Co-Variation Approaches to the Evolution of Protein Families

Abstract

In a multiple sequence alignment, sequence co-variations result from structural, functional, and/or phylogenetic constraints. Numerous methods have been developed to calculate co-variation scores, but few studies have compared these methods to identify which methods are best suited for the analysis of protein family divergence. Here, we give an overview of widely used methods and identify simple rules for selection of appropriate methods. Specifically, we found that methods such as OMES and ELSC-which favor pairs with intermediate entropy and covariation networks with hub structure-are well suited to reveal evolutionary information on family divergence. When applied to G protein-coupled receptors, these methods support an epistasis model of protein evolution in which, after a key mutation, co-evolution of several residues was necessary to restore and/or shift protein function.