Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
- University of Minnesota, United States
- 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.
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Massively parallel identification of cis-regulatory variants in yeast promotersNCBI Gene Expression Omnibus, GSE155944.
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Genetics of trans-regulatory variation in gene expressionVarious supplementary Data Tables.
Article and author information
Author details
Kaushik Renganaath
Frank Wolfgang Albert
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
- Christian R Landry, Université Laval, Canada
Version history
- Received: September 2, 2020
- Accepted: November 11, 2020
- Accepted Manuscript published: November 12, 2020 (version 1)
- 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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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
Further reading
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