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ISMB, June.26.2005 From protein sequences…to protein networks Query Sequence GACTGCATTAC Cellular response of interest Database DNA and protein sequences Family of homologous genes Database / Scaffold of Molecular Interactions Interaction pathways associated with cellular response Core Features • Customize network data display using visual styles • Powerful graph layout tools • Easily organize multiple networks • Easily navigate large networks Cytoscape.org Cytoscape is a freely-available (open-source, java-based) bioinformatics software platform for visualizing biological networks (e.g. molecular interaction networks) and analyzing networks with gene expression profiles and other state data. • Filter the network • Plugin API Input/Output • Protein protein interactions from BIND, TRANSFAC databases • Gene functional annotations from Gene Ontology (GO) and KEGG databases • Biological models from Systems Biology Markup Language (SBML) • cPath: Cancer Pathway database • Proteomics Standards Initiative Molecular Interaction (PSI-MI) or Biopathway Exchange Language (BioPAX) formats • Oracle Spatial Network data model www.cytoscape.org Additional features are available as plugins. • jActiveModules: identify significant “active” subnetworks • Expression Correlation Network: cluster expression data • Agilent Literature Search: build networks by extracting interactions from scientific literature. • MCODE: finds clusters of highly interconnected regions in networks • cPath: query, retrieve and visualize interactions from the MSKCC Cancer Pathway database • BiNGO: determine which Gene Ontology (GO) categories are statistically over-represented in a set of genes • Motif Finder: runs a Gibbs sampling motif detector on sequences for nodes in a Cytoscape network. • CytoTalk: Interact with Cytoscape from Perl, Python, R, shell scripts or C or C++ programs. Outline • Introduction (5 min) • Cytoscape as a network integration and query tool • Basic features demo (15 min) • • • • • Load network Navigate/Zoom/Select/Filter Nodes Create subnetworks Visual styles Layout • Plugin demo (25 min) • MCODE and BinGO • Agilent Literature Search Plug-in • cPATH • Future work (5 min) www.cytoscape.org cPath PlugIn • cPath: Overview • cPath: XML Web Service • cPath Cytoscape PlugIn – Demo: Download sample protein-protein interaction network. – Demo: Drill down to protein details. www.cytoscape.org www.cytoscape.org cPath: XML Web Services API • Provides a URL-HTTP XML Web Services API to all cPath Data. • Formats: – PSI-MI: Proteomics Standards Initiative Molecular Interaction Format – BioPAX: Biological Pathway Exchange Format • Commands: – Query by keyword; query by interactor name; query by Pub Med ID, etc. • Example Query: • http://www.cbio.mskcc.org/cpath/webservice.do?version=1.0 &cmd=get_by_interactor_name_xref&q=P04273&format=psi _mi&startIndex=0&organism=&maxHits=10 www.cytoscape.org cPath Cytoscape PlugIn • Enables Cytoscape users to easily query, download and visually render interactions stored in cPath. • Utilizes the cPath XML Web Service • Automatically bundled with Cytoscape 2.1 – Works out of the box • Additional details available on the Cytoscape PlugIn home page: – http://cytoscape.org/plugins2.php www.cytoscape.org cPath PlugIn Demo www.cytoscape.org cPath PlugIn Demo www.cytoscape.org FUTURE DIRECTIONS: Cross-comparison of networks (1) Alignment of networks across species (network conservation) (2) Correspondence between physical and genetic networks (3) Conserved regions in the presence vs. absence of stimulus Baker’s yeast (Saccharomyes cerevisiae) Nematode worm (Caenorhabditis elegans) www.cytoscape.org http://www.pathblast.org Fruit fly (Drosophila melanogaster) Network alignment with PathBLAST S P log10 vP log10 eP p v prandom qe qrandom P is a path in the global alignment graph. The v and e represent vertices