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Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network

Nature Methods volume 6, pages 47–54 (2009)Cite this article

Abstract

To provide accurate biological hypotheses and elucidate global properties of cellular networks, systematic identification of protein-protein interactions must meet high quality standards. We present an expanded C. elegans protein-protein interaction network, or 'interactome' map, derived from testing a matrix of ∼10,000 × ∼10,000 proteins using a highly specific, high-throughput yeast two-hybrid system. Through a new empirical quality control framework, we show that the resulting data set (Worm Interactome 2007, or WI-2007) was similar in quality to low-throughput data curated from the literature. We filtered previous interaction data sets and integrated them with WI-2007 to generate a high-confidence consolidated map (Worm Interactome version 8, or WI8). This work allowed us to estimate the size of the worm interactome at ∼116,000 interactions. Comparison with other types of functional genomic data shows the complementarity of distinct experimental approaches in predicting different functional relationships between genes or proteins.

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Figure 1: Construction and characterization of WI-2007.
Figure 2: WI8: an extended, high-quality, protein-protein interaction network.
Figure 3: Biological relevance.
Figure 4: Examples of multiple-evidence subnetworks.

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Acknowledgements

We thank F. Piano and members of the Cancer Center for System Biology and the Vidal laboratory for discussions, A. Petcherski from WormBase for assistance with worm genetic interactions, and Z. Hu for VisANT assistance. The worm interactome project was supported by grants from the US National Institutes of Health—R01 HG001715 (M.V. and F.P.R.), R01 HG003224 (F.P.R.), F32 HG004098 (M. Tasan), T32 CA09361 (K.V.)—a University of Ghent grant GOA12051401 (J.T.), and the Fonds Wetenschappelijk Onderzoek – Vlaanderen (FWO-V) G.0031.06 (J.T.). I.L. was supported by a postdoctoral fellowship from the FWO-V. K.C.G. and H.-L.K. were supported by US Department of the Army Award W81XWH-04-1-0307 and the State of New York's Science and Tech Resources contract C040066. M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium).

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Author notes

  1. Jean-François Rual, Kavitha Venkatesan, Sebiha Cevik, Niels Klitgord, Ning Li, Nono Ayivi-Guedehoussou, Nicolas Bertin, David Szeto, Christophe Simon, Muneesh Tewari, Mike Boxem & Stuart Milstein

    Present address: Present addresses: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA (J.-F.R.), Novartis Institutes for Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (K.V.), School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland (S.C.), Bioinformatics Program, Boston University, 705 Commonwealth Avenue, Boston, Massachusetts 02215, USA (N.K.), Wyeth Pharmaceuticals Inc., 35 Cambridgepark Drive, Cambridge, Massachusetts 02140, USA (N.L.), Harvard School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA (N.A.-G.), RIKEN Omics Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan (N.B., C.S.), University of California San Francisco School of Medicine, 500 Parnassus Avenue, San Francisco, California 94143, USA (D.S.), Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA (M. Tewari), Utrecht University, Kruytgebouw N309, 8 Padualaan, 3584 CH Utrecht, The Netherlands (M.B.) and Alnylam Pharmaceutical, 300 Third Street, Cambridge, Massachusetts 02142, USA (S.M.).,

  2. Nicolas Simonis, Jean-François Rual, Anne-Ruxandra Carvunis, Murat Tasan and Irma Lemmens: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Nicolas Simonis, Jean-François Rual, Anne-Ruxandra Carvunis, Tomoko Hirozane-Kishikawa, Tong Hao, Julie M Sahalie, Kavitha Venkatesan, Fana Gebreab, Sebiha Cevik, Niels Klitgord, Changyu Fan, Pascal Braun, Ning Li, Nono Ayivi-Guedehoussou, Elizabeth Dann, Nicolas Bertin, David Szeto, Amélie Dricot, Muhammed A Yildirim, Chenwei Lin, Christophe Simon, Alex Smolyar, Jin Sook Ahn, Muneesh Tewari, Mike Boxem, Stuart Milstein, Haiyuan Yu, Matija Dreze, Michael E Cusick, David E Hill, Frederick P Roth & Marc Vidal

