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Extensive compensatory cis-trans regulation in the evolution of mouse gene expression

Gene expression levels are thought to diverge primarily via regulatory mutations in trans within species, and in cis between species. To test this hypothesis in mammals we used RNA-sequencing to measure gene expression divergence between C57BL/6J and CAST/EiJ mouse strains and allele-specific expres...

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Autores principales: Goncalves, Angela, Leigh-Brown, Sarah, Thybert, David, Stefflova, Klara, Turro, Ernest, Flicek, Paul, Brazma, Alvis, Odom, Duncan T., Marioni, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667/
https://www.ncbi.nlm.nih.gov/pubmed/22919075
http://dx.doi.org/10.1101/gr.142281.112
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author Goncalves, Angela
Leigh-Brown, Sarah
Thybert, David
Stefflova, Klara
Turro, Ernest
Flicek, Paul
Brazma, Alvis
Odom, Duncan T.
Marioni, John C.
author_facet Goncalves, Angela
Leigh-Brown, Sarah
Thybert, David
Stefflova, Klara
Turro, Ernest
Flicek, Paul
Brazma, Alvis
Odom, Duncan T.
Marioni, John C.
author_sort Goncalves, Angela
collection PubMed
description Gene expression levels are thought to diverge primarily via regulatory mutations in trans within species, and in cis between species. To test this hypothesis in mammals we used RNA-sequencing to measure gene expression divergence between C57BL/6J and CAST/EiJ mouse strains and allele-specific expression in their F1 progeny. We identified 535 genes with parent-of-origin specific expression patterns, although few of these showed full allelic silencing. This suggests that the number of imprinted genes in a typical mouse somatic tissue is relatively small. In the set of nonimprinted genes, 32% showed evidence of divergent expression between the two strains. Of these, 2% could be attributed purely to variants acting in trans, while 43% were attributable only to variants acting in cis. The genes with expression divergence driven by changes in trans showed significantly higher sequence constraint than genes where the divergence was explained by variants acting in cis. The remaining genes with divergent patterns of expression (55%) were regulated by a combination of variants acting in cis and variants acting in trans. Intriguingly, the changes in expression induced by the cis and trans variants were in opposite directions more frequently than expected by chance, implying that compensatory regulation to stabilize gene expression levels is widespread. We propose that expression levels of genes regulated by this mechanism are fine-tuned by cis variants that arise following regulatory changes in trans, suggesting that many cis variants are not the primary targets of natural selection.
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spelling pubmed-35146672012-12-20 Extensive compensatory cis-trans regulation in the evolution of mouse gene expression Goncalves, Angela Leigh-Brown, Sarah Thybert, David Stefflova, Klara Turro, Ernest Flicek, Paul Brazma, Alvis Odom, Duncan T. Marioni, John C. Genome Res Research Gene expression levels are thought to diverge primarily via regulatory mutations in trans within species, and in cis between species. To test this hypothesis in mammals we used RNA-sequencing to measure gene expression divergence between C57BL/6J and CAST/EiJ mouse strains and allele-specific expression in their F1 progeny. We identified 535 genes with parent-of-origin specific expression patterns, although few of these showed full allelic silencing. This suggests that the number of imprinted genes in a typical mouse somatic tissue is relatively small. In the set of nonimprinted genes, 32% showed evidence of divergent expression between the two strains. Of these, 2% could be attributed purely to variants acting in trans, while 43% were attributable only to variants acting in cis. The genes with expression divergence driven by changes in trans showed significantly higher sequence constraint than genes where the divergence was explained by variants acting in cis. The remaining genes with divergent patterns of expression (55%) were regulated by a combination of variants acting in cis and variants acting in trans. Intriguingly, the changes in expression induced by the cis and trans variants were in opposite directions more frequently than expected by chance, implying that compensatory regulation to stabilize gene expression levels is widespread. We propose that expression levels of genes regulated by this mechanism are fine-tuned by cis variants that arise following regulatory changes in trans, suggesting that many cis variants are not the primary targets of natural selection. Cold Spring Harbor Laboratory Press 2012-12 /pmc/articles/PMC3514667/ /pubmed/22919075 http://dx.doi.org/10.1101/gr.142281.112 Text en © 2012, Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research
Goncalves, Angela
Leigh-Brown, Sarah
Thybert, David
Stefflova, Klara
Turro, Ernest
Flicek, Paul
Brazma, Alvis
Odom, Duncan T.
Marioni, John C.
Extensive compensatory cis-trans regulation in the evolution of mouse gene expression
title Extensive compensatory cis-trans regulation in the evolution of mouse gene expression
title_full Extensive compensatory cis-trans regulation in the evolution of mouse gene expression
title_fullStr Extensive compensatory cis-trans regulation in the evolution of mouse gene expression
title_full_unstemmed Extensive compensatory cis-trans regulation in the evolution of mouse gene expression
title_short Extensive compensatory cis-trans regulation in the evolution of mouse gene expression
title_sort extensive compensatory cis-trans regulation in the evolution of mouse gene expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514667/
https://www.ncbi.nlm.nih.gov/pubmed/22919075
http://dx.doi.org/10.1101/gr.142281.112
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