Discovering missing reactions of metabolic networks by using gene co-expression data

Flux coupling analysis is a computational method which is able to explain co-expression of metabolic genes by analyzing the topological structure of a metabolic network. It has been suggested that if genes in two seemingly fully-coupled reactions are not highly co-expressed, then these two reactions are not fully coupled in reality, and hence, there is a gap or missing reaction in the network. Here, we present GAUGE as a novel approach for gap filling of metabolic networks, which is a two-step algorithm based on a mixed integer linear programming formulation. In GAUGE, the discrepancies between experimental co-expression data and predicted flux coupling relations is minimized by adding a minimum number of reactions to the network. We show that GAUGE is able to predict missing reactions of E. coli metabolism that are not detectable by other popular gap filling approaches. We propose that our algorithm may be used as a complementary strategy for the gap filling problem of metabolic networks. Since GAUGE relies only on gene expression data, it can be potentially useful for exploring missing reactions in the metabolism of non-model organisms, which are often poorly characterized, cannot grow in the laboratory, and lack genetic tools for generating knockouts.