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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-7685706 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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