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SIAM San DiegoT Id kTrey IdekerJuly 11 2008y
Network Biology: Mapping pathways toNetwork Biology: Mapping pathways to understand and diagnose disease
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Many kinds of interaction technologiesPHYSICAL GENETIC
Protein-gene(transcriptional, ChIP-Chip22, 39) Epistatic orderings
a < b OR b < aORDERED
Cause and effectSignal transducing
Protein-RNA (RIP-chip80)
Protein-protein(kinase substrate
a b OR b a(EMAP28, 83)
Knock-down expression profiles(RNAi32 deletion mutants36, 37)Signal transducing (kinase-substrate
arrays21, LUMIER81)
Protein-compound82
(RNAi32, deletion mutants36, 37)
Expression QTLs41, 42
UNORDERED
Ambiguous
Protein-protein(co-IP/MS/MS18-20, Y2H15, 84-86)
Synthetic lethalityab << a, b, wt
(SGA88 dSLAM31 71 EMAP28 83gdirectionality Gene-gene (co-regulon87) (SGA88, dSLAM31, 71, EMAP28, 83,
chemogenomic profiling89)
Beyer, Bandyopadhyay, and Ideker Nat. Rev. Genetics (2007)
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Like sequence, molecular interaction d t idl iTwo overriding aims:data are rapidly growing…Two overriding aims:
IntAct Database Growthtotal interactions (thousands)
EMBL Database Growthtotal nucleotides (gigabases)
192 1001) Assemble many interactions and types into unified models
96 502) Get rid of false and non-functional interactions
1980 200019900
2008 2003 20062005 20082004 20070
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These aims lead to many subproblemsThese aims lead to many subproblems
Mapping transcriptional networks
Networks to interpret genetic variations
Networks to interpret combinatorialNetworks to interpret combinatorial perturbations (e.g. synthetic lethals)
Network evolution
Network-based diagnosisNetwork based diagnosis
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Assembly ofAssembly ofphysical and genetic interactions
to map transcriptional circuits
(Chris Workman, Craig Mak with L S Ri h d K l d )Leona Samson, Richard Kolodner)
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Can this apparent paradox beCan this apparent paradox be explained by a physical model of the DNA damage response?the DNA damage response?
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ChIP-chip measurement of protein→DNA interactions
From Figure 1 of Simon et al. Cell 2001
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Mapping DNA Damage Response Networks
Numbers of promoters bound by each of 30 transcription factors (TFs) before and after exposure to methyl-methane sulfonate (MMS)
MMS only−MMS only
+MMS only
bothboth
Workman, Mak, et al. Science 2006
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Integration of cause-and-effect interactions with physical networks
Perturbationeffects
TF-promoter bindingPerturbation causes up-regulationProtein-protein bindingPerturbation causes down-regulation
Yeang, Mak et al. Genome Biology 2005
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Such methods can yield large regulatory networks
Workman, Mak, et al. Science 2006
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Sensitivity of the TF knockout phenotype correlates with its number of regulated targetscorrelates with its number of regulated targets
sed
gen
esre
gula
tem
ber o
f N
u
MMS sensitivity of TF knockout
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Mapping Pathways inSynthetic Lethal Networks
(Ryan Kelley, Sourav Bandyopadhyaywith Nevan Krogan)
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Finding physical pathways to explain genetic interactions
Genetic Interactions:
• Classical method used to h i d lmap pathways in model
species
• Highly analogous to• Highly analogous tomulti-genic interaction in human disease and combination therapy
• Thousands are being uncovered through systematic studiessystematic studies
Thus as with other types, the number of known genetic
Adapted from Tong et al., Science 2001
number of known genetic interactions isexponentially increasing…
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Integration of genetic and physical interactions
160 between-pathway models
101 within-pathway modelsp y
Num interactions:1,102 genetic933 physical933 physical
Kelley and Ideker Nature Biotechnology (2005)
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Systematic identification of “parallel pathway” relationships in yeastparallel pathway relationships in yeast
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Global organization of genetic linkages between physical modules (A Z)between physical modules (A-Z)
BridgingBridging genetic interactions
Overlapping pathwaysp y
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Towards a generative module mapU ti d l f ll hi h id k d l• Use generative model of cell which considers k modules
simultaneously along with their inter-module functional relationships.
• Consider both positive and negative quantitative genetic interactions (alleviating and aggravating)
•
Physical interaction score
Genetic interaction score
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Functional maps of protein complexes
with Nevan Krogan
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Using protein networks to understand molecular evolution
(with Roded Sharan, Richard Karp, and others)p, )
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Cross-comparison of networks:(1) Conserved regions in the presence vs. absence of stimulus(2) Conserved regions across different species
Kelley et al. PNAS 2003Ideker & Sharan Gen Res 2008
Sharan et al. RECOMB 2004Scott et al. RECOMB 2005Sharan & Ideker Nat. Biotech. 2006
Suthram et al. Nature 2005
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Plasmodium: a network apart?
