Abstract
Although many studies have been successful in the discovery of cooperating groups of genes, mapping these groups to phenotypes has proved a much more challenging task. In this paper, we present the first genome-wide mapping of gene coexpression modules onto the phenome. We annotated coexpression networks from 136 microarray datasets with phenotypes from the Unified Medical Language System (UMLS). We then designed an efficient graph-based simulated annealing approach to identify coexpression modules frequently and specifically occurring in datasets related to individual phenotypes. By requiring phenotype-specific recurrence, we ensure the robustness of our findings. We discovered 9,183 modules specific to 47 phenotypes, and developed validation tests combining Gene Ontology, GeneRIF and UMLS. Our method is generally applicable to any kind of abundant network data with defined phenotype association, and thus paves the way for genome-wide, gene network-phenotype maps.
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References
Lander, E.S., Schork, N.J.: Genetic dissection of complex traits. Science 265(5181), 2037–2048 (1994)
Risch, N.J.: Searching for genetic determinants in the new millennium. Nature 405(6788), 847–856 (2000)
Zhou, X., Kao, M.C.J., Wong, W.H.: Transitive functional annotation by shortest-path analysis of gene expression data. Proc. Natl. Acad. Sci. USA 99(20), 12783–12788 (2002)
Bader, G.D., Hogue, C.W.V.: An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 4, 2 (2003)
Spirin, V., Mirny, L.A.: Protein complexes and functional modules in molecular networks. Proc. Natl. Acad. Sci. USA 100(21), 12123–12128 (2003)
Kelley, B.P., Sharan, R., Karp, R.M., Sittler, T., Root, D.E., Stockwell, B.R., Ideker, T.: Conserved pathways within bacteria and yeast as revealed by global protein network alignment. Proc. Natl. Acad. Sci. U.S.A. 100(20), 11394–11399 (2003)
Hu, H., Yan, X., Huang, Y., Han, J., Zhou, X.J.: Mining coherent dense subgraphs across massive biological networks for functional discovery. Bioinformatics 21(Suppl 1), i213–i221 (2005)
Yip, A.M., Horvath, S.: Gene network interconnectedness and the generalized topological overlap measure. BMC Bioinformatics 8, 22 (2007)
Butte, A.J., Kohane, I.S.: Creation and implications of a phenome-genome network. Nat. Biotechnol. 24(1), 55–62 (2006)
Barrett, T., Troup, D.B., Wilhite, S.E., Ledoux, P., Rudnev, D., Evangelista, C., Kim, I.F., Soboleva, A., Tomashevsky, M., Edgar, R.: Ncbi geo: mining tens of millions of expression profiles–database and tools update. Nucleic Acids Res. 35(Database issue), D760–D765 (2007)
Lage, K., Karlberg, E.O., Størling, Z.M., Olason, P.I., Pedersen, A.G., Rigina, O., Hinsby, A.M., Tümer, Z., Pociot, F., Tommerup, N., Moreau, Y., Brunak, S.: A human phenome-interactome network of protein complexes implicated in genetic disorders. Nat. Biotechnol. 25(3), 309–316 (2007)
Bodenreider, O.: The unified medical language system (umls): integrating biomedical terminology. Nucleic Acids Res. 32(Database issue), D267–D270 (2004)
Kirkpatrick, S., Gelatt, C., Vecchi, M.: Optimization by simulated annealing. Science 220(4598), 671–680 (1983)
Zhou, X.J., Kao, M.C.J., Huang, H., Wong, A., Nunez-Iglesias, J., Primig, M., Aparicio, O.M., Finch, C.E., Morgan, T.E., Wong, W.H.: Functional annotation and network reconstruction through cross-platform integration of microarray data. Nat. Biotechnol. 23(2), 238–243 (2005)
Yan, X., Mehan, M.R., Huang, Y., Waterman, M.S., Yu, P.S., Zhou, X.J.: A graph-based approach to systematically reconstruct human transcriptional regulatory modules. Bioinformatics 23(13), i577–586 (2007)
Consortium, G.O.: The gene ontology (go) project in 2006. Nucleic Acids Res 34(Database issue), D322–D326 (2006)
Mitchell, J.A., Aronson, A.R., Mork, J.G., Folk, L.C., Humphrey, S.M., Ward, J.M.: Gene indexing: characterization and analysis of nlm’s generifs. In: AMIA Annual Symposium proceedings / AMIA Symposium AMIA Symposium, January 2003, pp. 460–464 (2003)
Freimer, N., Sabatti, C.: The human phenome project. Nat. Genet. 34(1), 15–21 (2003)
Butte, A.J., Chen, R.: Finding disease-related genomic experiments within an international repository: first steps in translational bioinformatics. In: AMIA Annual Symposium proceedings / AMIA Symposium AMIA Symposium, pp. 106–110 (2006)
Suman, B., Kumar, P.: A survey of simulated annealing as a tool for single and multiobjective optimization. Journal of the Operational Research Society 57(10), 1143–1160 (2006)
Collette, Y., Siarry, P.: Multiobjective Optimization: Principles and Case Studies, 2nd edn., pp. 45–51. Springer, Heidelberg (2004)
Geman, S., Geman, D.: Stochastic relaxation, gibbs distributions, and the bayesian restoration of images. IEEE-PAMI 6, 721–741 (1984)
Jeffery, C.J.: Multifunctional proteins: examples of gene sharing. Ann. Med. 35(1), 28–35 (2003)
Jeffery, C.J.: Moonlighting proteins: old proteins learning new tricks. Trends Genet. 19(8), 415–417 (2003)
Zhang, M.: Multiple functions of maspin in tumor progression and mouse development. Front. Biosci. 9, 2218–2226 (2004)
Han, J.D.J., Bertin, N., Hao, T., Goldberg, D.S., Berriz, G.F., Zhang, L.V., Dupuy, D., Walhout, A.J.M., Cusick, M.E., Roth, F.P., Vidal, M.: Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature 430(6995), 88–93 (2004)
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Mehan, M.R., Nunez-Iglesias, J., Kalakrishnan, M., Waterman, M.S., Zhou, X.J. (2008). An Integrative Network Approach to Map the Transcriptome to the Phenome. In: Vingron, M., Wong, L. (eds) Research in Computational Molecular Biology. RECOMB 2008. Lecture Notes in Computer Science(), vol 4955. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78839-3_20
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DOI: https://doi.org/10.1007/978-3-540-78839-3_20
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