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Mutation bias favors protein folding stability in the evolution of small populations.

Mendez R, Fritsche M, Porto M, Bastolla U - PLoS Comput. Biol. (2010)

Bottom Line: This result is robust with respect to the definition of the fitness function and to the protein structures studied.This provides a possible explanation to the observation that most species adopting obligatory intracellular lifestyles with a consequent reduction of effective population size shifted their mutation spectrum towards AT.To test these predictions we estimated the effective population sizes of bacterial species using the optimal codon usage coefficients computed by dos Reis et al. and the synonymous to non-synonymous substitution ratio computed by Daubin and Moran.

View Article: PubMed Central - PubMed

Affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.

ABSTRACT
Mutation bias in prokaryotes varies from extreme adenine and thymine (AT) in obligatory endosymbiotic or parasitic bacteria to extreme guanine and cytosine (GC), for instance in actinobacteria. GC mutation bias deeply influences the folding stability of proteins, making proteins on the average less hydrophobic and therefore less stable with respect to unfolding but also less susceptible to misfolding and aggregation. We study a model where proteins evolve subject to selection for folding stability under given mutation bias, population size, and neutrality. We find a non-neutral regime where, for any given population size, there is an optimal mutation bias that maximizes fitness. Interestingly, this optimal GC usage is small for small populations, large for intermediate populations and around 50% for large populations. This result is robust with respect to the definition of the fitness function and to the protein structures studied. Our model suggests that small populations evolving with small GC usage eventually accumulate a significant selective advantage over populations evolving without this bias. This provides a possible explanation to the observation that most species adopting obligatory intracellular lifestyles with a consequent reduction of effective population size shifted their mutation spectrum towards AT. The model also predicts that large GC usage is optimal for intermediate population size. To test these predictions we estimated the effective population sizes of bacterial species using the optimal codon usage coefficients computed by dos Reis et al. and the synonymous to non-synonymous substitution ratio computed by Daubin and Moran. We found that the population sizes estimated in these ways are significantly smaller for species with small and large GC usage compared to species with no bias, which supports our prediction.

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Negative correlation between misfolding and unfolding stability.Upper plot: Simulation results for average misfolding stability  versus unfolding stability  for various mutation biases, three population sizes and neutrality exponent  (non-neutral regime) and  (neutral regime). Bottom plot: Estimated misfolding versus unfolding stability for families of homologous proteins in prokaryotic genomes (data from Ref. [12]). We distinguish genomes according to  content at third codon position. The solid line represents a linear fit of misfolding stability for genomes with moderate or no mutation bias ().
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pcbi-1000767-g010: Negative correlation between misfolding and unfolding stability.Upper plot: Simulation results for average misfolding stability versus unfolding stability for various mutation biases, three population sizes and neutrality exponent (non-neutral regime) and (neutral regime). Bottom plot: Estimated misfolding versus unfolding stability for families of homologous proteins in prokaryotic genomes (data from Ref. [12]). We distinguish genomes according to content at third codon position. The solid line represents a linear fit of misfolding stability for genomes with moderate or no mutation bias ().

Mentions: Finally, we reanalysed our data on protein folding stabilities computationally estimated for orthologous proteins in different prokaryotic genomes [12]. Unfolding and misfolding stabilities are negatively correlated, as predicted by our model (see Fig. 10). We found that most of the organisms evolving with mutation bias have proteins whose misfolding stability is lower than what could be expected based on their unfolding stability, see Fig. 11. This further supports the idea that these species are characterized by reduced effective population sizes.


Mutation bias favors protein folding stability in the evolution of small populations.

Mendez R, Fritsche M, Porto M, Bastolla U - PLoS Comput. Biol. (2010)

Negative correlation between misfolding and unfolding stability.Upper plot: Simulation results for average misfolding stability  versus unfolding stability  for various mutation biases, three population sizes and neutrality exponent  (non-neutral regime) and  (neutral regime). Bottom plot: Estimated misfolding versus unfolding stability for families of homologous proteins in prokaryotic genomes (data from Ref. [12]). We distinguish genomes according to  content at third codon position. The solid line represents a linear fit of misfolding stability for genomes with moderate or no mutation bias ().
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865504&req=5

pcbi-1000767-g010: Negative correlation between misfolding and unfolding stability.Upper plot: Simulation results for average misfolding stability versus unfolding stability for various mutation biases, three population sizes and neutrality exponent (non-neutral regime) and (neutral regime). Bottom plot: Estimated misfolding versus unfolding stability for families of homologous proteins in prokaryotic genomes (data from Ref. [12]). We distinguish genomes according to content at third codon position. The solid line represents a linear fit of misfolding stability for genomes with moderate or no mutation bias ().
Mentions: Finally, we reanalysed our data on protein folding stabilities computationally estimated for orthologous proteins in different prokaryotic genomes [12]. Unfolding and misfolding stabilities are negatively correlated, as predicted by our model (see Fig. 10). We found that most of the organisms evolving with mutation bias have proteins whose misfolding stability is lower than what could be expected based on their unfolding stability, see Fig. 11. This further supports the idea that these species are characterized by reduced effective population sizes.

Bottom Line: This result is robust with respect to the definition of the fitness function and to the protein structures studied.This provides a possible explanation to the observation that most species adopting obligatory intracellular lifestyles with a consequent reduction of effective population size shifted their mutation spectrum towards AT.To test these predictions we estimated the effective population sizes of bacterial species using the optimal codon usage coefficients computed by dos Reis et al. and the synonymous to non-synonymous substitution ratio computed by Daubin and Moran.

View Article: PubMed Central - PubMed

Affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.

ABSTRACT
Mutation bias in prokaryotes varies from extreme adenine and thymine (AT) in obligatory endosymbiotic or parasitic bacteria to extreme guanine and cytosine (GC), for instance in actinobacteria. GC mutation bias deeply influences the folding stability of proteins, making proteins on the average less hydrophobic and therefore less stable with respect to unfolding but also less susceptible to misfolding and aggregation. We study a model where proteins evolve subject to selection for folding stability under given mutation bias, population size, and neutrality. We find a non-neutral regime where, for any given population size, there is an optimal mutation bias that maximizes fitness. Interestingly, this optimal GC usage is small for small populations, large for intermediate populations and around 50% for large populations. This result is robust with respect to the definition of the fitness function and to the protein structures studied. Our model suggests that small populations evolving with small GC usage eventually accumulate a significant selective advantage over populations evolving without this bias. This provides a possible explanation to the observation that most species adopting obligatory intracellular lifestyles with a consequent reduction of effective population size shifted their mutation spectrum towards AT. The model also predicts that large GC usage is optimal for intermediate population size. To test these predictions we estimated the effective population sizes of bacterial species using the optimal codon usage coefficients computed by dos Reis et al. and the synonymous to non-synonymous substitution ratio computed by Daubin and Moran. We found that the population sizes estimated in these ways are significantly smaller for species with small and large GC usage compared to species with no bias, which supports our prediction.

Show MeSH