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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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A schematic diagram of the model.A model organism has 4 genes, which are expressed into multiple copies of model proteins. Proteins can stay as monomers or form dimers whose concentrations are determined by binding constants of interactions among them and law of mass action equations. Green cubes represent proteins in their functional states that contribute an organism's replication rate according to Eq.(1). Blue cubes represent functional MMR homodimers, whose concentration determines the mutation rate of their organism. Red cubes represent proteins in their non-functional states.
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pcbi-1000710-g001: A schematic diagram of the model.A model organism has 4 genes, which are expressed into multiple copies of model proteins. Proteins can stay as monomers or form dimers whose concentrations are determined by binding constants of interactions among them and law of mass action equations. Green cubes represent proteins in their functional states that contribute an organism's replication rate according to Eq.(1). Blue cubes represent functional MMR homodimers, whose concentration determines the mutation rate of their organism. Red cubes represent proteins in their non-functional states.

Mentions: The protein product of the fourth gene determines the mutation rate of its genome by acting as a prototype of mutS, which forms dimers of dimers. The fidelity of an organism's DNA replication is proportional to the concentration of functional MMR homodimers formed by products of gene 4 (see Model for details). Protein concentrations are epigenetically heritable but can fluctuate; reflecting long-time correlated noise in protein production in living cells [26]. and are exactly calculated for a given set of by solving equations of the Law of Mass Action (LMA) (see Model for details). Thus, mutation rates can increase upon a drop in concentration of functional MMR homodimers, or upon mutations of the MMR gene that disfavor its functional homodimerization, or both. (See Figure 1 and Model below for illustration and details.)


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

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

A schematic diagram of the model.A model organism has 4 genes, which are expressed into multiple copies of model proteins. Proteins can stay as monomers or form dimers whose concentrations are determined by binding constants of interactions among them and law of mass action equations. Green cubes represent proteins in their functional states that contribute an organism's replication rate according to Eq.(1). Blue cubes represent functional MMR homodimers, whose concentration determines the mutation rate of their organism. Red cubes represent proteins in their non-functional states.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000710-g001: A schematic diagram of the model.A model organism has 4 genes, which are expressed into multiple copies of model proteins. Proteins can stay as monomers or form dimers whose concentrations are determined by binding constants of interactions among them and law of mass action equations. Green cubes represent proteins in their functional states that contribute an organism's replication rate according to Eq.(1). Blue cubes represent functional MMR homodimers, whose concentration determines the mutation rate of their organism. Red cubes represent proteins in their non-functional states.
Mentions: The protein product of the fourth gene determines the mutation rate of its genome by acting as a prototype of mutS, which forms dimers of dimers. The fidelity of an organism's DNA replication is proportional to the concentration of functional MMR homodimers formed by products of gene 4 (see Model for details). Protein concentrations are epigenetically heritable but can fluctuate; reflecting long-time correlated noise in protein production in living cells [26]. and are exactly calculated for a given set of by solving equations of the Law of Mass Action (LMA) (see Model for details). Thus, mutation rates can increase upon a drop in concentration of functional MMR homodimers, or upon mutations of the MMR gene that disfavor its functional homodimerization, or both. (See Figure 1 and Model below for illustration and details.)

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