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Title: Why diminishing-returns epistasis is so common
Plain: In many experiments a beneficial mutation helps less in a fitter genome, as if all mutations interact through one shared fitness value. Whether this pattern emerges generically from many hidden molecular interactions, and when, is not settled.
Precise: Global epistasis: the effect s of a mutation depends approximately linearly on background fitness F, $s \sim a - b F \text{ with } b > 0$, across many yeast and E. coli data sets. Determine the conditions on a microscopic genotype-to-fitness map (random additive plus pairwise interactions, nonlinear phenotype-to-fitness maps) under which this linear dependence holds for most mutations, and predict b from measurable quantities.
Settled by: A theory predicting the distribution of slopes b from independently measured interaction statistics, confirmed on combinatorial mutant data.
Kind: well-posed
Answer type: mechanism
References: (empty)
Literature status: partially-resolved
Status note: A 2021 model (Reddy and Desai) showed that many idiosyncratic interactions generically produce global epistasis; conditions and slope values remain open.
Posed since: (empty)