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Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets

Nature Genetics volume 38, pages 285–293 (2006)Cite this article

Abstract

We present the first analysis of the human proteome with regard to interactions between proteins. We also compare the human interactome with the available interaction datasets from yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans) and fly (Drosophila melanogaster). Of >70,000 binary interactions, only 42 were common to human, worm and fly, and only 16 were common to all four datasets. An additional 36 interactions were common to fly and worm but were not observed in humans, although a coimmunoprecipitation assay showed that 9 of the interactions do occur in humans. A re-examination of the connectivity of essential genes in yeast and humans indicated that the available data do not support the presumption that the number of interaction partners can accurately predict whether a gene is essential. Finally, we found that proteins encoded by genes mutated in inherited genetic disorders are likely to interact with proteins known to cause similar disorders, suggesting the existence of disease subnetworks. The human interaction map constructed from our analysis should facilitate an integrative systems biology approach to elucidating the cellular networks that contribute to health and disease states.

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Figure 1: Human protein interactome.
Figure 2: Overlap of PPI datasets.
Figure 3: Validation of PPIs in human orthologs derived from overlap between worm and fly Y2H datasets.
Figure 4: Distribution of PPIs for essential or nonessential genes (log10 scale).
Figure 5: Correlation of PPIs with subcellular localization and disease association.

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Acknowledgements

A.P., J.D.B. and J.S.B. were supported by a grant from the National Institutes of Health (U54 RR020839). G.P. was supported by a grant from the National Science Foundation (NSF 034211), J.S.B. was supported by grants from the US National Institutes of Health (R41 GM073492 and R01 GM067761) and the Whitaker Foundation and S.P. was supported by the IZKF Würzburg project. The authors thank J. Eppig and C. Bult for providing knockout data from the Mouse Genome Database and B. Migeon, N. Katsanis and J. Mendell for helpful suggestions. The HPRD was developed with funding from the National Institutes of Health and the Institute of Bioinformatics.

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Authors and Affiliations

  1. Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India

    T K B Gandhi, Suresh Mathivanan, L Karthick, K N Chandrika, S Sujatha Mohan, Salil Sharma, Shilpa Nagaraju, Balamurugan Periaswamy, Goparani Mishra, Kannabiran Nandakumar, Nandan Deshpande, Rashmi Nayak & Malabika Sarker

  2. McKusick-Nathans Institute of Genetic Medicine and the Departments of Biological Chemistry and Pathology, Johns Hopkins University, Baltimore, 21205, Maryland, USA

    Jun Zhong, Salil Sharma, Beiyi Shen & Akhilesh Pandey

  3. Department of Bioinformatics, Biozentrum, University Würzburg, Am Hubland, 97074, Würzburg, Germany

    Stefan Pinkert & Jörg Schultz

  4. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, 21205, Maryland, USA

    Giovanni Parmigiani & Akhilesh Pandey

  5. The High Throughput Biology Center, Johns Hopkins University, Baltimore, 21205, Maryland, USA

    Jef D Boeke & Joel S Bader

  6. Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, 21205, Maryland, USA

    Jef D Boeke

  7. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21205, Maryland, USA

    Joel S Bader

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Correspondence to Akhilesh Pandey.

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Competing interests

The Human Protein Reference Database was developed with funding from the US National Institutes of Health and the Institute of Bioinformatics. A.P. serves as Chief Scientific Advisor to the Institute of Bioinformatics. A.P. is entitled to a share of the licensing fees paid to the Johns Hopkins University by commercial entities for use of the database. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Supplementary information

Supplementary Fig. 1

Subclusters conserved between human and fly (PDF 216 kb)

Supplementary Fig. 2

Subclusters conserved between human and worm (PDF 231 kb)

Supplementary Fig. 3

Subclusters conserved between human and yeast (PDF 230 kb)

Supplementary Fig. 4

PPIs in essential versus non-essential genes (PDF 207 kb)

Supplementary Table 1

Overlap of worm and fly Y2H data with human protein-protein interactions. (PDF 109 kb)

Supplementary Table 2

Overlap of worm and fly interaction but not in humans (with corresponding orthologs in humans). (PDF 139 kb)

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Gandhi, T., Zhong, J., Mathivanan, S. et al. Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet 38, 285–293 (2006). https://doi.org/10.1038/ng1747

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