Nature Genetics 38, 896 - 903 (2006)
Published online: 16 July 2006; | doi:10.1038/ng1844
Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathwaysBen Lehner1, 2, Catriona Crombie1, Julia Tischler1, Angelo Fortunato1, 2 & Andrew G Fraser11
The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. 2
Present addresses: CRG-EMBL Systems Biology Program, Center for Genomic Regulation, Barcelona, Spain (B.L.); Molecular Medicine, Department of Neuroscience, University of Siena, Via A. Moro 5, 53100 Siena, Italy (A.F.).
Correspondence should be addressed to Andrew G Fraser agf@sanger.ac.uk Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elegans to systematically test  65,000 pairs of genes for their ability to interact genetically. We identify 350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.
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