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

Nature Genetics volume 38, pages 896–903 (2006)Cite this article

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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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.

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References

  1. Badano, J.L. & Katsanis, N. Beyond Mendel: an evolving view of human genetic disease transmission. Nat. Rev. Genet. 3, 779–789 (2002).

    Article  CAS  Google Scholar 

  2. Fearon, E.R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  Google Scholar 

  3. Hartman, J.L.t., Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001).

    Article  CAS  Google Scholar 

  4. Tong, A.H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364–2368 (2001).

    Article  CAS  Google Scholar 

  5. Tong, A.H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808–813 (2004).

    Article  CAS  Google Scholar 

  6. Davierwala, A.P. et al. The synthetic genetic interaction spectrum of essential genes. Nat. Genet. 37, 1147–1152 (2005).

    Article  CAS  Google Scholar 

  7. van Haaften, G., Vastenhouw, N.L., Nollen, E.A., Plasterk, R.H. & Tijsterman, M. Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality. Proc. Natl. Acad. Sci. USA 101, 12992–12996 (2004).

    Article  CAS  Google Scholar 

  8. Baugh, L.R. et al. Synthetic lethal analysis of Caenorhabditis elegans posterior embryonic patterning genes identifies conserved genetic interactions. Genome Biol. 6, R45 (2005).

    Article  Google Scholar 

  9. Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395, 854 (1998).

    Article  CAS  Google Scholar 

  10. Kamath, R.S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003).

    Article  CAS  Google Scholar 

  11. Sundaram, M.V. RTK/Ras/MAP kinase signaling. WormBook [online] <http://www.wormbook.org>, published online 11 February 2006 (doi/10.1895/wormbook.1.80.1).

  12. Wang, D. et al. Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants. Nature 436, 593–597 (2005).

    Article  CAS  Google Scholar 

  13. Lehner, B. et al. Loss of LIN-35, the Caenorhabditis elegans ortholog of the tumor suppressor p105Rb, results in enhanced RNA interference. Genome Biol. 7, R4 (2006).

    Article  Google Scholar 

  14. Kinchen, J.M. & Hengartner, M.O. Tales of cannibalism, suicide, and murder: programmed cell death in C. elegans. Curr. Top. Dev. Biol. 65, 1–45 (2005).

    CAS  PubMed  Google Scholar 

  15. Howard, R.M. & Sundaram, M.V. C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component. Genes Dev. 16, 1815–1827 (2002).

    Article  CAS  Google Scholar 

  16. Kokel, M., Borland, C.Z., DeLong, L., Horvitz, H.R. & Stern, M.J. clr-1 encodes a receptor tyrosine phosphatase that negatively regulates an FGF receptor signaling pathway in Caenorhabditis elegans. Genes Dev. 12, 1425–1437 (1998).

    Article  CAS  Google Scholar 

  17. Bergman, A. & Siegal, M.L. Evolutionary capacitance as a general feature of complex gene networks. Nature 424, 549–552 (2003).

    Article  CAS  Google Scholar 

  18. Rutherford, S.L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).

    Article  CAS  Google Scholar 

  19. Queitsch, C., Sangster, T.A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002).

    Article  CAS  Google Scholar 

  20. Ceol, C.J. & Horvitz, H.R. A new class of C. elegans synMuv genes implicates a Tip60/NuA4-like HAT complex as a negative regulator of Ras signaling. Dev. Cell 6, 563–576 (2004).

    Article  CAS  Google Scholar 

  21. Moghal, N. & Sternberg, P.W. A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in C. elegans. Development 130, 57–69 (2003).

    Article  CAS  Google Scholar 

  22. Jiang, L.I. & Sternberg, P.W. An HMG1-like protein facilitates Wnt signaling in Caenorhabditis elegans. Genes Dev. 13, 877–889 (1999).

    Article  CAS  Google Scholar 

  23. Ludewig, A.H. et al. A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging. Genes Dev. 18, 2120–2133 (2004).

    Article  CAS  Google Scholar 

  24. Herman, M.A. et al. EGL-27 is similar to a metastasis-associated factor and controls cell polarity and cell migration in C. elegans. Development 126, 1055–1064 (1999).

    CAS  PubMed  Google Scholar 

  25. Sollars, V. et al. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat. Genet. 33, 70–74 (2003).

    Article  CAS  Google Scholar 

  26. George, S.E., Simokat, K., Hardin, J. & Chisholm, A.D. The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis in C. elegans. Cell 92, 633–643 (1998).

    Article  CAS  Google Scholar 

  27. Clark, D.V., Suleman, D.S., Beckenbach, K.A., Gilchrist, E.J. & Baillie, D.L. Molecular cloning and characterization of the dpy-20 gene of Caenorhabditis elegans. Mol. Gen. Genet. 247, 367–378 (1995).

    Article  CAS  Google Scholar 

  28. Zhang, H. & Emmons, S.W. The novel C. elegans gene sop-3 modulates Wnt signaling to regulate Hox gene expression. Development 128, 767–777 (2001).

