TopoFun: a machine learning method to improve the functional similarity of gene co-expression modules

A comprehensive, accurate functional annotation of genes is key to systems-level approaches. As functionally related genes tend to be co-expressed, one possible approach to identify functional modules or supplement existing gene annotations is to analyse gene co-expression. We describe TopoFun, a machine learning method that combines topological and functional information to improve the functional similarity of gene co-expression modules. Using LASSO, we selected topological descriptors that discriminated modules made of functionally related genes and random modules. Using the selected topological descriptors, we performed linear discriminant analysis to construct a topological score that predicted the type of a module, random-like or functional-like. We combined the topological score with a functional similarity score in a fitness function that we used in a genetic algorithm to explore the co-expression network. To illustrate the use of TopoFun, we started from a subset of the Gene Ontology Biological Processes (GO-BPs) and showed that TopoFun efficiently retrieved genes that we omitted, and aggregated a number of novel genes to the initial GO-BP while improving module topology and functional similarity. Using an independent protein-protein interaction database, we confirmed that the novel genes gathered by TopoFun were functionally related to the original gene set.