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A gene ontology inferred from molecular networks

Nature Biotechnology volume 31, pages 38–45 (2013)Cite this article

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Abstract

Ontologies have proven very useful for capturing knowledge as a hierarchy of terms and their interrelationships. In biology a major challenge has been to construct ontologies of gene function given incomplete biological knowledge and inconsistencies in how this knowledge is manually curated. Here we show that large networks of gene and protein interactions in Saccharomyces cerevisiae can be used to infer an ontology whose coverage and power are equivalent to those of the manually curated Gene Ontology (GO). The network-extracted ontology (NeXO) contains 4,123 biological terms and 5,766 term-term relations, capturing 58% of known cellular components. We also explore robust NeXO terms and term relations that were initially not cataloged in GO, a number of which have now been added based on our analysis. Using quantitative genetic interaction profiling and chemogenomics, we find further support for many of the uncharacterized terms identified by NeXO, including multisubunit structures related to protein trafficking or mitochondrial function. This work enables a shift from using ontologies to evaluate data to using data to construct and evaluate ontologies.

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Figure 1: Automated assembly and alignment of gene ontologies.
Figure 2: The NeXO ontology.
Figure 3: Validation.
Figure 4: Evaluation of protein trafficking terms using genetic interaction profiling.
Figure 5: Updating GO with additional terms and term relations.

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Acknowledgements

We are grateful to J. Bader and Y. Park for assistance with the HAC-ML software and to I. Lee and E. Marcotte for advice on YeastNet. We would also like to thank D. Botstein, C. Boone, R. Sharan and R. Shamir for constructive advice on the manuscript. This work was generously supported by US National Institutes of Health grants P41-GM103504 and P50-GM085764 (TI) and R01-GM084448 and P50-GM081879 (N.J.K.). N.J.K. is a Searle Scholar and Keck Young Investigator.

Author information

Authors and Affiliations

  1. Departments of Medicine and Bioengineering, University of California San Diego, La Jolla, California, USA

    Janusz Dutkowski, Michael Kramer & Trey Ideker

  2. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

    Michal A Surma

  3. Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA

    Michal A Surma & Nevan J Krogan

  4. Department of Genetics, Stanford University, Stanford, California, USA

    Rama Balakrishnan & J Michael Cherry

  5. J. David Gladstone Institutes, San Francisco, California, USA

    Nevan J Krogan

  6. Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA

    Trey Ideker

Authors
  1. Janusz Dutkowski
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  3. Michal A Surma
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  4. Rama Balakrishnan
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Contributions

J.D. and T.I. conceived and designed the analysis. J.D. performed initial data analysis, constructed the NeXO ontology and performed all computational experiments. M.K. designed and implemented the ontology alignment procedure with guidance from J.D. M.S. and N.J.K. performed the quantitative genetic interaction profiling and interpreted the data. R.B. and J.M.C. investigated and curated the new ontology terms and relations. J.D. and T.I. wrote the manuscript. All authors contributed to the manuscript and approved its final version.

Corresponding authors

Correspondence to Janusz Dutkowski or Trey Ideker.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1, Supplementary Note and Supplementary Figs. 1–10 (PDF 3024 kb)

Supplementary Table 2

New terms in NeXO (XLSX 189 kb)

Supplementary Table 3

New term-term relations (XLSX 15 kb)

Supplementary Table 4

Genetic interaction profiles for 73 query genes (XLSX 531 kb)

Supplementary Table 5

New NeXO terms enriched within chemogenomic profiles (XLSX 53 kb)

Supplementary Table 6

Integrated high-confidence interaction network (XLSX 1745 kb)

Supplementary File 1

NeXO in Cytoscape Format (File NeXO.cys provided separately) Direct download: http://chianti.ucsd.edu/~janusz/nexo/NeXO.zip (ZIP 7119 kb)

Supplementary File 2

NeXO in Open Biomedical Ontology (OBO) Format (File NeXO.obo provided separately) (ZIP 422 kb)

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Dutkowski, J., Kramer, M., Surma, M. et al. A gene ontology inferred from molecular networks. Nat Biotechnol 31, 38–45 (2013). https://doi.org/10.1038/nbt.2463

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