    CAS  PubMed  Google Scholar 

  29. Solari, F. & Ahringer, J. NURD-complex genes antagonise Ras-induced vulval development in Caenorhabditis elegans. Curr. Biol. 10, 223–226 (2000).

    Article  CAS  Google Scholar 

  30. Ch'ng, Q. & Kenyon, C. egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function. Development 126, 3303–3312 (1999).

    CAS  PubMed  Google Scholar 

  31. Rebay, I. et al. A genetic screen for novel components of the Ras/Mitogen-activated protein kinase signaling pathway that interact with the yan gene of Drosophila identifies split ends, a new RNA recognition motif-containing protein. Genetics 154, 695–712 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, F. & Rebay, I. split ends, a new component of the Drosophila EGF receptor pathway, regulates development of midline glial cells. Curr. Biol. 10, 943–946 (2000).

    Article  CAS  Google Scholar 

  33. Lin, H.V. et al. Splits ends is a tissue/promoter specific regulator of Wingless signaling. Development 130, 3125–3135 (2003).

    Article  CAS  Google Scholar 

  34. Staehling-Hampton, K., Ciampa, P.J., Brook, A. & Dyson, N. A genetic screen for modifiers of E2F in Drosophila melanogaster. Genetics 153, 275–287 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wiellette, E.L. et al. spen encodes an RNP motif protein that interacts with Hox pathways to repress the development of head-like sclerites in the Drosophila trunk. Development 126, 5373–5385 (1999).

    CAS  PubMed  Google Scholar 

  36. Kuang, B., Wu, S.C., Shin, Y., Luo, L. & Kolodziej, P. split ends encodes large nuclear proteins that regulate neuronal cell fate and axon extension in the Drosophila embryo. Development 127, 1517–1529 (2000).

    CAS  PubMed  Google Scholar 

  37. Kuroda, K. et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18, 301–312 (2003).

    Article  CAS  Google Scholar 

  38. Oswald, F. et al. SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J. 21, 5417–5426 (2002).

    Article  CAS  Google Scholar 

  39. Shi, Y. et al. Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. Genes Dev. 15, 1140–1151 (2001).

    Article  CAS  Google Scholar 

  40. Bach, E.A., Vincent, S., Zeidler, M.P. & Perrimon, N. A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway. Genetics 165, 1149–1166 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Janody, F., Benlali, A., Martirosyan, Z. & Treisman, J. Blind spot and Kohtalo, two components of the Drosophila mediator complex, act together to control a subset of Hedgehog and Wingless target genes. A. Dros. Res. Conf. 43, 90 (2002).

    Google Scholar 

  42. Carrera, I., Janody, F., Martirosyan, Z. & Treisman, J. Two subunits of the mediator complex act as adaptors for Notch and Wingless signaling. A. Dros. Res. Conf. 44, 346A (2003).

    Google Scholar 

  43. Gause, M. et al. Nipped-A, the Tra1/TRRAP subunit of the Drosophila SAGA and Tip60 complexes, has multiple roles in Notch signaling during wing development. Mol. Cell. Biol. 26, 2347–2359 (2006).

    Article  CAS  Google Scholar 

  44. Xiao, H., Chung, J., Kao, H.Y. & Yang, Y.C. Tip60 is a co-repressor for STAT3. J. Biol. Chem. 278, 11197–11204 (2003).

    Article  CAS  Google Scholar 

  45. Feng, Y., Lee, N. & Fearon, E.R. TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. Cancer Res. 63, 8726–8734 (2003).

    CAS  PubMed  Google Scholar 

  46. Taubert, S. et al. E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol. Cell. Biol. 24, 4546–4556 (2004).

    Article  CAS  Google Scholar 

  47. Berns, K. et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428, 431–437 (2004).

    Article  CAS  Google Scholar 

  48. Inoue, T. et al. Gene expression markers for Caenorhabditis elegans vulval cells. Mech. Dev. 119 (Suppl.), S203–S209 (2002).

    Article  Google Scholar 

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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

Author notes

  1. Ben Lehner

    Present address: CRG-EMBL Systems Biology Program, Center for Genomic Regulation, Barcelona, Spain

  2. Angelo Fortunato

    Present address: Molecular Medicine, Department of Neuroscience, University of Siena, Via A. Moro 5, 53100, Siena, Italy

Authors and Affiliations

  1. The Wellcome Trust Sanger Institute, Hinxton, CB10 1HH, Cambridge, UK

    Ben Lehner, Catriona Crombie, Julia Tischler, Angelo Fortunato & Andrew G Fraser

  2. CRG-EMBL Systems Biology Program, Center for Genomic Regulation, Barcelona, Spain

    Angelo Fortunato

  3. Molecular Medicine, Department of Neuroscience, University of Siena, Via A. Moro 5, 53100, Siena, Italy

    Ben Lehner

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Contributions

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..

Corresponding author

Correspondence to Andrew G Fraser.

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The authors declare no competing financial interests.

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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Lehner, B., Crombie, C., Tischler, J. et al. Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways. Nat Genet 38, 896–903 (2006). https://doi.org/10.1038/ng1844

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