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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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Related in: MedlinePlus

Causes of the rise and fall of mutator clones.Frequencies of non-mutator (freqW) and mutator (freqM) clones that arise from various causes are shown as function of time (t). Colors indicate main molecular causes of the rise and fall of mutators: Red represents genotypic mutation (Mut), blue represents stochastic phenotype switching (SS), and magenta represents an environmental change (Env). The black line (Init) is the original non-mutator population. Panels A, B, and C respectively correspond to population dynamics in undergoing heat shock, stationary phase, and starvation stress at t = 20000.
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pcbi-1000710-g004: Causes of the rise and fall of mutator clones.Frequencies of non-mutator (freqW) and mutator (freqM) clones that arise from various causes are shown as function of time (t). Colors indicate main molecular causes of the rise and fall of mutators: Red represents genotypic mutation (Mut), blue represents stochastic phenotype switching (SS), and magenta represents an environmental change (Env). The black line (Init) is the original non-mutator population. Panels A, B, and C respectively correspond to population dynamics in undergoing heat shock, stationary phase, and starvation stress at t = 20000.

Mentions: Change in concentration of the MMR protein, due to stochastic fluctuations, was the primary factor causing the rise of mutators in initial adaptation. As for adaptation to stress which took place at a later time t = 20,000, fluctuation in MMR protein production level was primarily responsible for the rise of the mutator phenotype at stationary phase and starvation stresses (see Figure 3B and Table 1), except for the strain in stationary phase stress which reached high fitness b∼1 in initial adaptation. For this strain no further adaptation took place after stress, and a mutator phenotype did not fix. For heat-shock stress, destabilization of the MMR protein and its homodimeric complex at higher temperature was the primary cause of the rise of a mutator phenotype (Figure 3A). The recovery of a normal, non-mutator phenotype was mostly due to mutations in the MMR gene, which increased stability of the functional MMR complex. In order to determine precisely the microscopic causes of phenotypic switches between mutators and non-mutators, we traced all transitions between them for all adaptation events on all trajectories. The summary picture is presented in Figure 4. Green lines in all panels of Figure 4 highlight the instances when the mutator phenotype was switched on or off by variation of concentration of MMR protein . Most mutators in the bottom panel of Figure 4, except in the temperature jump case, initially emerged from stochastic variation of protein concentrations, i.e. they represented switches due to epigenetic events. The transitions between fixation of mutators and non-mutators mostly occurred in a specific microscopic order, depending on the nature of stress (see Figure 4 and Table 1). The heat-shock stress resulted in thermal destabilization of the MMR complex, which gave rise to higher mutation rates. On the other hand, the stationary phase and starvation stresses decreased the growth rate, which prevented the constitutive mutators from being purged away from their finite populations by genetic drift. Sequentially, highly mutating strains in all cases discovered mutations, which stabilized functional interactions in RCGs providing strains of higher fitness, so that mutator strains hitchhiked to fixation in stationary phase and starvation stresses. Finally a mutation in the MMR protein stabilized the complex bringing mutation rates in the population back to the original low level. On a microscopic level, the behavior of generating mutator strains in response to temperature stress is somewhat different from the behavior to stationary phase and starvation stresses. In the former case, stress induces the mutator strain directly by disrupting the MMR complex. Meanwhile, in the latter case it does not induce mutator strains per se but sets in motion a chain of microscopic and populational events, such as hitchhiking, which result in a similar phenotypic phenomenology as adaptation to a temperature jump.


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

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

Causes of the rise and fall of mutator clones.Frequencies of non-mutator (freqW) and mutator (freqM) clones that arise from various causes are shown as function of time (t). Colors indicate main molecular causes of the rise and fall of mutators: Red represents genotypic mutation (Mut), blue represents stochastic phenotype switching (SS), and magenta represents an environmental change (Env). The black line (Init) is the original non-mutator population. Panels A, B, and C respectively correspond to population dynamics in undergoing heat shock, stationary phase, and starvation stress at t = 20000.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000710-g004: Causes of the rise and fall of mutator clones.Frequencies of non-mutator (freqW) and mutator (freqM) clones that arise from various causes are shown as function of time (t). Colors indicate main molecular causes of the rise and fall of mutators: Red represents genotypic mutation (Mut), blue represents stochastic phenotype switching (SS), and magenta represents an environmental change (Env). The black line (Init) is the original non-mutator population. Panels A, B, and C respectively correspond to population dynamics in undergoing heat shock, stationary phase, and starvation stress at t = 20000.
Mentions: Change in concentration of the MMR protein, due to stochastic fluctuations, was the primary factor causing the rise of mutators in initial adaptation. As for adaptation to stress which took place at a later time t = 20,000, fluctuation in MMR protein production level was primarily responsible for the rise of the mutator phenotype at stationary phase and starvation stresses (see Figure 3B and Table 1), except for the strain in stationary phase stress which reached high fitness b∼1 in initial adaptation. For this strain no further adaptation took place after stress, and a mutator phenotype did not fix. For heat-shock stress, destabilization of the MMR protein and its homodimeric complex at higher temperature was the primary cause of the rise of a mutator phenotype (Figure 3A). The recovery of a normal, non-mutator phenotype was mostly due to mutations in the MMR gene, which increased stability of the functional MMR complex. In order to determine precisely the microscopic causes of phenotypic switches between mutators and non-mutators, we traced all transitions between them for all adaptation events on all trajectories. The summary picture is presented in Figure 4. Green lines in all panels of Figure 4 highlight the instances when the mutator phenotype was switched on or off by variation of concentration of MMR protein . Most mutators in the bottom panel of Figure 4, except in the temperature jump case, initially emerged from stochastic variation of protein concentrations, i.e. they represented switches due to epigenetic events. The transitions between fixation of mutators and non-mutators mostly occurred in a specific microscopic order, depending on the nature of stress (see Figure 4 and Table 1). The heat-shock stress resulted in thermal destabilization of the MMR complex, which gave rise to higher mutation rates. On the other hand, the stationary phase and starvation stresses decreased the growth rate, which prevented the constitutive mutators from being purged away from their finite populations by genetic drift. Sequentially, highly mutating strains in all cases discovered mutations, which stabilized functional interactions in RCGs providing strains of higher fitness, so that mutator strains hitchhiked to fixation in stationary phase and starvation stresses. Finally a mutation in the MMR protein stabilized the complex bringing mutation rates in the population back to the original low level. On a microscopic level, the behavior of generating mutator strains in response to temperature stress is somewhat different from the behavior to stationary phase and starvation stresses. In the former case, stress induces the mutator strain directly by disrupting the MMR complex. Meanwhile, in the latter case it does not induce mutator strains per se but sets in motion a chain of microscopic and populational events, such as hitchhiking, which result in a similar phenotypic phenomenology as adaptation to a temperature jump.

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