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.
-
Massively parallel identification of cis-regulatory variants in yeast promotersNCBI Gene Expression Omnibus, GSE155944.
-
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.
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.
Metrics
-
- 2,880
- views
-
- 296
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Genetics and Genomics
- Microbiology and Infectious Disease
The sustained success of Mycobacterium tuberculosis as a pathogen arises from its ability to persist within macrophages for extended periods and its limited responsiveness to antibiotics. Furthermore, the high incidence of resistance to the few available antituberculosis drugs is a significant concern, especially since the driving forces of the emergence of drug resistance are not clear. Drug-resistant strains of Mycobacterium tuberculosis can emerge through de novo mutations, however, mycobacterial mutation rates are low. To unravel the effects of antibiotic pressure on genome stability, we determined the genetic variability, phenotypic tolerance, DNA repair system activation, and dNTP pool upon treatment with current antibiotics using Mycobacterium smegmatis. Whole-genome sequencing revealed no significant increase in mutation rates after prolonged exposure to first-line antibiotics. However, the phenotypic fluctuation assay indicated rapid adaptation to antibiotics mediated by non-genetic factors. The upregulation of DNA repair genes, measured using qPCR, suggests that genomic integrity may be maintained through the activation of specific DNA repair pathways. Our results, indicating that antibiotic exposure does not result in de novo adaptive mutagenesis under laboratory conditions, do not lend support to the model suggesting antibiotic resistance development through drug pressure-induced microevolution.
-
- Developmental Biology
- Genetics and Genomics
O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.
