Skip to main content

Prioritizing Genes for Pathway Impact Using Network Analysis

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 563))

Abstract

Prioritization, or ranking, of gene lists is becoming increasingly important for analyzing data generated from high-throughput assays like expression profiling and RNAi-based screening. This is especially the case when specific genes in a list need to be further validated using low-throughput experiments. In addition to gene set overlap enrichment methods, a complementary approach is to examine molecular interaction networks. These can provide putative functional insights based on gene connectivity, especially when many genes contain little or no annotation. For bench and computational biologists alike, using networks requires an informed selection of interaction data for network construction and strategies for managing network complexity. Moreover, graph theory and social network analysis methods can be used to isolate critical subnetworks and quantify network properties. Here, I discuss the basic components of networks, implications of their structure for functional interpretation, and common metrics used for prioritization. Although this is still an ongoing area of research, networks are providing new ways for gauging pathway impact in large-scale data sets.

This is a preview of subscription content, log in via an institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Hood, L., and Perlmutter, R. M. (2004) The impact of systems approaches on biological problems in drug discovery. Nat Biotechnol 22, 1215–7.

    Article  PubMed  CAS  Google Scholar 

  2. Hiesinger, P. R., and Hassan, B. A. (2005) Genetics in the age of systems biology. Cell 123, 1173–4.

    Article  PubMed  CAS  Google Scholar 

  3. Ideker, T., Thorsson, V., Ranish, J. A., Christmas, R., Buhler, J., Eng, J. K., Bumgarner, R., Goodlett, D. R., Aebersold, R., and Hood, L. (2001) Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Science 292, 929–34.

    Article  PubMed  CAS  Google Scholar 

  4. Wei, G., Twomey, D., Lamb, J., Schlis, K., Agarwal, J., Stam, R. W., Opferman, J. T., Sallan, S. E., den Boer, M. L., Pieters, R., Golub, T. R., and Armstrong, S. A. (2006) Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10, 331–42.

    Article  PubMed  CAS  Google Scholar 

  5. Whitehurst, A. W., Bodemann, B. O., Cardenas, J., Ferguson, D., Girard, L., Peyton, M., Minna, J. D., Michnoff, C., Hao, W., Roth, M. G., Xie, X. J., and White, M. A. (2007) Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446, 815–9.

    Article  PubMed  CAS  Google Scholar 

  6. Ruffner, H., Bauer, A., and Bouwmeester, T. (2007) Human protein-protein interaction networks and the value for drug discovery. Drug Discov Today 12, 709–16.

    Article  PubMed  CAS  Google Scholar 

  7. Sachs, K., Perez, O., Pe’er, D., Lauffenburger, D. A., and Nolan, G. P. (2005) Causal protein-signaling networks derived from multiparameter single-cell data. Science 308, 523–9.

    Article  PubMed  CAS  Google Scholar 

  8. Matthews, L. R., Vaglio, P., Reboul, J., Ge, H., Davis, B. P., Garrels, J., Vincent, S., and Vidal, M. (2001) Identification of potential interaction networks using sequence-based searches for conserved protein-protein interactions or “interologs”. Genome Res 11, 2120–6.

    Article  PubMed  CAS  Google Scholar 

  9. Friedman, N. (2004) Inferring cellular networks using probabilistic graphical models. Science 303, 799–805.

    Article  PubMed  CAS  Google Scholar 

  10. Beyer, A., Bandyopadhyay, S., and Ideker, T. (2007) Integrating physical and genetic maps: from genomes to interaction networks. Nat Rev Genet 8, 699–710.

    Article  PubMed  CAS  Google Scholar 

  11. Alm, E., and Arkin, A. P. (2003) Biological networks. Curr Opin Struct Biol 13, 193–202.

    Article  PubMed  CAS  Google Scholar 

  12. Joyce, A. R., and Palsson, B. O. (2006) The model organism as a system: integrating “omics” data sets. Nat Rev Mol Cell Biol 7, 198–210.