  2. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Nicolas Simonis, Jean-François Rual, Anne-Ruxandra Carvunis, Tomoko Hirozane-Kishikawa, Tong Hao, Julie M Sahalie, Kavitha Venkatesan, Fana Gebreab, Sebiha Cevik, Niels Klitgord, Changyu Fan, Pascal Braun, Ning Li, Nono Ayivi-Guedehoussou, Elizabeth Dann, Nicolas Bertin, David Szeto, Amélie Dricot, Muhammed A Yildirim, Chenwei Lin, Christophe Simon, Alex Smolyar, Jin Sook Ahn, Muneesh Tewari, Mike Boxem, Stuart Milstein, Haiyuan Yu, Matija Dreze, Michael E Cusick, David E Hill & Marc Vidal

  3. Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble (TIMC-IMAG), Unité Mixte de Recherche 5525 Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine, Université Joseph Fourier, La Tronche Cedex, 38706, France

    Anne-Ruxandra Carvunis

  4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Murat Tasan & Frederick P Roth

  5. Department of Medical Protein Research, and Department of Biochemistry, Vlaams Instituut voor Biotechnologie, Faculty of Medicine and Health Sciences, Ghent University, 3 Albert Baertsoenkaai, Ghent, 9000, Belgium

    Irma Lemmens, Anne-Sophie de Smet & Jan Tavernier

  6. Division of Engineering and Applied Sciences, Harvard University, 29 Oxford Street, Cambridge, 02138, Massachusetts, USA

    Muhammed A Yildirim

  7. Department of Biology, Center for Genomics and Systems Biology, New York University, 100 Washington Square East, New York, 10003, New York, USA

    Huey-Ling Kao & Kristin C Gunsalus

  8. Massachusetts General Hospital Center for Cancer Research, Building 149, 13th Street, Charlestown, 02129, Massachusetts, USA

    Mike Boxem

  9. Unité de Recherche en Biologie Moléculaire, Facultés Notre-Dame de la Paix, 61 Rue de Bruxelles, Namur, 5000, Belgium

    Matija Dreze & Jean Vandenhaute

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  1. Nicolas Simonis
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Contributions

J.-F.R., N.S. and A.-R.C. coordinated experiments and data analysis. J.-F.R., T.H.-K., J.M.S., F.G., S.C., P.B., N.L., N.A.-G., E.D., D.S., A.D., C.S., M.V., H.Y., M.B., S.M., M.D., M. Tewari and J.S.A. performed the high-throughput ORF cloning and Y2H screens. I.L., A.-S.d.S., P.B. and J.T. conducted the MAPPIT experiments. N.S., A.-R.C., M. Tasan, T.H., N.K., K.V., C.F., N.B., M.A.Y., C.L., A.S., H.-L.K. and K.C.G. performed the computational analyses. M. Tasan, N.S., C.F., A.-R.C., H.-L.K. and K.C.G. adapted or built the website and visualization tools. N.S., A.-R.C., J.-F.R., M.E.C., J.V., F.P.R. and M.V. wrote the manuscript. M.V. conceived the project. D.E.H., J.T., F.P.R. and M.V. co-directed the project.

Corresponding authors

Correspondence to David E Hill, Jan Tavernier, Frederick P Roth or Marc Vidal.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1–5, Supplementary Discussion, Supplementary Methods (PDF 987 kb)

Supplementary Data 1

WI8 MIMIX (TXT 2857 kb)

Supplementary Data 2

Integrated functional network (TXT 7021 kb)

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Simonis, N., Rual, JF., Carvunis, AR. et al. Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network. Nat Methods 6, 47–54 (2009). https://doi.org/10.1038/nmeth.1279

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