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dc.contributor.authorHeo, Muyoung
dc.contributor.authorShakhnovich, Eugene Isaacovitch
dc.date.accessioned2017-07-18T18:37:20Z
dc.date.issued2010
dc.identifierQuick submit: 2017-05-15T21:31:07-0400
dc.identifier.citationHeo, Muyoung, and Eugene I. Shakhnovich. 2010. “Interplay Between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Response.” Edited by Rustom Antia. PLoS Computational Biology 6 (3) (March 12): e1000710. doi:10.1371/journal.pcbi.1000710.en_US
dc.identifier.issn1553-7358en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:33464145
dc.description.abstractMutators 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.en_US
dc.description.sponsorshipChemistry and Chemical Biologyen_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Science (PLoS)en_US
dc.relation.isversionof10.1371/journal.pcbi.1000710en_US
dash.licenseLAA
dc.titleInterplay between Pleiotropy and Secondary Selection Determines Rise and Fall of Mutators in Stress Responseen_US
dc.typeJournal Articleen_US
dc.date.updated2017-05-16T01:30:25Z
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Computational Biologyen_US
dash.depositing.authorShakhnovich, Eugene Isaacovitch
dc.date.available2010
dc.date.available2017-07-18T18:37:20Z
dc.identifier.doi10.1371/journal.pcbi.1000710*
dash.contributor.affiliatedHeo, Muyoung
dash.contributor.affiliatedShakhnovich, Eugene


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