    Article  PubMed  CAS  Google Scholar 

  13. Gunsalus, K. C., Ge, H., Schetter, A. J., Goldberg, D. S., Han, J. D., Hao, T., Berriz, G. F., Bertin, N., Huang, J., Chuang, L. S., Li, N., Mani, R., Hyman, A. A., Sonnichsen, B., Echeverri, C. J., Roth, F. P., Vidal, M., and Piano, F. (2005) Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis. Nature 436, 861–5.

    Article  PubMed  CAS  Google Scholar 

  14. Spirin, V., and Mirny, L. A. (2003) Protein complexes and functional modules in molecular networks. Proc Natl Acad Sci U S A 100, 12123–8.

    Article  PubMed  CAS  Google Scholar 

  15. Walhout, A. J. (2006) Unraveling transcription regulatory networks by protein-DNA and protein-protein interaction mapping. Genome Res 16, 1445–54.

    Article  PubMed  CAS  Google Scholar 

  16. Albert, R., Jeong, H., and Barabasi, A. L. (2000) Error and attack tolerance of complex networks. Nature 406, 378–82.

    Article  PubMed  CAS  Google Scholar 

  17. Joyner, A. L. (2000) Gene Targeting: A Practical Approach, Oxford University Press, Oxford, UK.

    Google Scholar 

  18. Selbach, M., and Mann, M. (2006) Protein interaction screening by quantitative immunoprecipitation combined with knockdown (QUICK). Nat Methods 3, 981–3.

    Article  PubMed  CAS  Google Scholar 

  19. Alon, U. (2007) An Introduction to Systems Biology: Design Principles of Biological Circuits, Chapman & Hall/CRC Press, London, UK.

    Google Scholar 

  20. Wagner, A. (2005) Robustness and Evolvability in Living Systems, Princeton University Press, Princeton, NJ.

    Google Scholar 

  21. Davidson, E. H. (2006) The Regulatory Genome: Gene Regulatory Networks in Development and Evolution, Academic Press, Burlington, MA.

    Google Scholar 

  22. Chang, A. N., Cantor, A. B., Fujiwara, Y., Lodish, M. B., Droho, S., Crispino, J. D., and Orkin, S. H. (2002) GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proc Natl Acad Sci U S A 99, 9237–42.

    Article  PubMed  CAS  Google Scholar 

  23. Eyckerman, S., Lemmens, I., Catteeuw, D., Verhee, A., Vandekerckhove, J., Lievens, S., and Tavernier, J. (2005) Reverse MAPPIT: screening for protein-protein interaction modifiers in mammalian cells. Nat Methods 2, 427–33.

    Article  PubMed  CAS  Google Scholar 

  24. Wasserman, S., and Faust, K. (1999) Social Network Analysis, Methods and Applications, Cambridge University Press, Cambridge, UK.

    Google Scholar 

  25. Jeong, H., Mason, S. P., Barabasi, A. L., and Oltvai, Z. N. (2001) Lethality and centrality in protein networks. Nature 411, 41–2.

    Article  PubMed  CAS  Google Scholar 

  26. Lee, I., Lehner, B., Crombie, C., Wong, W., Fraser, A. G., and Marcotte, E. M. (2008) Asingle gene network accurately predicts phenotypic effects of gene perturbation in Caenorhabditis elegans. Nat Genet 40, 181–8.

    Article  PubMed  CAS  Google Scholar 

  27. Jonsson, P. F., and Bates, P. A. (2006) Global topological features of cancer proteins in the human interactome. Bioinformatics 22, 2291–7.

    Article  PubMed  CAS  Google Scholar 

  28. Chakrabarti, S. (2003) Mining the Web: Discovering Knowledge from Hypertext Data, Morgan Kaufmann Publishers, San Francisco, CA.

