TY - JOUR T1 - The molecular basis of genetic interaction diversity in a metabolic pathway JF - bioRxiv DO - 10.1101/362327 SP - 362327 AU - Harry E. Kemble AU - Catherine Eisenhauer AU - Alejandro Couce AU - Audrey E. Chapron AU - Mélanie A. Magnan AU - Gregory Gautier AU - Hervé Le Nagard AU - Philippe Nghe AU - Olivier Tenaillon Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/07/04/362327.abstract N2 - Metabolic imbalances underlie a large spectrum of diseases, spanning congenital and chronic conditions and cancer1. Our ability to explain and predict such imbalances remains severely limited by the diversity of underlying mutation effects and their dependence on the genetic background and environment2–6, but it is unclear whether these complicating factors can be reduced to simple quantitative rules. Here, we characterise their interplay in determining cell physiology and fitness by systematically quantifying almost 4,000 interactions between expression variants of two genes from a classical sugar-utilisation pathway containing a toxic metabolite in the model bacterium, Escherichia coli, in different environments. We detect a remarkable variety of types and trends of intergenic interaction in this linear pathway, which cannot be reliably predicted from the effects of each variant in isolation, along with a dependence of this epistasis on the environment. Despite such apparent complexity, the fitness consequences of interactions between alleles and environment are explained by a mechanistic model accounting for catabolic flux and toxic metabolite concentration. Our findings reveal how, contrary to a common assumption7–13, the nature of fitness interactions is governed by more than just the topology of the molecular network underlying a selected trait. Our prospects of predicting disease and evolution will therefore improve by expanding our knowledge of the links among proteome, metabolome and physiology14. ER -