RT Journal Article SR Electronic T1 Emergence and Propagation of Epistasis in Metabolic Networks JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.05.24.113001 DO 10.1101/2020.05.24.113001 A1 Sergey Kryazhimskiy YR 2020 UL http://biorxiv.org/content/early/2020/05/26/2020.05.24.113001.abstract AB The effect of one mutation on a phenotype of interest often depends on other mutations in the genome. Genome-wide measurements of such genetic interactions (epistasis) are a widespread and powerful tool for probing functional relationships between genes. However, a rigorous theory for interpreting epistasis in terms of the underlying biological functions is lacking. A major challenge is that epistasis is usually measured at the level of a whole-organism phenotype, such as fitness, while it emerges at lower phenotypic levels, such as fluxes through metabolic pathways. Here, I develop an analytically tractable model for understanding how epistasis emerges and propagates in a hierarchical metabolic network. First, I show that negative and strong positive epistasis at a lower level of the hierarchy induce negative and strong positive epistasis at all higher levels, respectively. Remarkably, this property is dependent of the topology or kinetic parameters of the network. Second, negative or strong positive epistasis between mutations that affect individual reactions emerges when these reactions are in a strictly parallel or strictly serial topological relationship, respectively. Furthermore, the analysis of a computational model of glycolysis indicates that the emergence and propagation of epistasis in realistic metabolic networks may follow similar rules. These results provide a heretofore absent null expectation for interpreting empirical measurements of intergene epistasis. They also suggest that pairwise and higher-order epistasis should be extremely common and that epistasis coefficients measured for high-level phenotypes carry some albeit incomplete information about the underlying functional relationships between gene products.Competing Interest StatementThe authors have declared no competing interest.