Detecting functional modules in the yeast protein-protein interaction network

MOTIVATION Identification of functional modules in protein interaction networks is a first step in understanding the organization and dynamics of cell functions. To ensure that the identified modules are biologically meaningful, network-partitioning algorithms should take into account not only topological features but also functional relationships, and identified modules should be rigorously validated. RESULTS In this study we first integrate proteomics and microarray datasets and represent the yeast protein-protein interaction network as a weighted graph. We then extend a betweenness-based partition algorithm, and use it to identify 266 functional modules in the yeast proteome network. For validation we show that the functional modules are indeed densely connected subgraphs. In addition, genes in the same functional module confer a similar phenotype. Furthermore, known protein complexes are largely contained in the functional modules in their entirety. We also analyze an example of a functional module and show that functional modules can be useful for gene annotation. CONTACT yuan.33@osu.edu SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

[1]  Stefan Westermann,et al.  The Dam1 kinetochore ring complex moves processively on depolymerizing microtubule ends , 2006, Nature.

[2]  Marc Vidal,et al.  Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis , 2005, Nature.

[3]  Yasushi Hiraoka,et al.  Dissociation of the Nuf2-Ndc80 complex releases centromeres from the spindle-pole body during meiotic prophase in fission yeast. , 2005, Molecular biology of the cell.

[4]  Haruki Nakamura,et al.  Filtering high-throughput protein-protein interaction data using a combination of genomic features , 2005, BMC Bioinformatics.

[5]  Peter K Sorger,et al.  Molecular organization of the Ndc80 complex, an essential kinetochore component. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Olga G. Troyanskaya,et al.  Putting microarrays in a context: Integrated analysis of diverse biological data , 2005, Briefings Bioinform..

[7]  Brian Raught,et al.  Advances in protein complex analysis using mass spectrometry , 2005, The Journal of physiology.

[8]  E. Nogales,et al.  Formation of a dynamic kinetochore- microtubule interface through assembly of the Dam1 ring complex. , 2005, Molecular cell.

[9]  Gavin Sherlock,et al.  The Stanford Microarray Database accommodates additional microarray platforms and data formats , 2004, Nucleic Acids Res..

[10]  Hui Xiong,et al.  Identification of Functional Modules in Protein Complexes via Hyperclique Pattern Discovery , 2004, Pacific Symposium on Biocomputing.

[11]  Arun K. Ramani,et al.  Protein interaction networks from yeast to human. , 2004, Current opinion in structural biology.

[12]  Roded Sharan,et al.  Revealing modularity and organization in the yeast molecular network by integrated analysis of highly heterogeneous genomewide data. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Z. Oltvai,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[14]  A. Vespignani,et al.  The architecture of complex weighted networks. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Werner Waldhäusl,et al.  The ATP-dependent helicase RUVBL1/TIP49a associates with tubulin during mitosis. , 2003, Cell motility and the cytoskeleton.

[16]  L. Mirny,et al.  Protein complexes and functional modules in molecular networks , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Claudio Castellano,et al.  Defining and identifying communities in networks. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Anton J. Enright,et al.  Detection of functional modules from protein interaction networks , 2003, Proteins.

[19]  Michael Lässig,et al.  Local graph alignment and motif search in biological networks. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  L. Starita,et al.  Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells , 2003, Oncogene.

[21]  Alexander Rives,et al.  Modular organization of cellular networks , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Yaniv Ziv,et al.  Revealing modular organization in the yeast transcriptional network , 2002, Nature Genetics.

[23]  Ronald W. Davis,et al.  Functional profiling of the Saccharomyces cerevisiae genome , 2002, Nature.

[24]  B. Snel,et al.  Comparative assessment of large-scale data sets of protein–protein interactions , 2002, Nature.

[25]  Gary D Bader,et al.  Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry , 2002, Nature.

[26]  M E J Newman,et al.  Community structure in social and biological networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Ozawa,et al.  A comprehensive two-hybrid analysis to explore the yeast protein interactome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Sanjuán,et al.  Tracing the origin of the compensasome: evolutionary history of DEAH helicase and MYST acetyltransferase gene families. , 2001, Molecular biology and evolution.

[29]  M. Newman,et al.  Scientific collaboration networks. II. Shortest paths, weighted networks, and centrality. , 2000, Physical review. E, Statistical, nonlinear, and soft matter physics.

[30]  D. Bentley.  The Human Genome Project—An Overview , 2000 .

[31]  James R. Knight,et al.  A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae , 2000, Nature.

[32]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[33]  W. Jo.  Functional profiling of the Saccharomyces cerevisiae genome in the study of mechanisms of metal and metalloid toxicity , 2008 .

[34]  J. Rothberg,et al.  Gaining confidence in high-throughput protein interaction networks , 2004, Nature Biotechnology.

[35]  D. Bentley.  The Human Genome Project--an overview. , 2000, Medicinal research reviews.