Identifying gene function and module connections by the integration of multispecies expression compendia

The functions of many eukaryotic genes are still poorly understood. Here, 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, ene- odule ssociation etermination (G-MAD) allows the annotation of gene function. Second, odule- odule ssociation etermination (M-MAD) allows predicting connectivity among modules. We applied the GeneBridge tools to large-scale multispecies expression compendia-1700 data sets with over 300,000 samples from human, mouse, rat, fly, worm, and yeast-collected in this study. G-MAD identifies novel functions of genes-for example, in mitochondrial respiration and in T cell activation-and also suggests novel components for modules, such as for cholesterol biosynthesis. By applying G-MAD on data sets from respective tissues, tissue-specific functions of genes were identified-for instance, the roles of in liver and kidney, as well as in brain and liver. Using M-MAD, we identified a list of module-module associations, such as those between mitochondria and proteasome, mitochondria and histone demethylation, as well as ribosomes and lipid biosynthesis. The GeneBridge tools together with the expression compendia are available as an open resource, which will facilitate the identification of connections linking genes, modules, phenotypes, and diseases.