Why highly expressed proteins evolve slowly.

By D. A. Drummond, Jesse D. Bloom, Christoph Adami, Claus O. Wilke, Frances H. Arnold. Proceedings of the National Academy of Sciences of the United States of America, 2005

805 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a9f0200d2decaf4a74007d3e0d984e455946d57f

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Citations in the corpus

Outlook for cellulase improvement: screening and selection strategies. (2006, background): “Furthermore, if amylases already have a little higher specific activity than cellulases, less expression of amylase for utilizing substrates could result in a higher evolution rate than cellulases because of different expression levels (Drummond et al., 2005).”
Origin and evolution of the genetic code: the universal enigma (2008, background): “Indeed, recent theoretical and empirical studies on correlations between gene sequence evolution and expression strongly suggest that minimization of the production of potentially toxic misfolded proteins is a crucial factor of evolution (Drummond et al. 2005; Drummond, Raval, and Wilke 2006; Wilke ”
The Patterns and Causes of Variation in Plant Nucleotide Substitution Rates (2011, background): “The third explanation is that there is selection for robustness against mistranslation (Drummond et al. 2005).”
Latent Effects of Hsp90 Mutants Revealed at Reduced Expression Levels (2013, neutral): “protein properties are interdependent [7,8].”
Evolutionary and Physiological Importance of Hub Proteins (2006, neutral): “by far the strongest predictor of rates of evolution [17,18].”
PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life (2012, background): “…largely by its function— has a surprisingly large impact on its evolutionary trajectory, controlling the extent of purifying selection on its amino acid sequence (22), its codon usage (23), translation regime (24), folding accuracy (25, 26), and its genomic organization (27, 28), among others.”
Stability effects of mutations and protein evolvability. (2009, background): “Phenotypic mutations may account for the slower rates of evolution in proteins expressed at high levels [46], and the selection against the toxicity of mis-folded proteins generated by translational errors seems to be a major force, especially in neuronal tissues.”
Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line (2010, background): “Correct protein folding is a major determinant of expression levels (Drummond et al, 2005), and the ability to fold fast and correctly may decrease with sequence length, rendering the inverse correlation plausible.”