Dataset Information

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

ABSTRACT:

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.

Conclusion

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.

SUBMITTER: Imielinski M

PROVIDER: S-EPMC2390508 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Imielinski Marcin M Belta Calin C

BMC systems biology 20080430

<h4>Background</h4>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.<h4>Resu ...[more]

PMID: 18447928

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Project description:The phosphatidylinositol-4 kinase IIIβ (PI4KB)/oxysterol-binding protein (OSBP) family I pathway serves as an essential host pathway for the formation of viral replication complex for viral plus-strand RNA synthesis; however, poliovirus (PV) could evolve toward substantial independence from this host pathway with four mutations. Recessive epistasis of the two mutations (3A-R54W and 2B-F17L) is essential for viral RNA replication. Quantitative analysis of effects of the other two mutations (2B-Q20H and 2C-M187V) on each step of infection reveals functional couplings between viral replication, growth, and spread conferred by the 2B-Q20H mutation, while no enhancing effect was conferred by the 2C-M187V mutation. The effects of the 2B-Q20H mutation occur only via another recessive epistasis between the 3A-R54W/2B-F17L mutations. These mutations confer enhanced replication in PI4KB/OSBP-independent infection concomitantly with an increased ratio of viral plus-strand RNA to the minus-strand RNA. This work reveals the essential roles of the functional coupling and high-order, multi-tiered recessive epistasis in viral evolution toward independence from an obligatory host pathway. IMPORTANCE Each virus has a different strategy for its replication, which requires different host factors. Enterovirus, a model RNA virus, requires host factors PI4KB and OSBP, which form an obligatory functional axis to support viral replication. In an experimental evolution system in vitro, virus mutants that do not depend on these host factors could arise only with four mutations. The two mutations (3A-R54W and 2B-F17L) are required for the replication but are not sufficient to support efficient infection. Another mutation (2B-Q20H) is essential for efficient spread of the virus. The order of introduction of the mutations in the viral genome is essential (known as "epistasis"), and functional couplings of infection steps (i.e., viral replication, growth, and spread) have substantial roles to show the effects of the 2B-Q20H mutation. These observations would provide novel insights into an evolutionary pathway of the virus to require host factors for infection.

Dataset Information

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

Background

Results

Conclusion

Publications

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

Similar Datasets

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