Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross

  1. Kaushik Renganaath
  2. Rocky Cheung
  3. Laura Day
  4. Sriram Kosuri
  5. Leonid Kruglyak  Is a corresponding author
  6. Frank Wolfgang Albert  Is a corresponding author
  1. University of Minnesota, United States
  2. University of California, Los Angeles, United States

Abstract

Sequence variation in regulatory DNA alters gene expression and shapes genetically complex traits. However, the identification of individual, causal regulatory variants is challenging. Here, we used a massively parallel reporter assay to measure the cis-regulatory consequences of 5,832 natural DNA variants in the promoters of 2,503 genes in the yeast Saccharomyces cerevisiae. We identified 451 causal variants, which underlie genetic loci known to affect gene expression. Several promoters harbored multiple causal variants. In five promoters, pairs of variants showed non-additive, epistatic interactions. Causal variants were enriched at conserved nucleotides, tended to have low derived allele frequency, and were depleted from promoters of essential genes, which is consistent with the action of negative selection. Causal variants were also enriched for alterations in transcription factor binding sites. Models integrating these features provided modest, but statistically significant, ability to predict causal variants. This work revealed a complex molecular basis for cis-acting regulatory variation.

Data availability

Raw data and barcode assignments to oligos are available under GEO accession GSE155944. Source Data is provided for Figures 2, 3, 4, 5, and 6. Additional processed data and the MPRA design are available as Supplementary Files.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kaushik Renganaath

    Department of Genetics, Cell Biology, & Development, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1010-3604
  2. Rocky Cheung

    Department of Chemistry & Biochemistry, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Laura Day

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sriram Kosuri

    Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4661-0600
  5. Leonid Kruglyak

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    LKruglyak@mednet.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8065-3057
  6. Frank Wolfgang Albert

    Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, United States
    For correspondence
    falbert@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1380-8063

Funding

National Institutes of Health (R35GM124676)

  • Frank Wolfgang Albert

Howard Hughes Medical Institute

  • Leonid Kruglyak

Pew Charitable Trusts

  • Frank Wolfgang Albert

Alfred P. Sloan Foundation

  • Frank Wolfgang Albert

Kinship Foundation

  • Sriram Kosuri

Department of Energy, Labor and Economic Growth (DE-FC02-02ER63421)

  • Sriram Kosuri

National Institutes of Health (R01GM102308)

  • Leonid Kruglyak

National Institutes of Health (DP2GM114829)

  • Sriram Kosuri

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christian R Landry, Université Laval, Canada

Publication history

  1. Received: September 2, 2020
  2. Accepted: November 11, 2020
  3. Accepted Manuscript published: November 12, 2020 (version 1)
  4. Version of Record published: November 24, 2020 (version 2)

Copyright

© 2020, Renganaath 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. Kaushik Renganaath
  2. Rocky Cheung
  3. Laura Day
  4. Sriram Kosuri
  5. Leonid Kruglyak
  6. Frank Wolfgang Albert
(2020)
Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
eLife 9:e62669.
https://doi.org/10.7554/eLife.62669

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