Diverse environmental perturbations reveal the evolution and context-dependency of genetic effects on gene expression levels

There is increasing appreciation that human complex traits are determined by poorly understood interactions between our genomes and daily environments. These “genotype x environment” (GxE) interactions remain difficult to map at the organismal level, but can be uncovered using molecular phenotypes. To do so at large-scale, we profiled transcriptomes across 12 cellular environments using 544 immortalized B cell lines from the 1000 Genomes Project. We mapped the genetic basis of gene expression across environments and revealed a context-dependent genetic architecture: the average heritability of gene expression levels increased in treatment relative to control conditions and, on average, each treatment revealed expression quantitative trait loci (eQTL) at 11% of genes. In total, 22% of all eQTL were context-dependent, and this group was enriched for trait- and disease-associated loci. Further, evolutionary analyses revealed that positive selection has shaped GxE loci involved in responding to immune challenges and hormones, but not man-made chemicals, suggesting there is reduced opportunity for selection to act on responses to molecules recently introduced into human environments. Together, our work highlights the importance of considering an exposure’s evolutionary history when studying and interpreting GxE interactions, and provides new insight into the evolutionary mechanisms that maintain GxE loci in human populations. ### Competing Interest Statement The authors have declared no competing interest.