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Higher-order epistasis creates idiosyncrasy, confounding predictions in protein evolution”
Higher-order epistasis creates idiosyncrasy, confounding predictions in protein evolution
Karol Buda, Charlotte M. Miton, and Nobuhiko Tokuriki
September 8, 2022
Epistasis shapes evolutionary outcomes during protein adaptation. In particular, when the effects of single mutations or mutational interactions are idiosyncratic, that is, unique to a genetic background, the predictability of protein evolution becomes greatly impaired. Here, we unveil a quantitative picture of the prevalence and role of idiosyncrasy in protein evolution by analysing 45 protein fitness landscapes, generated from seven enzymes. We found that mutational effects and epistasis are highly idiosyncratic across the landscapes. Idiosyncrasy obscured functional predictions of mutated proteins when using limited mutational data, and often continued to impair prediction upon incorporation of epistatic information. We show that idiosyncrasy stems from higher-order epistasis, and highlight examples where it permits, or restricts, evolutionary accessibility of certain genotypes. Our work suggests that idiosyncrasy deeply confounds predictions in protein evolution necessitating its incorporation into predictive models and in-depth exploration of its underlying molecular mechanisms.
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Epistasis, a phenomenon where mutations interact rather than behaving independently, has long been of interest to biologists. In the molecular context, it describes a situation where the whole is different than the sum of its parts - that is, when the fitness effect of a set of mutations is not …
the PREreview by Christian Macdonald et al.