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Discovery of uncharacterized cellular systems by genome-wide analysis of functional linkages

Nature Biotechnology volume 21, pages 1055–1062 (2003)Cite this article

Abstract

We introduce a general computational method, applicable on a genome-wide scale, for the systematic discovery of uncharacterized cellular systems. Quantitative analysis of the coinheritance of pairs of genes among different organisms, calculated using phylogenetic profiles, allows the prediction of thousands of functional linkages between the corresponding proteins. A comparison of these functional linkages to known pathways reveals that calculated linkages are comparable in accuracy to genome-wide yeast two-hybrid screens or mass spectrometry interaction assays. In aggregate, these linkages describe the structure of large-scale networks, with the resulting yeast network composed of 3,875 linkages among 804 proteins, and the resulting pathogenic Escherichia coli network composed of 2,043 linkages among 828 proteins. The search of such networks for groups of uncharacterized, linked proteins led to the identification of 27 novel cellular systems from one nonpathogenic and three pathogenic bacterial genomes.

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Figure 1: A schematic representation of the systematic method for identification of novel cellular systems.
Figure 2: Two measures of the quality of functional linkages are presented.
Figure 3: Predicted genome-wide protein networks for yeast23.
Figure 4: Predicted genome-wide protein networks for pathogenic E. coli O157:H7 (ref. 46).
Figure 5: Clusters representing potentially new pathways selected from reconstructions of genome-wide interaction networks of four different organisms.
Figure 6: The phylogenetic profiles drawn for the core components of the gene clusters in Figure 5.

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Acknowledgements

This work was supported by grants from the Welch Foundation (F-1515), the Texas Advanced Research Program, a Camille and Henry Dreyfus New Faculty Award, National Science Foundation (EIA – 0219061) and a Packard Fellowship.

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Authors and Affiliations

  1. Center for Computational Biology and Bioinformatics, Institute for Cellular and Molecular Biology, 1 University Station A4800, Austin, 78712-1064, Texas, USA

    Shailesh V Date & Edward M Marcotte

  2. Department of Chemistry and Biochemistry, 1 University Station A4800, Austin, 78712-1064, Texas, USA

    Edward M Marcotte

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Correspondence to Edward M Marcotte.

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Date, S., Marcotte, E. Discovery of uncharacterized cellular systems by genome-wide analysis of functional linkages. Nat Biotechnol 21, 1055–1062 (2003). https://doi.org/10.1038/nbt861

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