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Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response.

Heo M, Shakhnovich EI - PLoS Comput. Biol. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.

ABSTRACT
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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The importance of stochastic switching for mutator fixation and adaptation.Population (P), mean birth rate (b), mean total concentration of MMR protein 4 (), and the frequency of mutator allele (freq) in the population are plotted as function of time (t). The lines represent simulations at various expression level fluctuation rates: r = 10−2 (black), 10−3 (red), 10−4 (green) and 0 (blue). The initial growth of the population with higher fluctuation rate is limited due to the genetic load of deleterious mutation caused by high frequency of mutators (see the upper panel and Figure 6). All traces for r>0 showed decreased gene expression levels () of MMR protein during and immediately after adaptation events. The concentrations at r = 0.01 (black curves) decayed fast due to the high fluctuation rate, while the decays of concentrations at lower r (red and green) appeared less and slower. Without stochastic switching (blue), no fixation of mutators could arise and adaptation was severely impaired.
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pcbi-1000710-g005: The importance of stochastic switching for mutator fixation and adaptation.Population (P), mean birth rate (b), mean total concentration of MMR protein 4 (), and the frequency of mutator allele (freq) in the population are plotted as function of time (t). The lines represent simulations at various expression level fluctuation rates: r = 10−2 (black), 10−3 (red), 10−4 (green) and 0 (blue). The initial growth of the population with higher fluctuation rate is limited due to the genetic load of deleterious mutation caused by high frequency of mutators (see the upper panel and Figure 6). All traces for r>0 showed decreased gene expression levels () of MMR protein during and immediately after adaptation events. The concentrations at r = 0.01 (black curves) decayed fast due to the high fluctuation rate, while the decays of concentrations at lower r (red and green) appeared less and slower. Without stochastic switching (blue), no fixation of mutators could arise and adaptation was severely impaired.

Mentions: Why did mutators preferentially emerge through epigenetic stochastic switching rather than a genotypic change (mutation)? To address this question we studied adaptation in response to the stress of stationary phase at various rates r of stochastic fluctuation of protein concentrations, from r = 10−2 to 10−3, 10−4, and r = 0 – the case where no fluctuations of protein concentration were allowed (Figure 5; see Model and Table 2 for definition of fluctuation rates r). To correctly compare simulations in four different conditions with one another, we assigned unequal concentrations to the RCG proteins and MMR protein, setting them similar to those reached after the first adaptation event. Otherwise the inability to relax an imbalance among equally fixed protein concentrations at the control of might constraint the evolution of fitness. Deceleration of fluctuation rate delayed fixation of mutators, and furthermore, no mutators (and, strikingly, adaptation) were observed when r = 0.


Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response.

Heo M, Shakhnovich EI - PLoS Comput. Biol. (2010)

The importance of stochastic switching for mutator fixation and adaptation.Population (P), mean birth rate (b), mean total concentration of MMR protein 4 (), and the frequency of mutator allele (freq) in the population are plotted as function of time (t). The lines represent simulations at various expression level fluctuation rates: r = 10−2 (black), 10−3 (red), 10−4 (green) and 0 (blue). The initial growth of the population with higher fluctuation rate is limited due to the genetic load of deleterious mutation caused by high frequency of mutators (see the upper panel and Figure 6). All traces for r>0 showed decreased gene expression levels () of MMR protein during and immediately after adaptation events. The concentrations at r = 0.01 (black curves) decayed fast due to the high fluctuation rate, while the decays of concentrations at lower r (red and green) appeared less and slower. Without stochastic switching (blue), no fixation of mutators could arise and adaptation was severely impaired.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837395&req=5

pcbi-1000710-g005: The importance of stochastic switching for mutator fixation and adaptation.Population (P), mean birth rate (b), mean total concentration of MMR protein 4 (), and the frequency of mutator allele (freq) in the population are plotted as function of time (t). The lines represent simulations at various expression level fluctuation rates: r = 10−2 (black), 10−3 (red), 10−4 (green) and 0 (blue). The initial growth of the population with higher fluctuation rate is limited due to the genetic load of deleterious mutation caused by high frequency of mutators (see the upper panel and Figure 6). All traces for r>0 showed decreased gene expression levels () of MMR protein during and immediately after adaptation events. The concentrations at r = 0.01 (black curves) decayed fast due to the high fluctuation rate, while the decays of concentrations at lower r (red and green) appeared less and slower. Without stochastic switching (blue), no fixation of mutators could arise and adaptation was severely impaired.
Mentions: Why did mutators preferentially emerge through epigenetic stochastic switching rather than a genotypic change (mutation)? To address this question we studied adaptation in response to the stress of stationary phase at various rates r of stochastic fluctuation of protein concentrations, from r = 10−2 to 10−3, 10−4, and r = 0 – the case where no fluctuations of protein concentration were allowed (Figure 5; see Model and Table 2 for definition of fluctuation rates r). To correctly compare simulations in four different conditions with one another, we assigned unequal concentrations to the RCG proteins and MMR protein, setting them similar to those reached after the first adaptation event. Otherwise the inability to relax an imbalance among equally fixed protein concentrations at the control of might constraint the evolution of fitness. Deceleration of fluctuation rate delayed fixation of mutators, and furthermore, no mutators (and, strikingly, adaptation) were observed when r = 0.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus