Mutation Bias Favors Protein Folding Stability in the Evolution of Small Populations

• Published in: PLoS computational biology Vol. 6; no. 5; p. e1000767
• Main Authors: Mendez, Raul, Fritsche, Miriam, Porto, Markus, Bastolla, Ugo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2010; Public Library of Science (PLoS)
• Subjects: Analysis; Bacteria; Bacteria - genetics; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Base Composition; Biophysics/Protein Folding; Codon; Computational Biology/Evolutionary Modeling; Computer Simulation; Evolution; Evolution, Molecular; Evolutionary Biology/Evolutionary and Comparative Genetics; Genetic aspects; Genetic Fitness; Models, Genetic; Molecular Biology/Molecular Evolution; Mutation; Mutation (Biology); Physiological aspects; Population; Prokaryotes; Protein Folding; Protein Stability; Proteins; Proteins - chemistry; Proteins - genetics; Species Specificity; Studies; Germany; Proteins; Genetic Fitness; Species Specificity; Base Composition; Computer Simulation; Bacteria; Models, Genetic; Mutation; Protein Stability; Protein Folding; Bacterial Proteins; Evolution, Molecular
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1000767

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.