ismb, june.26.2005. from protein sequences…to protein networks database dna and protein sequences...
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ISMB, June.26.2005
From protein sequences…to protein networks
DatabaseDNA and protein
sequences
Query Sequence
GACTGCATTAC
Family ofhomologous genes
Cellular responseof interest
Interaction pathwaysassociated with
cellular response
Database / Scaffold ofMolecular Interactions
www.cytoscape.org
Cytoscape.orgCytoscape is a freely-available (open-source, java-based) bioinformatics software platform forvisualizing biological networks (e.g. molecular interaction networks) andanalyzing networks with gene expression profiles and other state data.
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.
Core Features
• Customize network data display using visual styles
• Powerful graph layout tools
• Easily organize multiple networks
• Easily navigate large networks
• Filter the network
• Plugin APIInput/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
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
Baker’s yeast(Saccharomyes
cerevisiae)
Nematode worm(Caenorhabditis
elegans)
http://www.pathblast.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
Fruit fly(Drosophila
melanogaster)
Network alignment with PathBLAST
Pe random
Pv random
q
eq
p
vpPS
10
10
log
log
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 between-pathway models
101 within-pathway models
Num interactions:1,102 genetic933 physical
Ryan Kelley et al. Nature Biotechnology 2005
A between-pathway model
www.cytoscape.org
Upcoming Events
• Cytoscape ConferenceNov 30th and Dec 1st, 2005
• RECOMB Satellite Conference on Network Biology and Gene RegulationDec 2nd-4th, 2005
Mailing lists– [email protected]– [email protected]
www.cytoscape.org
Cytoscape Team
Trey IdekerMark AndersonNerius LandysRyan KelleyChris Workman
Past contributors:Nada AminOwen OzierJonathan Wang
Benno SchwikowskiLee HoodRichard BonneauRowan Christmas
Past contributors:Iliana Avila-CampilloLarissa KamenkovichAndrew MarkielPaul Shannon
Chris SanderGary BaderEthan CeramiRob Sheridan
AgilentAnnette AdlerAllan KuchinskyAditya VailayaMike Creech
www.cytoscape.org
Funding Sources
• NIH (NIGMS) R01 GM070743-01Program Manager: John Whitmarsh
• NCI caBIGKen Buetow, Peter Kovitz
• Unilever, PLCGuy Werner
• PathBLAST network comparisonNSF Quantitative Systems Biology
Program Manager: Mitra Basu
www.cytoscape.org
ExtensibleArchitecture: 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
yFiles Organic
yFiles Circular
www.cytoscape.org
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
Visual Styles
Load “Your Favorite Network”
Visual Styles
Load “Your Favorite Expression”Dataset
Visual Styles
Map expression valuesto node colors using acontinuous mapper
Visual Styles
Expression data mappedto node colors
www.cytoscape.org
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
Proteasome 26S
Proteasome 20S
Ribosome
RNA Pol core
RNA Splicing
Biomodules (ISB)
Prinz S, Avila-Campillo I, Aldridge C, Srinivasan A,Dimitrov K, Siegel AF, and Galitski TGenome Res. 2004 14: 380-390
www.cytoscape.org
Agilent Literature Search Plugin for Cytoscape
Extract Nouns/Verbs
(User Context/BNS)
SentenceTokenization
No
Is InterestingSentence?
Yes
Normalize Nouns(User Context/BNS)
Classify Sentence Into Interaction Type
BindCleaveInhibitPromoteCatalyze
Convert to ALFA
Retrieved Documents
Meta-Search
Terms Context
Query
Get Document
Output ALFANetwork
Query Interface
Information Extraction Routine
Output CytoscapeNetwork
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 AFBioinformatics. 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,Dimitrov K, Siegel AF, and Galitski TGenome Res. 2004 14: 380-390