Evolutionary Rate at the Protein Domain Level is Constrained by Importance to Network Dynamics

A fundamental question for evolutionary biology is why different proteins evolve at dramatically different rates. As the evolutionary time between two species and their common ancestor increases they accumulate a proportional number of amino acid changes between homologous proteins, but this proportional increase is not the same for all proteins. This difference in rate is attributed to the action of natural selection. While intuition suggests that natural selection acts most strongly to preserve and improve the function of proteins, little evidence supports this idea. Instead, the strongest predictor of protein evolutionary rate found to date is protein expression level, suggesting that selection acts primarily to prevent protein mis-folding. Here we suggest this apparent contradiction arises because the methods used to measure protein functional importance are ill-suited to capture the subtle interplay between protein structure and function. We introduce a measure of functional importance called Dynamical Influence, leveraging computational models of cellular systems for a much finer view of the functional importance of a protein in its network context. Comparing this measure with protein evolutionary rates across the vertebrate evolutionary tree we find strong evidence that selection operates to preserve and refine protein function to a much greater extent than previously observed