Sequencing of the protein coding genome has revealed many different missense mutations of human proteins and different population frequencies of corresponding haplotypes, which consist of different sets of those mutations. Here, we present evidence for pairwise intramolecular epistasis (i.e., nonadditive interactions) between many such mutations through an analysis of protein dynamics. We suggest that functional compensation for conserving protein dynamics is a likely evolutionary mechanism that maintains high-frequency mutations that are individually nonneutral but epistatically compensating within proteins. This analysis is the first of its type to look at human proteins with specific high population frequency mutations and examine the relationship between mutations that make up that observed high-frequency protein haplotype. Importantly, protein dynamics revealed a separation between high and low frequency haplotypes within a target protein cytochrome P450 2A7, with the high-frequency haplotypes showing behavior closer to the wild-type protein. Common protein haplotypes containing two mutations display dynamic compensation in which one mutation can correct for the dynamic effects of the other. We also utilize a dynamics-based metric, EpiScore, that evaluates the epistatic interactions and allows us to see dynamic compensation within many other proteins.
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