and edges in P. The value p(v) is the prob. of true homology for the proteins aligned at v. The value q(e) is the prob. that the protein interaction at e is real, i.e., not a false-positive. Example yeast/worm/fly alignments Roded Sharan et al. PNAS 2005 Integration of genetic and physical interactions 160 betweenpathway models 101 withinpathway models Num interactions: 1,102 genetic 933 physical Ryan Kelley et al. Nature Biotechnology 2005 A between-pathway model Upcoming Events • Cytoscape Conference Nov 30th and Dec 1st, 2005 • RECOMB Satellite Conference on Network Biology and Gene Regulation Dec 2nd-4th, 2005 Mailing lists – [email protected] – [email protected] www.cytoscape.org Cytoscape Team Benno Schwikowski Lee Hood Richard Bonneau Rowan Christmas Trey Ideker Mark Anderson Nerius Landys Ryan Kelley Chris Workman Chris Sander Gary Bader Ethan Cerami Rob Sheridan Agilent Past contributors: Iliana Avila-Campillo Past contributors: Annette Adler Allan Kuchinsky Larissa Kamenkovich Nada Amin Aditya Vailaya Andrew Markiel Owen Ozier Paul Shannon Jonathan Wang Mike Creech www.cytoscape.org Funding Sources • NIH (NIGMS) R01 GM070743-01 Program Manager: John Whitmarsh • NCI caBIG Ken Buetow, Peter Kovitz • Unilever, PLC Guy Werner • PathBLAST network comparison NSF Quantitative Systems Biology Program Manager: Mitra Basu www.cytoscape.org Extensible Architecture: 100% open source Java – Core + plugin API – Plugins are independently licensed – “Just need to write the algorithm” – Template code samples Plugin www.cytoscape.org Layout • 16 algorithms available through plugins • Zooming, hide/show, alignment www.cytoscape.org yFiles Organic yFiles Circular Visual Styles • Map graph attributes to visual attributes • Define visual styles for later use • Graph has node and edge attributes • E.g. expression data, interaction type, GO function • Mapped to visual attributes • E.g. node/edge size, shape, color, font… • Take continuous gene expression data and visualize it as continuous node colors www.cytoscape.org Visual Styles Load “Your Favorite Network” Visual Styles Load “Your Favorite Expression” Dataset Visual Styles Map expression values to node colors using a continuous mapper Visual Styles Expression data mapped to node colors Visual Styles • Node attributes: node color, border color, border type, node shape, size, label, font • Edge attributes: edge color, line types, arrows, label, font • Multidimensional visual attribute mapping soon www.cytoscape.org MCODE and Biomodules Plugins (MSKCC and ISB) • Clusters in a protein-protein interaction network have been shown to represent protein complexes and parts of pathways • Clusters in a protein similarity network represent protein families • Network clustering is available through the MCODE Cytoscape plugin www.cytoscape.org Proteasome 26S Ribosome Proteasome 20S RNA Splicing RNA Pol core Biomodules (ISB) Prinz S, Avila-Campillo I, Aldridge C, Srinivasan A, Dimitrov K, Siegel AF, and Galitski T Genome Res. 2004 14: 380-390 Agilent Literature Search Plugin for Cytoscape Terms Output ALFA Network Context Convert to ALFA Query Meta-Search Query Interface Output Cytoscape Network Classify Sentence Into Interaction Type Normalize Nouns (User Context/BNS) Retrieved Documents Get Document Bind Cleave Inhibit Promote Catalyze Yes Sentence Tokenization Extract Nouns/Verbs (User Context/ BNS) No Is Interesting Sentence? Information Extraction Routine www.cytoscape.org www.cytoscape.org Cytoscape Network produced by Literature Search. Abstract from the scientific literature Sentences for an edge www.cytoscape.org Active Modules (UCSD) Ideker T, Ozier O, Schwikowski B, Siegel AF Bioinformatics. 2002;18 Suppl 1:S233-40 www.cytoscape.org Active Modules www.cytoscape.org Biomodules (ISB) Prinz S, Avila-Campillo I, Aldridge C, Srinivasan A, www.cytoscape.org Dimitrov K, Siegel AF, and Galitski T Genome Res. 2004 14: 380-390