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Negative feedback buffers effects of regulatory variants

Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the...

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Autores principales: Bader, Daniel M, Wilkening, Stefan, Lin, Gen, Tekkedil, Manu M, Dietrich, Kim, Steinmetz, Lars M, Gagneur, Julien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332157/
https://www.ncbi.nlm.nih.gov/pubmed/25634765
http://dx.doi.org/10.15252/msb.20145844
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author Bader, Daniel M
Wilkening, Stefan
Lin, Gen
Tekkedil, Manu M
Dietrich, Kim
Steinmetz, Lars M
Gagneur, Julien
author_facet Bader, Daniel M
Wilkening, Stefan
Lin, Gen
Tekkedil, Manu M
Dietrich, Kim
Steinmetz, Lars M
Gagneur, Julien
author_sort Bader, Daniel M
collection PubMed
description Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments.
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spelling pubmed-43321572015-03-09 Negative feedback buffers effects of regulatory variants Bader, Daniel M Wilkening, Stefan Lin, Gen Tekkedil, Manu M Dietrich, Kim Steinmetz, Lars M Gagneur, Julien Mol Syst Biol Articles Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments. BlackWell Publishing Ltd 2015-01-29 /pmc/articles/PMC4332157/ /pubmed/25634765 http://dx.doi.org/10.15252/msb.20145844 Text en © 2015 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Bader, Daniel M
Wilkening, Stefan
Lin, Gen
Tekkedil, Manu M
Dietrich, Kim
Steinmetz, Lars M
Gagneur, Julien
Negative feedback buffers effects of regulatory variants
title Negative feedback buffers effects of regulatory variants
title_full Negative feedback buffers effects of regulatory variants
title_fullStr Negative feedback buffers effects of regulatory variants
title_full_unstemmed Negative feedback buffers effects of regulatory variants
title_short Negative feedback buffers effects of regulatory variants
title_sort negative feedback buffers effects of regulatory variants
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332157/
https://www.ncbi.nlm.nih.gov/pubmed/25634765
http://dx.doi.org/10.15252/msb.20145844
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