Much recent work has explored molecular and population-genetic constraints on
the rate of protein sequence evolution. The best predictor of evolutionary rate
is expression level, for reasons which have remained unexplained. Here, we
hypothesize that selection to reduce the burden of protein misfolding will
favor protein sequences with increased robustness to translational missense
errors. Pressure for translational robustness increases with expression level
and constrains sequence evolution. Using several sequenced yeast genomes,
global expression and protein abundance data, and sets of paralogs traceable to
an ancient whole-genome duplication in yeast, we rule out several confounding
effects and show that expression level explains roughly half the variation in
Saccharomyces cerevisiae protein evolutionary rates. We examine causes for
expression's dominant role and find that genome-wide tests favor the
translational robustness explanation over existing hypotheses that invoke
constraints on function or translational efficiency. Our results suggest that
proteins evolve at rates largely unrelated to their functions, and can explain
why highly expressed proteins evolve slowly across the tree of life.Comment: 40 pages, 3 figures, with supporting informatio