    Google Scholar 

  29. Przulj, N. (2007) Biological network comparison using graphlet degree distribution. Bioinformatics 23, e177–83.

    Article  PubMed  CAS  Google Scholar 

  30. Barabasi, A. L., and Oltvai, Z. N. (2004) Network biology: understanding the cell’s functional organization. Nat Rev Genet 5, 101–13.

    Article  PubMed  CAS  Google Scholar 

  31. Wong, S. L., Zhang, L. V., Tong, A. H., Li, Z., Goldberg, D. S., King, O. D., Lesage, G., Vidal, M., Andrews, B., Bussey, H., Boone, C., and Roth, F. P. (2004) Combining biological networks to predict genetic interactions. Proc Natl Acad Sci U S A 101, 15682–7.

    Article  PubMed  CAS  Google Scholar 

  32. Sedgewick, R. (2004) Algorithms in Java, Third Edition, Addison Wesley, Boston, MA.

    Google Scholar 

  33. Ulitsky, I., and Shamir, R. (2007) Pathway redundancy and protein essentiality revealed in the Saccharomyces cerevisiae interaction networks. Mol Syst Biol 3, 104.

    Article  PubMed  Google Scholar 

  34. Przulj, N., Wigle, D. A., and Jurisica, I. (2004) Functional topology in a network of protein interactions. Bioinformatics 20, 340–8.

    Article  PubMed  CAS  Google Scholar 

  35. Watts, D. J. (1999) Small Worlds: The Dynamics of Networks Between Order and Randomness, Princeton University Press, Princeton, NJ.

    Google Scholar 

  36. Zhou, X., Kao, M. C., and Wong, W. H. (2002) Transitive functional annotation by shortest-path analysis of gene expression data. Proc Natl Acad Sci U S A 99, 12783–8.

    Article  PubMed  CAS  Google Scholar 

  37. Ye, P., Peyser, B. D., Spencer, F. A., and Bader, J. S. (2005) Commensurate distances and similar motifs in genetic congruence and protein interaction networks in yeast. BMC Bioinformatics 6, 270.

    Article  PubMed  Google Scholar 

  38. Tuck, D. P., Kluger, H. M., and Kluger, Y. (2006) Characterizing disease states from topological properties of transcriptional regulatory networks. BMC Bioinformatics 7, 236.

    Article  PubMed  Google Scholar 

  39. Yao, L., and Rzhetsky, A. (2007) Quantitative systems-level determinants of human genes targeted by successful drugs. Genome Res 2008 Feb; 18(2): 206–13.

    Google Scholar 

  40. Yu, H., Kim, P. M., Sprecher, E., Trifonov, V., and Gerstein, M. (2007) The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol 3, e59.

    Article  PubMed  Google Scholar 

  41. Valente, A. X., and Cusick, M. E. (2006) Yeast protein interactome topology provides framework for coordinated-functionality. Nucleic Acids Res 34, 2812–9.

    Article  PubMed  CAS  Google Scholar 

  42. Barriot, R., Sherman, D. J., and Dutour, I. (2007) How to decide which are the most pertinent overly-represented features during gene set enrichment analysis. BMC Bioinformatics 8, 332.

    Article  PubMed  Google Scholar 

  43. Huang, X., Lai, J., and Jennings, S. F. (2006) Maximum common subgraph: some upper bound and lower bound results. BMC Bioinformatics 7 Suppl 4, S6.

    Article  PubMed  Google Scholar 

  44. Palla, G., Derenyi, I., Farkas, I., and Vicsek, T. (2005) Uncovering the overlapping community structure of complex networks in nature and society. Nature 435, 814–8.

    Article  PubMed  CAS  Google Scholar 

  45. Vazquez, A., Dobrin, R., Sergi, D., Eckmann, J. P., Oltvai, Z. N., and Barabasi, A. L. (2004) The topological relationship between the large-scale attributes and local interaction patterns of complex networks. Proc Natl Acad Sci U S A 101, 17940–5.

    Article  PubMed  CAS  Google Scholar 

  46. Wuchty, S., Oltvai, Z. N., and Barabasi, A. L. (2003) Evolutionary conservation of motif constituents in the yeast protein interaction network. Nat Genet 35, 176–9.

