Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, United States of America.
Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, California, United States of America.
PLoS Genet. 2021 Sep 27;17(9):e1009493. doi: 10.1371/journal.pgen.1009493. eCollection 2021 Sep.
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.
古人类迁徙导致了世界各地不同环境背景下人群的定居。适应当地环境在多大程度上塑造了人类遗传多样性，这是人类进化中一个长期存在的问题。最近的研究表明，古人类等位基因的渐渗可能有助于人类适应环境压力，如病原体暴露。功能基因组研究表明，个体之间和对环境扰动的基因表达变异是复杂性状变异的主要机制。我们认为基因表达对体外处理的反应是一种分子表型，以鉴定可能在适应当地环境方面发挥重要作用的基因和调控变体。我们研究了尼安德特人在人类基因组中的渐渗是否可能有助于对环境扰动的转录反应。为此，我们使用了在 52 种细胞环境中差异表达的基因的 eQTLs，这些基因来自 5 种细胞类型和 26 种处理，包括激素、维生素、药物和环境污染物。我们发现，具有渐渗尼安德特人等位基因（N-SNPs）的 SNP 会破坏对环境反应至关重要的转录因子的结合，包括电离辐射和缺氧，以及葡萄糖代谢。我们在 8 种处理（包括皮质醇、咖啡因和维生素 D）引起的基因差异表达的 eQTL 中发现了 N-SNPs 的富集。使用大规模平行报告基因分析（MPRA）数据，我们验证了人类基因组中 21 个渐渗尼安德特变体的调控功能，这些变体对应于 8 个调节 15 个基因对环境扰动反应的 eQTL。这些发现扩展了古人类渐渗可能有助于现代人类适应当地环境的环境范围，并为渐渗变体的调控功能提供了实验验证。
