Three independent determinants of protein evolutionary rate

One of the most widely accepted ideas related to the evolutionary rates of proteins is that functionally important residues or regions evolve slower than other regions, a reasonable outcome of which should be a slower evolutionary rate of the proteins with a higher density of functionally important sites. Oddly, the role of functional importance, mainly measured by essentiality, in determining evolutionary rate has been challenged in recent studies. Several variables other than protein essentiality, such as expression level, gene compactness, protein-protein interactions, etc., have been suggested to affect protein evolutionary rate. In the present review, we try to refine the concept of functional importance of a gene, and consider three factors-functional importance, expression level, and gene compactness, as independent determinants of evolutionary rate of a protein, based not only on their known correlation with evolutionary rate but also on a reasonable mechanistic model. We suggest a framework based on these mechanistic models to correctly interpret the correlations between evolutionary rates and the various variables as well as the interrelationships among the variables.