Expression level, evolutionary rate, and the cost of expression.

There is great variation in the rates of sequence evolution among proteins encoded by the same genome. The strongest correlate of evolutionary rate is expression level: highly expressed proteins tend to evolve slowly. This observation has led to the proposal that a major determinant of protein evolutionary rate involves the toxic effects of protein that misfolds due to transcriptional and translational errors (the mistranslation-induced misfolding [MIM] hypothesis). Here, I present a model that explains the correlation of evolutionary rate and expression level by selection for function. The basis of this model is that selection keeps expression levels near optima that reflect a trade-off between beneficial effects of the protein's function and some nonspecific cost of expression (e.g., the biochemical cost of synthesizing protein). Simulations confirm the predictions of the model. Like the MIM hypothesis, this model predicts several other relationships that are observed empirically. Although the model is based on selection for protein function, it is consistent with findings that a protein's rate of evolution is at most weakly correlated with its importance for fitness as measured by gene knockout experiments.