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

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.

Author: Marcin Imielinski and Calin Belta
Credits/Source: BMC Systems Biology 2008, 2:40

Published on: 2008-04-30

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