Lin Wenhe, Li Mingyuan, Allen Olivia, Burnett Jonathan, Popp Joshua M, Stephens Matthew, Battle Alexis, Gilad Yoav
Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
bioRxiv. 2025 May 4:2025.04.30.651602. doi: 10.1101/2025.04.30.651602.
Many of the genetic loci associated with disease are expected to have context-dependent regulatory effects that are underrepresented in the transcriptomes of healthy, steady-state adult tissues. To understand gene regulation across diverse environmental conditions and cellular contexts, we treated a broad array of human cell types with three environmental exposures . With single-cell RNA-sequencing data from 1.4 million cells across 51 individuals, we identified hundreds of response expression quantitative loci (eQTLs) that are associated with inter-individual differences in regulatory changes following treatment with nicotine, caffeine, or ethanol in diverse cell types. We also identified dynamic regulatory effects that vary across differentiation trajectories in response to exposure. In contrast to steady-state eQTLs, and similar to disease risk loci, response eQTLs are enriched in distal enhancers and are regulating genes that experienced strong selective constraint, contain complex regulatory landscapes, and display diverse biological functions. We identified response eQTLs that coincide with disease-associated loci not explained by steady-state eQTLs. Our results highlight the complexity of genetic regulatory effects and suggest that our ability to interpret disease-associated loci will benefit from the pursuit of studies of gene-by-environment interactions in diverse biological contexts.
许多与疾病相关的基因座预计具有依赖于背景的调控效应，而这些效应在健康、稳态的成年组织转录组中代表性不足。为了了解不同环境条件和细胞背景下的基因调控，我们用三种环境暴露处理了多种人类细胞类型。利用来自51个个体的140万个细胞的单细胞RNA测序数据，我们鉴定出数百个响应表达数量性状基因座（eQTL），这些基因座与不同细胞类型中用尼古丁、咖啡因或乙醇处理后的调控变化中的个体间差异相关。我们还鉴定出了随着分化轨迹响应暴露而变化的动态调控效应。与稳态eQTL不同，且与疾病风险基因座相似，响应eQTL在远端增强子中富集，并且调控经历强烈选择约束、具有复杂调控格局并表现出多样生物学功能的基因。我们鉴定出了与稳态eQTL无法解释的疾病相关基因座重合的响应eQTL。我们的结果凸显了遗传调控效应的复杂性，并表明我们解释疾病相关基因座的能力将受益于在不同生物学背景下开展基因与环境相互作用的研究。
