A signature of Neanderthal introgression on molecular mechanisms of environmental responses.

Anthony S Findley,Francesca Luca,Kirk E Lohmueller,Yen Lung Lin,Roger Pique-Regi,Carly Boye,Cynthia A Kalita,Xinjun Zhang,Luis Barreiro,Justin C Fay

doi:10.1371/journal.pgen.1009493

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 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.

Highlights

Studies of ancient DNA samples in recent years have discovered that interbreeding occurred between modern humans and our extinct relatives [1,2,3]
We investigated whether the Neanderthal sequences present in modern human genomes contribute to our ability to respond to environmental changes
We found that DNA sequences from Neanderthals modify the molecular mechanisms that regulate gene activity in different environments, including in response to stress hormones, caffeine, and vitamin D

Summary

Introduction

Studies of ancient DNA samples in recent years have discovered that interbreeding occurred between modern humans and our extinct relatives [1,2,3]. The uneven distribution of these introgressed sequences in the human genome suggests that natural selection may have acted to remove Neanderthal sequences that were deleterious for modern humans [5]. Neanderthal introgressed haplotypes have been found to occur at higher frequency than expected by drift and to impact genes with important biological functions for human adaptations in different environments [10,11]. These include for example BNC2, a gene associated with skin pigmentation [5,12] and several genes with important immunological functions [13]

Methods

Results

Discussion

Conclusion