Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
- Wayne State University, United States
- University of Chicago, United States
- UCLA, United States
- University of Michigan, United States
- Henry Ford Hospital, United States
Abstract
Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.
Data availability
Sequencing files have been uploaded to the Sequence Read Archive (SRA) under Bioproject PRJNA694697
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Gene expression of LCLs, IPSCs, and CMs following 28 perturbationsNCBI Bioproject, PRJNA694697.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM109215)
- Roger Pique-Regi
- Francesca Luca
National Institute of General Medical Sciences (R35GM131726)
- Yoav Gilad
National Institute of General Medical Sciences (F30GM131580)
- Anthony S Findley
National Institute of General Medical Sciences (R35GM125055)
- Sriram Sankararaman
National Science Foundation (III-1705121)
- Ali Pazokitoroudi
- Sriram Sankararaman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stephen CJ Parker, University of Michigan, United States
Version history
- Received: February 1, 2021
- Accepted: May 13, 2021
- Accepted Manuscript published: May 14, 2021 (version 1)
- Version of Record published: July 1, 2021 (version 2)
Copyright
© 2021, Findley et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
eLife 10:e67077.
https://doi.org/10.7554/eLife.67077
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