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

dc.contributor.authorLea, Amanda J.
dc.contributor.authorPeng, Julie
dc.contributor.authorAyroles, Julien F.
dc.identifier.othereISSN 1549-5469
dc.identifier.otherPubMed ID36229124
dc.description.abstractThere is increasing appreciation that, in addition to being shaped by an individual's genotype and environment, most complex traits are also determined by poorly understood interactions between these two factors. So-called "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 used TM3'seq to profile transcriptomes across 12 cellular environments in 544 immortalized B cell lines from the 1000 Genomes Project. We mapped the genetic basis of gene expression levels 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 new expression quantitative trait loci (eQTLs) at 11% of genes. Across our experiments, 22% of all identified eQTLs were context-dependent, and this group was enriched for trait- and disease-associated loci. Further, evolutionary analyses suggested that positive selection has shaped GxE loci involved in responding to immune challenges and hormones but not to man-made chemicals. We hypothesize that this reflects a 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.en_US
dc.description.sponsorshipWe thank all members of the Ayroles laboratory for their feedback and support during the completion of this project. We also thank Andrea Graham and members of the Graham laboratory for thoughtful input and discussion. We thank Aaron Wolf, Christina Hansen, and Edward Schrom for assistance with cell culture protocols and facilities. This study was supported by the Lewis-Sigler Institute for Integrative Genomics at Princeton University, as well as a grant from the National Institutes of Health/National Institute of Environmental Health Sciences to J.F.A. (R01-ES029929). A.J.L. was supported by a postdoctoral fellowship from the Helen Hay Whitney Foundation.en_US
dc.publisherGenome Researchen_US
dc.rights© 2022 Lea et al.; Published by Cold Spring Harbor Laboratory Press This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at
dc.titleDiverse environmental perturbations reveal the evolution and context-dependency of genetic effects on gene expression levelsen_US

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