Inference of epistatic effects in a key mitochondrial protein

We use Potts model inference to predict pair epistatic effects in a key mitochondrial protein -- cytochrome c oxidase subunit 2 -- for ray--finned fishes. We examine the effect of phylogenetic correlations on our predictions using a simple exact fitness model, and we find that, although epistatic effects are under--predicted, they maintain a roughly linear relationship to their true (model) values. After accounting for these corrections, epistatic effects in the protein are still relatively weak, leading to fitness valleys of depth 2Ns ≈ -5 in compensatory double mutants. Positive epistasis is more pronounced than negative epistasis, and the strongest positive effects capture nearly all sites subject to positive selection in fishes, similar to virus proteins evolving under selection pressure in the context of drug therapy.