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Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response

Mutators are clones whose mutation rate is about two to three orders of magnitude higher than the rate of wild-type clones and their roles in adaptive evolution of asexual populations have been controversial. Here we address this problem by using an ab initio microscopic model of living cells, which...

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Autores principales: Heo, Muyoung, Shakhnovich, Eugene I.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837395/
https://www.ncbi.nlm.nih.gov/pubmed/20300650
http://dx.doi.org/10.1371/journal.pcbi.1000710
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author Heo, Muyoung
Shakhnovich, Eugene I.
author_facet Heo, Muyoung
Shakhnovich, Eugene I.
author_sort Heo, Muyoung
collection PubMed
description Mutators are clones whose mutation rate is about two to three orders of magnitude higher than the rate of wild-type clones and their roles in adaptive evolution of asexual populations have been controversial. Here we address this problem by using an ab initio microscopic model of living cells, which combines population genetics with a physically realistic presentation of protein stability and protein-protein interactions. The genome of model organisms encodes replication controlling genes (RCGs) and genes modeling the mismatch repair (MMR) complexes. The genotype-phenotype relationship posits that the replication rate of an organism is proportional to protein copy numbers of RCGs in their functional form and there is a production cost penalty for protein overexpression. The mutation rate depends linearly on the concentration of homodimers of MMR proteins. By simulating multiple runs of evolution of populations under various environmental stresses—stationary phase, starvation or temperature-jump—we find that adaptation most often occurs through transient fixation of a mutator phenotype, regardless of the nature of stress. By contrast, the fixation mechanism does depend on the nature of stress. In temperature jump stress, mutators take over the population due to loss of stability of MMR complexes. In contrast, in starvation and stationary phase stresses, a small number of mutators are supplied to the population via epigenetic stochastic noise in production of MMR proteins (a pleiotropic effect), and their net supply is higher due to reduced genetic drift in slowly growing populations under stressful environments. Subsequently, mutators in stationary phase or starvation hitchhike to fixation with a beneficial mutation in the RCGs, (second order selection) and finally a mutation stabilizing the MMR complex arrives, returning the population to a non-mutator phenotype. Our results provide microscopic insights into the rise and fall of mutators in adapting finite asexual populations.
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spelling pubmed-28373952010-03-17 Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response Heo, Muyoung Shakhnovich, Eugene I. PLoS Comput Biol Research Article Mutators are clones whose mutation rate is about two to three orders of magnitude higher than the rate of wild-type clones and their roles in adaptive evolution of asexual populations have been controversial. Here we address this problem by using an ab initio microscopic model of living cells, which combines population genetics with a physically realistic presentation of protein stability and protein-protein interactions. The genome of model organisms encodes replication controlling genes (RCGs) and genes modeling the mismatch repair (MMR) complexes. The genotype-phenotype relationship posits that the replication rate of an organism is proportional to protein copy numbers of RCGs in their functional form and there is a production cost penalty for protein overexpression. The mutation rate depends linearly on the concentration of homodimers of MMR proteins. By simulating multiple runs of evolution of populations under various environmental stresses—stationary phase, starvation or temperature-jump—we find that adaptation most often occurs through transient fixation of a mutator phenotype, regardless of the nature of stress. By contrast, the fixation mechanism does depend on the nature of stress. In temperature jump stress, mutators take over the population due to loss of stability of MMR complexes. In contrast, in starvation and stationary phase stresses, a small number of mutators are supplied to the population via epigenetic stochastic noise in production of MMR proteins (a pleiotropic effect), and their net supply is higher due to reduced genetic drift in slowly growing populations under stressful environments. Subsequently, mutators in stationary phase or starvation hitchhike to fixation with a beneficial mutation in the RCGs, (second order selection) and finally a mutation stabilizing the MMR complex arrives, returning the population to a non-mutator phenotype. Our results provide microscopic insights into the rise and fall of mutators in adapting finite asexual populations. Public Library of Science 2010-03-12 /pmc/articles/PMC2837395/ /pubmed/20300650 http://dx.doi.org/10.1371/journal.pcbi.1000710 Text en Heo, Shakhnovich. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Heo, Muyoung
Shakhnovich, Eugene I.
Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response
title Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response
title_full Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response
title_fullStr Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response
title_full_unstemmed Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response
title_short Interplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response
title_sort interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837395/
https://www.ncbi.nlm.nih.gov/pubmed/20300650
http://dx.doi.org/10.1371/journal.pcbi.1000710
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