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Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways

Abstract

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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Acknowledgements

We thank the C. elegans Genetics Center for providing strains and E. Marcotte, D. Stemple, I. Barroso and T. Vavouri for comments on the manuscript. B.L. is supported by a Sanger Institute Postdoctoral Fellowship. C.C., J.T., A.F. and A.G.F. are supported by the Wellcome Trust.

Author information

B.L. and A.G.F. designed the experiments. B.L., C.C., J.T., A.F. and A.G.F. performed the experiments. B.L. and A.G.F. analyzed the data and wrote the paper.

Note: Supplementary information is available on the Nature Genetics website..

Competing interests

The authors declare no competing financial interests.

Correspondence to Andrew G Fraser.

Supplementary information

Supplementary Table 1

Tab-delimited list of the library RNAi bacterial feeding clones screened in each strain. (XLS 249 kb)

Supplementary Table 2

Tab-delimited list of identified synthetic genetic enhancer interactions. (XLS 62 kb)

Supplementary Table 3

Identification of EGF pathway genes and genes previously shown to interact genetically with EGF pathway components. (PDF 44 kb)

Supplementary Table 4

Genes that interact with two or more components of the EGF pathway. (PDF 60 kb)

Supplementary Table 5

Interactions of additional genes with the top six hub genes. (PDF 54 kb)

Supplementary Table 6

Known functions of the fly and mammalian orthologs of the six most highly connected hub genes in the genetic interaction network. (PDF 75 kb)

Supplementary Methods (PDF 58 kb)

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Further reading

Figure 1: Identifying genetic enhancer interactions by RNAi.
Figure 2: A genetic interaction network for EGF signaling.
Figure 3: Highly connected genetic buffers encode components of chromatin-modifying complexes.
Figure 4: Hub genes genetically buffer postembryonic phenotypes.
Figure 5: Hub genes and genetic disease in humans.