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

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 5832 natural DNA va...

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Autores principales: Renganaath, Kaushik, Chong, Rockie, Day, Laura, Kosuri, Sriram, Kruglyak, Leonid, Albert, Frank W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685706/
https://www.ncbi.nlm.nih.gov/pubmed/33179598
http://dx.doi.org/10.7554/eLife.62669
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author Renganaath, Kaushik
Chong, Rockie
Day, Laura
Kosuri, Sriram
Kruglyak, Leonid
Albert, Frank W
author_facet Renganaath, Kaushik
Chong, Rockie
Day, Laura
Kosuri, Sriram
Kruglyak, Leonid
Albert, Frank W
author_sort Renganaath, Kaushik
collection PubMed
description 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 5832 natural DNA variants in the promoters of 2503 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.
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spelling pubmed-76857062020-11-30 Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross Renganaath, Kaushik Chong, Rockie Day, Laura Kosuri, Sriram Kruglyak, Leonid Albert, Frank W eLife Genetics and Genomics 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 5832 natural DNA variants in the promoters of 2503 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. eLife Sciences Publications, Ltd 2020-11-12 /pmc/articles/PMC7685706/ /pubmed/33179598 http://dx.doi.org/10.7554/eLife.62669 Text en © 2020, Renganaath et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
Renganaath, Kaushik
Chong, Rockie
Day, Laura
Kosuri, Sriram
Kruglyak, Leonid
Albert, Frank W
Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
title Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
title_full Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
title_fullStr Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
title_full_unstemmed Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
title_short Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
title_sort systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685706/
https://www.ncbi.nlm.nih.gov/pubmed/33179598
http://dx.doi.org/10.7554/eLife.62669
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