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    log 10
v P
  log 10
e P
p v 
p random
q e 
q random
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
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