Metabolic constraints modulate the likelihood and predictability of global epistasis

Epistasis, where a mutation’s effect depends on genetic background, is central to evolution. A striking pattern, global epistasis, results in fitness effects varying systematically with background fitness—often making beneficial mutations less effective in fitter genotypes. Despite its ubiquity and importance in predicting evolution, the cellular origin of this pattern is unclear. We present a microbial cell growth model and show that global epistasis arises naturally from the underlying metabolic structure, and is modulated by reaction speeds and flux redistribution in the cell. Mutations in standalone rate-limiting modules yield predictable fitness effects, while those in interconnected modules behave idiosyncratically. As genetic divergence increases, background fitness becomes a poorer predictor of fitness effects. Our framework links cellular metabolism to adaptation, offering mechanistic insights into evolutionary predictability.