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Prevalent positive epistasis in Escherichia coli and Saccharomyces cerevisiae metabolic networks.

He X, Qian W, Wang Z, Li Y, Zhang J - Nat. Genet. (2010)

Bottom Line: Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks, the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear.We found that negative epistasis occurs mainly between nonessential reactions with overlapping functions, whereas positive epistasis usually involves essential reactions, is highly abundant and, unexpectedly, often occurs between reactions without overlapping functions.We offer mechanistic explanations of these findings and experimentally validate them for 61 S. cerevisiae gene pairs.

View Article: PubMed Central - PubMed

Affiliation: Department of Ecology and Evolutionary Biology, Ann Arbor, Michigan, USA.

ABSTRACT
Epistasis refers to the interaction between genes. Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks, the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear. We have addressed this question through in silico mapping of positive and negative epistatic interactions amongst biochemical reactions within the metabolic networks of Escherichia coli and Saccharomyces cerevisiae using flux balance analysis. We found that negative epistasis occurs mainly between nonessential reactions with overlapping functions, whereas positive epistasis usually involves essential reactions, is highly abundant and, unexpectedly, often occurs between reactions without overlapping functions. We offer mechanistic explanations of these findings and experimentally validate them for 61 S. cerevisiae gene pairs.

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Functions of E. coli metabolic reactions under the glucose minimal medium. (a) Functions of 255 important reactions in producing 49 biomass constituents. Columns represent reactions and rows represent biomass constituents. (b) Distribution of the number of biomass constituents affected by a reaction.
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Figure 1: Functions of E. coli metabolic reactions under the glucose minimal medium. (a) Functions of 255 important reactions in producing 49 biomass constituents. Columns represent reactions and rows represent biomass constituents. (b) Distribution of the number of biomass constituents affected by a reaction.

Mentions: To examine whether metabolic reactions with epistatic relationships are functionally associated, we need to identify the function of each reaction in generating the E. coli biomass, which is composed of 49 constituents. If a reaction is important for producing a set of biomass constituents, the removal of these constituents from the biomass function will recover the biomass reduction caused by the deletion of the reaction. Based on this idea, we designed a removal-recovery method to determine the functions of 255 of the 270 important reactions in generating biomass constituents (Fig. 1a). For the remaining 15 reactions, the functions cannot be unambiguously determined and thus they are excluded from our analysis. The majority of the 255 reactions each contribute to only one biomass constituent, whereas a small number of reactions affect many or even all 49 constituents (Fig. 1b). Note that the glucose minimal medium is again used in determining the function of each reaction, because some reactions have variable functions in different media. Functional assignment by our method is generally consistent with the conventional functional annotation of E. coli reactions24, but our assignment is expected to be more precise in identifying the biomass constituents contributed by each reaction.


Prevalent positive epistasis in Escherichia coli and Saccharomyces cerevisiae metabolic networks.

He X, Qian W, Wang Z, Li Y, Zhang J - Nat. Genet. (2010)

Functions of E. coli metabolic reactions under the glucose minimal medium. (a) Functions of 255 important reactions in producing 49 biomass constituents. Columns represent reactions and rows represent biomass constituents. (b) Distribution of the number of biomass constituents affected by a reaction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837480&req=5

Figure 1: Functions of E. coli metabolic reactions under the glucose minimal medium. (a) Functions of 255 important reactions in producing 49 biomass constituents. Columns represent reactions and rows represent biomass constituents. (b) Distribution of the number of biomass constituents affected by a reaction.
Mentions: To examine whether metabolic reactions with epistatic relationships are functionally associated, we need to identify the function of each reaction in generating the E. coli biomass, which is composed of 49 constituents. If a reaction is important for producing a set of biomass constituents, the removal of these constituents from the biomass function will recover the biomass reduction caused by the deletion of the reaction. Based on this idea, we designed a removal-recovery method to determine the functions of 255 of the 270 important reactions in generating biomass constituents (Fig. 1a). For the remaining 15 reactions, the functions cannot be unambiguously determined and thus they are excluded from our analysis. The majority of the 255 reactions each contribute to only one biomass constituent, whereas a small number of reactions affect many or even all 49 constituents (Fig. 1b). Note that the glucose minimal medium is again used in determining the function of each reaction, because some reactions have variable functions in different media. Functional assignment by our method is generally consistent with the conventional functional annotation of E. coli reactions24, but our assignment is expected to be more precise in identifying the biomass constituents contributed by each reaction.

Bottom Line: Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks, the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear.We found that negative epistasis occurs mainly between nonessential reactions with overlapping functions, whereas positive epistasis usually involves essential reactions, is highly abundant and, unexpectedly, often occurs between reactions without overlapping functions.We offer mechanistic explanations of these findings and experimentally validate them for 61 S. cerevisiae gene pairs.

View Article: PubMed Central - PubMed

Affiliation: Department of Ecology and Evolutionary Biology, Ann Arbor, Michigan, USA.

ABSTRACT
Epistasis refers to the interaction between genes. Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks, the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear. We have addressed this question through in silico mapping of positive and negative epistatic interactions amongst biochemical reactions within the metabolic networks of Escherichia coli and Saccharomyces cerevisiae using flux balance analysis. We found that negative epistasis occurs mainly between nonessential reactions with overlapping functions, whereas positive epistasis usually involves essential reactions, is highly abundant and, unexpectedly, often occurs between reactions without overlapping functions. We offer mechanistic explanations of these findings and experimentally validate them for 61 S. cerevisiae gene pairs.

Show MeSH
Related in: MedlinePlus