부산대학교 도서관

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. Author summary: Humans have populated the entire world thus adapting to live in very different environments. Recent studies have suggested that the presence of Neanderthal DNA sequences in the genomes of modern humans contribute to our ability to respond to pathogens. Here we investigated whether the Neanderthal sequences present in modern human genomes also 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. We also found an important role of Neanderthal sequences in regulating sugar metabolism. Using experimental data, we provide evidence that Neanderthal sequences modify the activity of several genes in our genomes, including genes important for our ability to respond to a broad set of environmental stimuli. [ABSTRACT FROM AUTHOR]