Genomic signatures of asymmetric selection on membrane and cytoplasmic proteins.

Protein evolution is influenced by functional, structural, and ecological factors. Here, we propose that subcellular localization adds a critical but less understood dimension to evolutionary constraints. Specifically, we hypothesize that membrane proteins evolve under distinct pressures compared to cytoplasmic proteins, owing to the (a) association between co-translational folding and membrane integration and (b) roles at the interface with dynamic environments. Drawing from comparative genomics data of over 1,000 strains each of Escherichia coli and Saccharomyces cerevisiae, we present evidence suggesting that membrane proteins exhibit increased non-synonymous variation and reduced synonymous variation relative to cytoplasmic proteins. These patterns are stronger in E. coli, as compared to S. cerevisiae. Our data reveal systematic trends consistent with our hypothesis. We argue that recognizing localization-dependent selection could refine our understanding of evolutionary dynamics, inform molecular evolution models, and guide future synthetic and evolutionary studies.