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

  1. Anthony S Findley
  2. Alan Monziani
  3. Allison L Richards
  4. Katherine Rhodes
  5. Michelle C Ward
  6. Cynthia A Kalita
  7. Adnan Alazizi
  8. Ali Pazokitoroudi
  9. Sriram Sankararaman
  10. Xiaoquan Wen
  11. David E Lanfear
  12. Roger Pique-Regi  Is a corresponding author
  13. Yoav Gilad  Is a corresponding author
  14. Francesca Luca  Is a corresponding author
  1. Wayne State University, United States
  2. University of Chicago, United States
  3. UCLA, United States
  4. University of Michigan, United States
  5. 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

The following data sets were generated

Article and author information

Author details

  1. Anthony S Findley

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9922-3076
  2. Alan Monziani

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Allison L Richards

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Katherine Rhodes

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michelle C Ward

    Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1485-320X
  6. Cynthia A Kalita

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Adnan Alazizi

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ali Pazokitoroudi

    Department of Computer Science,, UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sriram Sankararaman

    Department of Computer Science,, UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaoquan Wen

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. David E Lanfear

    Center for Individualized and Genomic Medicine Research, Henry Ford Hospital, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Roger Pique-Regi

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    For correspondence
    rpique@wayne.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1262-2275
  13. Yoav Gilad

    Department of Medicine, University of Chicago, Chicago, United States
    For correspondence
    gilad@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8284-8926
  14. Francesca Luca

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    For correspondence
    fluca@wayne.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8252-9052

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

  1. Stephen CJ Parker, University of Michigan, United States

Version history

  1. Received: February 1, 2021
  2. Accepted: May 13, 2021
  3. Accepted Manuscript published: May 14, 2021 (version 1)
  4. 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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  1. Anthony S Findley
  2. Alan Monziani
  3. Allison L Richards
  4. Katherine Rhodes
  5. Michelle C Ward
  6. Cynthia A Kalita
  7. Adnan Alazizi
  8. Ali Pazokitoroudi
  9. Sriram Sankararaman
  10. Xiaoquan Wen
  11. David E Lanfear
  12. Roger Pique-Regi
  13. Yoav Gilad
  14. Francesca Luca
(2021)
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

Share this article

https://doi.org/10.7554/eLife.67077

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