Network Properties of Genes Harboring Inherited Disease Mutations

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 11; pp. 4323 - 4328
• Main Authors: Feldman, Igor, Rzhetsky, Andrey, Vitkup, Dennis
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18-03-2008; National Acad Sciences
• Subjects: Biological Sciences; Cells; Connectivity; Disease models; Essential genes; Gene expression; Gene Expression Regulation - genetics; Gene Regulatory Networks; Genes; Genetic diseases; Genetic disorders; Genetic inheritance; Genetic mutation; Genetic Predisposition to Disease - genetics; Genotype & phenotype; Humans; Multigene Family; Mutation; Mutation - genetics; Nervous system diseases; Phenotype; Phenotypes; Probability; Social interaction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0701722105

By analyzing, in parallel, large literature-derived and high-throughput experimental datasets we investigate genes harboring human inherited disease mutations in the context of molecular interaction networks. Our results demonstrate that network properties influence the likelihood and phenotypic consequences of disease mutations. Genes with intermediate connectivities have the highest probability of harboring germ-line disease mutations, suggesting that disease genes tend to occupy an intermediate niche in terms of their physiological and cellular importance. Our analysis of tissue expression profiles supports this view. We show that disease mutations are less likely to occur in essential genes compared with all human genes. Disease genes display significant functional clustering in the analyzed molecular network. For about one-third of known disorders with two or more associated genes we find physical clusters of genes with the same phenotype. These clusters are likely to represent disorder-specific functional modules and suggest a framework for identifying yet-undiscovered disease genes.