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Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

View ORCID ProfileAnthony S Findley, Alan Monziani, View ORCID ProfileAllison L Richards, Katie Rhodes, Michelle C Ward, View ORCID ProfileCynthia A Kalita, View ORCID ProfileAdnan Alazizi, View ORCID ProfileAli Pazokitoroudi, View ORCID ProfileSriram Sankararaman, View ORCID ProfileXiaoquan Wen, View ORCID ProfileDavid E Lanfear, View ORCID ProfileRoger Pique-Regi, View ORCID ProfileYoav Gilad, View ORCID ProfileFrancesca Luca
doi: https://doi.org/10.1101/2021.01.29.428868
Anthony S Findley
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
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Alan Monziani
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
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Allison L Richards
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
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Katie Rhodes
2Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
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Michelle C Ward
3Department of Medicine, University of Chicago, Chicago, IL 60637, USA
10Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
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Cynthia A Kalita
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
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Adnan Alazizi
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
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Ali Pazokitoroudi
4Department of Computer Science, UCLA, Los Angeles, CA, 90095, USA
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Sriram Sankararaman
4Department of Computer Science, UCLA, Los Angeles, CA, 90095, USA
5Department of Human Genetics, UCLA, Los Angeles, CA, 90095, USA
6Department of Computational Medicine, UCLA, Los Angeles, CA, 90095, USA
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Xiaoquan Wen
7Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
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David E Lanfear
8Center for Individualized and Genomic Medicine Research, Henry Ford Hospital, Detroit, MI 48202, USA
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Roger Pique-Regi
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
9Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA
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  • For correspondence: fluca@wayne.edu gilad@uchicago.edu rpique@wayne.edu
Yoav Gilad
2Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
3Department of Medicine, University of Chicago, Chicago, IL 60637, USA
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  • For correspondence: fluca@wayne.edu gilad@uchicago.edu rpique@wayne.edu
Francesca Luca
1Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
9Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA
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  • For correspondence: fluca@wayne.edu gilad@uchicago.edu rpique@wayne.edu
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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 processes, and were also highly variable across cell types and treatments. For thousands of genes, we identified variable allelic expression across contexts, and characterized different types of gene-environment interactions. Many of these G×E genes are associated with complex traits. We characterized promoter functional and evolutionary features that distinguish genes with elevated allelic imbalance mean and variance. More than 47% of the genes with dynamic regulatory interactions were missed by GTEx, but we identified them using a suitable allelic imbalance study design. This indicates the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 31, 2021.
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Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
Anthony S Findley, Alan Monziani, Allison L Richards, Katie Rhodes, Michelle C Ward, Cynthia A Kalita, Adnan Alazizi, Ali Pazokitoroudi, Sriram Sankararaman, Xiaoquan Wen, David E Lanfear, Roger Pique-Regi, Yoav Gilad, Francesca Luca
bioRxiv 2021.01.29.428868; doi: https://doi.org/10.1101/2021.01.29.428868
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Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
Anthony S Findley, Alan Monziani, Allison L Richards, Katie Rhodes, Michelle C Ward, Cynthia A Kalita, Adnan Alazizi, Ali Pazokitoroudi, Sriram Sankararaman, Xiaoquan Wen, David E Lanfear, Roger Pique-Regi, Yoav Gilad, Francesca Luca
bioRxiv 2021.01.29.428868; doi: https://doi.org/10.1101/2021.01.29.428868

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