Mutation Edgotype Drives Fitness Effect in Human

Missense mutations are known to perturb protein-protein interaction networks (known as interactome networks) in different ways. However, it remains unknown how different interactome perturbation patterns (“edgotypes”) impact organismal fitness. Here, we estimate the fitness effect of missense mutations with different interactome perturbation patterns in human, by calculating the fractions of neutral and deleterious mutations that do not disrupt PPIs (“quasi-wild-type”), or disrupt PPIs either by disrupting the binding interface (“edgetic”) or by disrupting overall protein stability (“quasi-null”). We first map pathogenic mutations and common non-pathogenic mutations onto homology-based three-dimensional structural models of proteins and protein-protein interactions in human. Next, we perform structure-based calculations to classify each mutation as either quasi-wild-type, edgetic, or quasi-null. Using our predicted as well as experimentally determined interactome perturbation patterns, we estimate that >∼40% of quasi-wild-type mutations are effectively neutral and the remaining are mostly mildly deleterious, that >∼75% of edgetic mutations are only mildly deleterious, and that up to ∼75% of quasi-null mutations may be strongly detrimental. These estimates are the first such estimates of fitness effect for different network perturbation patterns in any interactome. Our results suggest that while mutations that do not disrupt the interactome tend to be effectively neutral, the majority of human PPIs are under strong purifying selection and the stability of most human proteins is essential to human life.