Exploiting the pathway structure of metabolism to reveal high-order epistasis
1 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, USA
2 MD/PhD Program, University of Pennsylvania School of Medicine, Philadelphia, USA
3 Bioinformatics Graduate Program, Boston University, Brookline, USA
BMC Systems Biology 2008, 2:40 doi:10.1186/1752-0509-2-40Published: 30 April 2008
Biological robustness results from redundant pathways that achieve an essential objective, e.g. the production of biomass. As a consequence, the biological roles of many genes can only be revealed through multiple knockouts that identify a set of genes as essential for a given function. The identification of such "epistatic" essential relationships between network components is critical for the understanding and eventual manipulation of robust systems-level phenotypes.
We introduce and apply a network-based approach for genome-scale metabolic knockout design. We apply this method to uncover over 11,000 minimal knockouts for biomass production in an in silico genome-scale model of E. coli. A large majority of these "essential sets" contain 5 or more reactions, and thus represent complex epistatic relationships between components of the E. coli metabolic network.
The complex minimal biomass knockouts discovered with our approach illuminate robust essential systems-level roles for reactions in the E. coli metabolic network. Unlike previous approaches, our method yields results regarding high-order epistatic relationships and is applicable at the genome-scale.