Identifying gene function and module connections by the integration of multi-species expression compendia

The functions of many eukaryotic genes are still poorly understood. We developed and validated a new method, termed GeneBridge, which is based on two linked approaches to impute gene function and bridge genes with biological processes. First, G ene- M odule A ssociation D etermination (G-MAD) allows the annotation of gene function. Second, M odule- M odule A ssociation D etermination (M-MAD) allows predicting connectivity among modules. We applied the GeneBridge tools to large-scale multi-species expression compendia—1,700 datasets with over 300,000 samples from human, mouse, rat, fly, worm, and yeast—collected in this study. Unlike most existing bioinformatics tools, GeneBridge exploits both positive and negative gene/module-module associations. We constructed association networks, such as those bridging mitochondria and proteasome, mitochondria and histone demethylation, as well as ribosomes and lipid biosynthesis. The GeneBridge tools together with the expression compendia are available at systems-genetics.org , to facilitate the identification of connections linking genes, modules, phenotypes, and diseases.