Abstract
Epistasis or the non-additivity of mutational effects is a major force in protein evolution, but it has not been systematically quantified at the level of a proteome. Here, we estimated the extent of epistasis for 2,382 genes in E. coli using several hundreds of orthologs for each gene within the class Gammaproteobacteria. We found that the average epistasis is ~41% across genes in the proteome and that epistasis is stronger among highly expressed genes. This trend is quantitatively explained by the prevailing model of sequence evolution based on minimizing the fitness cost of protein unfolding and aggregation. The genes with the highest epistasis are also functionally involved in the maintenance of proteostasis, translation and central metabolism. In contrast, genes evolving with low epistasis mainly encode for membrane proteins and are involved in transport activity. Our results highlight the coupling between selection and epistasis in the long-term evolution of a proteome.
Highlights
Resolving the link between genotype and phenotype or the fitness landscape is a central goal in molecular biology and evolution
To determine if epistasis is experienced by all genes in a proteome we estimated epistasis in the evolution of 2,382 genes in E. coli using thousands of orthologs within the class gammaproteobacteria
A protein in E. coli evolves with ~41% epistasis. One interpretation of this result is that the rate of protein evolution is reduced by 41% due to background dependence of mutational effects
Summary
Resolving the link between genotype and phenotype or the fitness landscape is a central goal in molecular biology and evolution. To estimate the epistasis experienced by genes in long-term evolution, one approach is to compare two rates of amino acid substitutions[6] These two rates are the average pairwise substitution rate RdN/dS, which is background-dependent, and the rate of mutational usage Ru, which is background independent. The presence of epistasis implies that genetic background further screens substitutions, the background dependent RdN/dS is slower than the background independent Ru. The expression for epistasis (Eq 1) estimates how much epistasis or the background specificity of mutational effects slows down the rate of protein evolution. Kondrashov and coworkers[6] applied this method to estimate epistasis in the long-term evolution of 16 mammalian proteins and found epistasis to vary from ~40% to ~80% This slowing down of evolutionary rates can arise from the heterogeneity of fitness effects of mutations[8]
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