    Article  PubMed  CAS  Google Scholar 

  47. Shen-Orr, S. S., Milo, R., Mangan, S., and Alon, U. (2002) Network motifs in the transcriptional regulation network of Escherichia coli. Nat Genet 31, 64–8.

    Article  PubMed  CAS  Google Scholar 

  48. Assenov, Y., Ramirez, F., Schelhorn, S. E., Lengauer, T., and Albrecht, M. (2008) Computing topological parameters of biological networks. Bioinformatics 24, 282–4.

    Article  PubMed  CAS  Google Scholar 

  49. Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., and Ideker, T. (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13, 2498–504.

    Article  PubMed  CAS  Google Scholar 

  50. de Nooy, W., Mrvar, A., and Batagelj, V. (2005) Exploratory Social Network Analysis with Pajek, Cambridge University Press, Cambridge, UK.

    Google Scholar 

  51. Bender-deMoll, S., and McFarland, D. A. (2006) The art and science of dynamic network visualization. J Social Structure 7(2). http://www.cmu.edu/joss/content/articles/volume7/deMollMcFarland/

  52. Adar, E. (2006) in “Conference on Human Factors in Computing Systems” (ACM, Ed.), ACM, Montreal.

    Google Scholar 

  53. Bader, G. D., Cary, M. P., and Sander, C. (2006) Pathguide: a pathway resource list. Nucleic Acids Res 34, D504–6.

    Article  PubMed  CAS  Google Scholar 

  54. Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., and Kanehisa, M. (1999) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 27, 29–34.

    Article  PubMed  CAS  Google Scholar 

  55. www.biocarta.com.

  56. Longabaugh, W. J., Davidson, E. H., and Bolouri, H. (2005) Computational representation of developmental genetic regulatory networks. Dev Biol 283, 1–16.

    Article  PubMed  CAS  Google Scholar 

  57. Sevecka, M., and MacBeath, G. (2006) State-based discovery: a multidimensional screen for small-molecule modulators of EGF signaling. Nat Methods 3, 825–31.

    Article  PubMed  CAS  Google Scholar 

  58. Olsen, J. V., Blagoev, B., Gnad, F., Macek, B., Kumar, C., Mortensen, P., and Mann, M. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635–48.

    Article  PubMed  CAS  Google Scholar 

  59. Linding, R., Jensen, L. J., Ostheimer, G. J., van Vugt, M. A., Jorgensen, C., Miron, I. M., Diella, F., Colwill, K., Taylor, L., Elder, K., Metalnikov, P., Nguyen, V., Pasculescu, A., Jin, J., Park, J. G., Samson, L. D., Woodgett, J. R., Russell, R. B., Bork, P., Yaffe, M. B., and Pawson, T. (2007) Systematic discovery of in vivo phosphorylation networks. Cell 129, 1415–26.

    Article  PubMed  CAS  Google Scholar 

  60. Stites, E. C., Trampont, P. C., Ma, Z., and Ravichandran, K. S. (2007) Network analysis of oncogenic Ras activation in cancer. Science 318, 463–7.

    Article  PubMed  CAS  Google Scholar 

  61. Edwards, J. S., Covert, M., and Palsson, B. (2002) Metabolic modelling of microbes: the flux-balance approach. Environ Microbiol 4, 133–40.

    Article  PubMed  Google Scholar 

  62. Hu, Z., Mellor, J., Wu, J., Kanehisa, M., Stuart, J. M., and DeLisi, C. (2007) Towards zoomable multidimensional maps of the cell. Nat Biotechnol 25, 547–54.

    Article  PubMed  CAS  Google Scholar 

  63. Kelley, B. P., Yuan, B., Lewitter, F., Sharan, R., Stockwell, B. R., and Ideker, T. (2004) PathBLAST: a tool for alignment of protein interaction networks. Nucleic Acids Res 32, W83–8.

