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Dissecting the Fitness Costs of Complex Mutations

The fitness cost of complex pleiotropic mutations is generally difficult to assess. On the one hand, it is necessary to identify which molecular properties are directly altered by the mutation. On the other, this alteration modifies the activity of many genetic targets with uncertain consequences. H...

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Autores principales: Yubero, Pablo, Poyatos, Juan F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476139/
https://www.ncbi.nlm.nih.gov/pubmed/34175930
http://dx.doi.org/10.1093/molbev/msab193
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author Yubero, Pablo
Poyatos, Juan F
author_facet Yubero, Pablo
Poyatos, Juan F
author_sort Yubero, Pablo
collection PubMed
description The fitness cost of complex pleiotropic mutations is generally difficult to assess. On the one hand, it is necessary to identify which molecular properties are directly altered by the mutation. On the other, this alteration modifies the activity of many genetic targets with uncertain consequences. Here, we examine the possibility of addressing these challenges by identifying unique predictors of these costs. To this aim, we consider mutations in the RNA polymerase (RNAP) in Escherichia coli as a model of complex mutations. Changes in RNAP modify the global program of transcriptional regulation, with many consequences. Among others is the difficulty to decouple the direct effect of the mutation from the response of the whole system to such mutation. A problem that we solve quantitatively with data of a set of constitutive genes, those on which the global program acts most directly. We provide a statistical framework that incorporates the direct effects and other molecular variables linked to this program as predictors, which leads to the identification that some genes are more suitable to determine costs than others. Therefore, we not only identified which molecular properties best anticipate fitness, but we also present the paradoxical result that, despite pleiotropy, specific genes serve as more solid predictors. These results have connotations for the understanding of the architecture of robustness in biological systems.
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spelling pubmed-84761392021-09-28 Dissecting the Fitness Costs of Complex Mutations Yubero, Pablo Poyatos, Juan F Mol Biol Evol Discoveries The fitness cost of complex pleiotropic mutations is generally difficult to assess. On the one hand, it is necessary to identify which molecular properties are directly altered by the mutation. On the other, this alteration modifies the activity of many genetic targets with uncertain consequences. Here, we examine the possibility of addressing these challenges by identifying unique predictors of these costs. To this aim, we consider mutations in the RNA polymerase (RNAP) in Escherichia coli as a model of complex mutations. Changes in RNAP modify the global program of transcriptional regulation, with many consequences. Among others is the difficulty to decouple the direct effect of the mutation from the response of the whole system to such mutation. A problem that we solve quantitatively with data of a set of constitutive genes, those on which the global program acts most directly. We provide a statistical framework that incorporates the direct effects and other molecular variables linked to this program as predictors, which leads to the identification that some genes are more suitable to determine costs than others. Therefore, we not only identified which molecular properties best anticipate fitness, but we also present the paradoxical result that, despite pleiotropy, specific genes serve as more solid predictors. These results have connotations for the understanding of the architecture of robustness in biological systems. Oxford University Press 2021-06-27 /pmc/articles/PMC8476139/ /pubmed/34175930 http://dx.doi.org/10.1093/molbev/msab193 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Discoveries
Yubero, Pablo
Poyatos, Juan F
Dissecting the Fitness Costs of Complex Mutations
title Dissecting the Fitness Costs of Complex Mutations
title_full Dissecting the Fitness Costs of Complex Mutations
title_fullStr Dissecting the Fitness Costs of Complex Mutations
title_full_unstemmed Dissecting the Fitness Costs of Complex Mutations
title_short Dissecting the Fitness Costs of Complex Mutations
title_sort dissecting the fitness costs of complex mutations
topic Discoveries
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476139/
https://www.ncbi.nlm.nih.gov/pubmed/34175930
http://dx.doi.org/10.1093/molbev/msab193
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