Why highly expressed proteins evolve slowly

Abstract

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 that 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.

Fig. 1.

Expression level governs gene and paralog evolutionary rates in S. cerevisiae. (a) Highly expressed proteins evolve more slowly, and paralogs mirror the genome-wide pattern. Evolutionary rates measured relative to S. bayanus for 4,255 S. cerevisiae genes (gray squares) and 580 paralogous genes (black squares) correlate with expression levels. Lines show best log-log linear fit. For all genes (dashed line), r² = 0.28, P ≪ 10^-9; for paralogs (solid line), r² = 0.31, P ≪ 10^-9. (b) Within a paralog pair, the ratio of expression levels correlates with the ratio of evolutionary rates (r² = 0.29, P ≪ 10^-9), as predicted from the log-log linear relationship in a. Each pair generates two ratio points, making the plot symmetrical. (c) Relative expression level determines relative evolutionary rate. The percentage of pairs in which the higher-expressed paralog evolves slower are shown as a function of minimum paralog pair expression ratio (black squares). Point areas are proportional to the number of included pairs.

Fig. 2.

Phylogenetic relationships between analyzed yeast species. Relationships follow ref. , branch lengths indicate nucleotide substitution distances from ref. , and the indicated time of the WGD follows ref. .

Fig. 3.

Translational selection against the cost of misfolded proteins can act at two distinct points. mRNA (left) may be translated without errors to produce a folded protein (top); if an error is made, the resulting protein may still fold properly, or may misfold and undergo degradation (right). Selection can act at A to increase the proportion of error-free proteins through codon preference (translational accuracy), and also at B to increase the proportion of proteins that fold despite errors (translational robustness). We neglect misfolding of error-free proteins (see text).