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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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Mean unfolding stability  versus misfolding stability  for neutrality exponent  (non-neutral regime).The sets of points joined with solid lines correspond to constant GC usage, between  (largest ) and  (largest ).  grows and  decreases with . The sets of points joined with dashed lines correspond to constant population size , from  (smallest stability) to  (largest stability). Both stability variables  increase with . Data points are superimposed to a heat map of the fitness function, showing that fitness increases with . However, constant  lines do not correspond to constant fitness, but there are small variations, from which the optimal GC usage is derived. The solid white line shows  at which the selective pressures on  and  balance. One can see that, at large ,  is smaller than  for all , so that the selective pressure is stronger on the former.
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pcbi-1000767-g002: Mean unfolding stability versus misfolding stability for neutrality exponent (non-neutral regime).The sets of points joined with solid lines correspond to constant GC usage, between (largest ) and (largest ). grows and decreases with . The sets of points joined with dashed lines correspond to constant population size , from (smallest stability) to (largest stability). Both stability variables increase with . Data points are superimposed to a heat map of the fitness function, showing that fitness increases with . However, constant lines do not correspond to constant fitness, but there are small variations, from which the optimal GC usage is derived. The solid white line shows at which the selective pressures on and balance. One can see that, at large , is smaller than for all , so that the selective pressure is stronger on the former.

Mentions: All simulations presented here are based on the native structure of some natural protein. When not otherwise stated, we exemplify our numerical results using the protein lysozyme, PDB id. 31zt. In all cases, the starting sequence is the sequence in the PDB. Results are collected after fitness has converged to its stationary value, discarding the first accepted substitutions, which are enough for equilibration, as it can be seen in Fig. 2 in the Text S1.


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

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

Mean unfolding stability  versus misfolding stability  for neutrality exponent  (non-neutral regime).The sets of points joined with solid lines correspond to constant GC usage, between  (largest ) and  (largest ).  grows and  decreases with . The sets of points joined with dashed lines correspond to constant population size , from  (smallest stability) to  (largest stability). Both stability variables  increase with . Data points are superimposed to a heat map of the fitness function, showing that fitness increases with . However, constant  lines do not correspond to constant fitness, but there are small variations, from which the optimal GC usage is derived. The solid white line shows  at which the selective pressures on  and  balance. One can see that, at large ,  is smaller than  for all , so that the selective pressure is stronger on the former.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000767-g002: Mean unfolding stability versus misfolding stability for neutrality exponent (non-neutral regime).The sets of points joined with solid lines correspond to constant GC usage, between (largest ) and (largest ). grows and decreases with . The sets of points joined with dashed lines correspond to constant population size , from (smallest stability) to (largest stability). Both stability variables increase with . Data points are superimposed to a heat map of the fitness function, showing that fitness increases with . However, constant lines do not correspond to constant fitness, but there are small variations, from which the optimal GC usage is derived. The solid white line shows at which the selective pressures on and balance. One can see that, at large , is smaller than for all , so that the selective pressure is stronger on the former.
Mentions: All simulations presented here are based on the native structure of some natural protein. When not otherwise stated, we exemplify our numerical results using the protein lysozyme, PDB id. 31zt. In all cases, the starting sequence is the sequence in the PDB. Results are collected after fitness has converged to its stationary value, discarding the first accepted substitutions, which are enough for equilibration, as it can be seen in Fig. 2 in the Text S1.

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
Related in: MedlinePlus