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

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.

Amino Acid Usage Is Asymmetrically Biased in AT- and GC-Rich Microbial Genomes

“…This asymmetry between genomic %AT and protein evolution has been noted before; indeed hydrophobicity values linked to the secondary structures of proteins correlate with GC content [25], [32]. Moreover, proteins of GC-rich bacteria have been found to be less susceptible to misfolding, but more prone to unfolding [27]. AT content was also found to be linked with population size in the sense that AT-rich bacteria were living in small population sizes while GC-rich bacteria were usually of intermediary population size [33].…”

“…With respect to base content, we see from Figure 5 that AAUB differs between AT- and GC-rich genomes. This means that the strongest bias in amino acid usage is found in species with low AT content, which is supported by numerous studies [24]–[27]. There are now many indications that mutations in prokaryotes are generally AT-biased, meaning that in absence of selective pressure prokaryotic genomes (and possible eukaryotes) become more AT-rich [5].…”

Merging molecular mechanism and evolution: theory and computation at the interface of biophysics and evolutionary population genetics

“…In bacteria, species that are endosymbiotic have lower effective population sizes compared to the free-living counterparts. Mendez and co-workers argued that the bias towards higher AT (adenine and thymine) content among obligate endosymbiotic bacteria could be the response against less effective purifying selection against protein misfolding [48]. These bioinformatic studies strongly support the coupling between biophysical properties and evolutionary population variables, but a systematic survey of biophysical properties of proteins (such as folding stability) in genomes should be an exciting subject of future experimental work.…”

Gravitational Effects on Human Physiology

“…In addition, assembly chaperones have a pivotal role in all adaptive responses to environmental and ecological stresses that can shape species evolution. For example, the potential impact of the cellular chaperone complement on the preservation and evolution of the species by the moderation of genetic mutation (Mendez et al 2010;Bandyopadhyay et al 2012;Bogumil and Dagan 2012;Gros and Tenaillon 2009) is now emerging. Consequently, chaperones are at the forefront of adaptive responses of microbial (Tsai et al 2010;Ladner et al 2012;Li et al 2012), plant (Iki et al 2010;Ladner et al 2012;Brígido and Oliveira 2012;Goyal et al 2012) and animal (Stecyk et al 2012) life to different environments.…”