    Article  PubMed  CAS  Google Scholar 

  64. Flannick, J., Novak, A., Srinivasan, B. S., McAdams, H. H., and Batzoglou, S. (2006) Graemlin: general and robust alignment of multiple large interaction networks. Genome Res 16, 1169–81.

    Article  PubMed  CAS  Google Scholar 

  65. Krauthammer, M., Kaufmann, C. A., Gilliam, T. C., and Rzhetsky, A. (2004) Molecular triangulation: bridging linkage and molecular-network information for identifying candidate genes in Alzheimer’s disease. Proc Natl Acad Sci U S A 101, 15148–53.

    Article  PubMed  CAS  Google Scholar 

  66. Lim, J., Hao, T., Shaw, C., Patel, A. J., Szabo, G., Rual, J. F., Fisk, C. J., Li, N., Smolyar, A., Hill, D. E., Barabasi, A. L., Vidal, M., and Zoghbi, H. Y. (2006) A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801–14.

    Article  PubMed  CAS  Google Scholar 

  67. Workman, C. T., Mak, H. C., McCuine, S., Tagne, J. B., Agarwal, M., Ozier, O., Begley, T. J., Samson, L. D., and Ideker, T. (2006) A systems approach to mapping DNA damage response pathways. Science 312, 1054–9.

    Article  PubMed  CAS  Google Scholar 

  68. Chuang, H. Y., Lee, E., Liu, Y. T., Lee, D., and Ideker, T. (2007) Network-based classification of breast cancer metastasis. Mol Syst Biol 3, 140.

    Article  PubMed  Google Scholar 

  69. Yildirim, M. A., Goh, K. I., Cusick, M. E., Barabasi, A. L., and Vidal, M. (2007) Drug-target network. Nat Biotechnol 25, 1119–26.

    Article  PubMed  CAS  Google Scholar 

  70. Wang, J., Rao, S., Chu, J., Shen, X., Levasseur, D. N., Theunissen, T. W., and Orkin, S. H. (2006) A protein interaction network for pluripotency of embryonic stem cells. Nature 444, 364–8.

    Article  PubMed  CAS  Google Scholar 

  71. Endy, D. (2005) Foundations for engineering biology. Nature 438, 449–53.

    Article  PubMed  CAS  Google Scholar 

  72. Vidal, M. (2005) Interactome modeling. FEBS Lett 579, 1834–8.

    Article  PubMed  CAS  Google Scholar 

  73. Gandhi, T. K., Zhong, J., Mathivanan, S., Karthick, L., Chandrika, K. N., Mohan, S. S., Sharma, S., Pinkert, S., Nagaraju, S., Periaswamy, B., Mishra, G., Nandakumar, K., Shen, B., Deshpande, N., Nayak, R., Sarker, M., Boeke, J. D., Parmigiani, G., Schultz, J., Bader, J. S., and Pandey, A. (2006) Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet 38, 285–93.

    Article  PubMed  CAS  Google Scholar 

  74. Brideau, N. J., Flores, H. A., Wang, J., Maheshwari, S., Wang, X., and Barbash, D. A. (2006) Two Dobzhansky–Muller genes interact to cause hybrid lethality in Drosophila. Science 314, 1292–5.

    Article  PubMed  CAS  Google Scholar 

  75. Han, J. D., Bertin, N., Hao, T., Goldberg, D. S., Berriz, G. F., Zhang, L. V., Dupuy, D., Walhout, A. J., Cusick, M. E., Roth, F. P., and Vidal, M. (2004) Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature 430, 88–93.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Chang, A.N. (2009). Prioritizing Genes for Pathway Impact Using Network Analysis. In: Nikolsky, Y., Bryant, J. (eds) Protein Networks and Pathway Analysis. Methods in Molecular Biology, vol 563. Humana Press. https://doi.org/10.1007/978-1-60761-175-2_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-175-2_8

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-174-5

  • Online ISBN: 978-1-60761-175-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics