Exploiting the pathway structure of metabolism to reveal high-order epistasis.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Imielinski
Marcin
M
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, USA. imielinski@chop.edu
Belta
Calin
C
D001483:Base Sequence; D018533:Biomass; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D016680:Genome, Bacterial / Q000502:physiology*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008957:Models, Genetic; D010641:Phenotype; D017384:Sequence Deletion / Q000502:physiology*; D049490:Systems Biology / Q000379:methods