Fig. 2: The environment modulates the strength and shape of global epistasis.

a We analyzed how an environmental perturbation (in the form of a pyrimethamine concentration gradient) affects the global epistasis patterns observed in our four-mutation landscape. b As an example, we show that increasing drug dose alters the global epistasis pattern for mutation C59R, going from diminishing returns to increasing returns. c Drug concentration affects epistasis differently for each mutation, which can be thought of as mutations following different paths in our “epistasis map''. Arrows follow the direction of change as drug dose increases from 0 to 10³ μM. d–f The strength of epistasis (variance ratio var Δf/var f(B)), the degree to which epistasis is global (R²) and the shape of global epistasis (slope of the regression between Δf and f(B)) are modulated differently for each mutation.