PhenoGeneRanker: A Tool for Gene Prioritization Using Complete Multiplex Heterogeneous Networks

Uncovering genotype-phenotype relationships is a fundamental challenge in genomics. Gene prioritization is an important step for this endeavor to make a short manageable list from a list of thousands of genes coming from high-throughput studies. Network propagation methods are promising and state of the art methods for gene prioritization based on the premise that functionally-related genes tend to be close to each other in the biological networks. In this study, we present PhenoGeneRanker, an improved version of a recently developed network propagation method called Random Walk with Restart on Multiplex Heterogeneous Networks (RWR-MH). PhenoGeneRanker allows multi-layer gene and disease networks. It also calculates empirical p-values of gene ranking using random stratified sampling of genes based on their connectivity degree in the network. We ran PhenoGeneRanker using multi-omics datasets of rice to effectively prioritize the cold tolerance-related genes. We observed that top genes selected by PhenoGeneRanker were enriched in cold tolerance-related Gene Ontology (GO) terms whereas bottom ranked genes were enriched in general GO terms only. We also observed that top-ranked genes exhibited significant p-values suggesting that their rankings were independent of their degree in the network.