A gene-phenotype network for the laboratory mouse and its implications for systematic phenotyping.

Abstract

The laboratory mouse is the pre-eminent model organism for the dissection of human disease pathways. With the advent of a comprehensive panel of gene knockouts, projects to characterise the phenotypes of all knockout lines are being initiated. The range of genotype-phenotype associations can be represented using the Mammalian Phenotype ontology. Using publicly available data annotated with this ontology we have constructed gene and phenotype networks representing these associations. These networks show a scale-free, hierarchical and modular character and community structure. They also exhibit enrichment for gene coexpression, protein-protein interactions and Gene Ontology annotation similarity. Close association between gene communities and some high-level ontology terms suggests that systematic phenotyping can provide a direct insight into underlying pathways. However some phenotypes are distributed more diffusely across gene networks, likely reflecting the pleiotropic roles of many genes. Phenotype communities show a many-to-many relationship to human disease communities, but stronger overlap at more granular levels of description. This may suggest that systematic phenotyping projects should aim for high granularity annotations to maximise their relevance to human disease.