconstruct the regulatory role of Neandertal DNA through its interaction with TFs. However, the results of our study and other previous work that investigated the impact of Neandertal DNA on the modification of TF binding motif sequences [59,60] have demonstrated the importance of studying the interaction of Neandertal DNA and TF activity in the quest to complete the picture of the impact of Neandertal introgression on the transcriptomic landscape of people today.…”