Highly expressed and slowly evolving proteins share compositional properties with thermophilic proteins

Abstract

The sequences of proteins encoded by a genome evolve at different rates. A correlate of a protein's evolutionary rate is its expression level: highly expressed proteins tend to evolve slowly. Some explanations of rate variation and the correlation between rate and expression predict that more slowly evolving and more highly expressed proteins have more favorable equilibrium constants for folding. Proteins from thermophiles generally have more stable folds than proteins from mesophiles, and it is known that there are systematic differences in amino acid content between thermophilic and mesophilic proteins. I examined whether there are analogous correlations of amino acid frequencies with evolutionary rate and expression level within genomes. In most of the organisms analyzed, there is a striking tendency for more slowly evolving proteins to be more thermophile-like in their amino acid compositions when adjustments are made for variation in GC content. More highly expressed proteins also tend to be more thermophile-like by the same criteria. These results suggest that part of the evolutionary rate variation among proteins is due to variation in the strength of selection for stability of the folded state. They also suggest that increasing strength of this selective force with expression level plays a role in the correlation between evolutionary rate and expression level.

FIG. 1.

The relationship between amino acid frequency and evolutionary rate among human proteins. The curve for each amino acid conveys how its frequency varies with protein sequence distance when GC content is taken into account. Each curve was produced by smoothing the data with a Gaussian kernel with an SD of 1/ln(10). The raw data points were the residuals of cubic polynomial fits of amino acid frequencies and the logarithm (base 10) of sequence distance to GC fraction. (A) Amino acids that are overrepresented in thermophiles. (B) Amino acids that are underrepresented in thermophiles. (C) Other amino acids.

FIG. 2.

Summary of correlation results for dN across organisms. For each correlation, “+” indicates a statistically significant (P < 0.05) positive correlation, “−” indicates a significant negative correlation, and “ns” indicates that the correlation was not statistically significant. Negative correlations, which are predicted for amino acids more common are thermophiles, are also indicated by orange coloring, and positive correlations are indicated by blue coloring.