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

Abstract
Data availability
Article and author information
Metrics

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

1. Renganaath
2. Chong
3. et al
(2020) Massively parallel identification of cis-regulatory variants in yeast promoters
NCBI Gene Expression Omnibus, GSE155944.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE155944

The following previously published data sets were used

1. Albert FW
2. Bloom JS
3. Siegel J
4. Day L
5. Kruglyak L
(2018) Genetics of trans-regulatory variation in gene expression
Various supplementary Data Tables.

https://elifesciences.org/articles/35471
(2014) Genetic Influences on Translation in Yeast
Data S2.

https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004692
1. Sharon E
2. Kalma Y
3. Sharp A
4. Raveh-Sadka T
5. Levo M
6. Zeevi D
7. Keren L
8. Yakhini Z
9. Weinberger A
10. Segal E
(2012) Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters
Supplementary Table 3.

https://www.nature.com/articles/nbt.2205
(2013) Extensive transcriptional heterogeneity revealed by isoform profiling
Supplementary Data S2.

https://www.nature.com/articles/nature12121?

Article and author information

Author details

Kaushik Renganaath

Department of Genetics, Cell Biology, & Development, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1010-3604
Rockie Chong

Department of Chemistry & Biochemistry, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
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.
Sriram Kosuri

Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4661-0600
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.

"This ORCID iD identifies the author of this article:" 0000-0002-8065-3057
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.

"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.

Copyright

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.