Plasmodium-specificprotein complexes
Conserved Plasmodium / Saccharomyces protein complexes
protein complexes
Suthram et al. Nature 2005La Count et al. Nature 2005
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Pairwise alignment of the E. coli protein network versus the indicated species;
Sensitivity comparison of different methods
Flannick et al. Genome Research (2006) [Batzoglou Lab]
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1960BIOLOGICAL SEQUENCE COMPARISON
Haussler
1980 19901970
First protein
BIOLOGICAL SEQUENCE COMPARISON
Needleman/ Wunsch
PAM, BLOSUM
matrix
Swiss-Prot, GenBank,
EMBL-BankDayhoff,Jukes/Cantor Taylor,
Lipman,
Haussler, Borodovsky,
ChurchillSmith/
Waterman
First protein sequences by Sanger,
othersBLASTDoolittle
Stormo
Public genome-scale
databasesMathematical d l f
Wunschothers
Hidden Markov Models
A new type of data becomes routinely
Mining for motifs and domains
Scoring via transition
probabilities
Automated pairwise li t
Multiple alignment
models of evolution
Fast dynamic programming li t
routinely available
Analysis of global
properties; information
Database queries are
staple of molecular
alignment alignmentalignment information content
Interaction detection with
2-hybrid
MaWishInterologs; evolutionary
biology
Scale-free
Alon’s network motifs
????BIND, DIP, MINT, GRID
2-hybrid, mass. spec.
e o ut o a ymodels PathBLAST property;
robustness
ot s
Sharan/Karp/Ideker
????Ogata/ Kanehisa
BIOLOGICAL NETWORK COMPARISON1990 2005 2010?2001 20032002 2004
Sharan and Ideker Nat. Biotech (2006)
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Using protein networks for disease classification
(Han Yu Chuang)
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Such methods can yield large regulatory networks
Workman, Mak, et al. Science 2006
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Using protein networks to diagnose breast cancer metastasis
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Examples of “i f ti“informative
subnetworks”
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Network markers are more reproducible and increase classification accuracy of breast cancer metastasisy
Chuang et al. MSB, 2007
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www.cytoscape.orgOPEN SOURCE Java platform for integration of systems biology data
•Layout and query of interactionLayout and query of interaction networks (physical and genetic)
•Visual and programmatic integration of molecular state data (attributes)o o ecu a state data (att butes)
•The ultimate goal is to provide the tools to facilitate all aspects of pathway assembly and annotation.p y y
RECENT NEWS
•Version 2 5 released Summer 2007;Version 2.5 released Summer 2007; Scalability+efficiency now equivalent to best commercial packages•The Cytoscape Consortium is a 501(c)3 non-for-profit in the State of Californiay p ( ) p
•The Cytoscape ® Registered Trademark awarded
JOINTLY CODED with Agilent, ISB, Pasteur, Sloan-Kettering, UCSF, Unilever, U Toronto
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Genetic Interactions:
Ryan Kelley
DNA Damage Networks
Chris Workman Ryan Kelley,Sourav Bandyopadhyay,Nev Krogan (UCSF)
Craig MakLeona Samson (MIT)Tom Begley (U Albany)
Network Evolution:
Silpa SuthramRoded Sharan (Tel Aviv)
Cancer Diagnosis:Interpretation of eQTLs:
Roded Sharan (Tel Aviv)Richard Karp (Berkeley)
Han Yu Chuang,Steve Briggs,Tom Kipps,E j L (KAIST)
Interpretation of eQTLs:
Silpa SuthramAndreas BeyerYonina Eldar (Technion) Eunjun Lee (KAIST),
Doheon Lee (KAIST)Yonina Eldar (Technion)Richard Karp (Berkeley)
Funding: NIEHS, NIGMS, NSF, Packard, Agilent, Unilever
Websites: www.pathblast.org; www.cytoscape.org
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Networks perturbed by individual genetic variations
(Silpa Suthram)
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eQTLs generate cause-effect interactionseQTLs generate cause effect interactions
• Expression Quantitative pTrait Loci (eQTLs) look for associations between SNPs and geneSNPs and gene expression levels.
• All-vs-All analysis: ALL SNP l t d f G
enes
SNPs are evaluated for association with ALL gene expression levels.
G• This process can
generate thousands of associations SNPsassociations. SNPs
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Cause and effect interactionsCause and effect interactions
Knock-down expression profiles(RNAi deletion mutants)(RNAi, deletion mutants)
ORORExpression QTLs
Knockout causes up-regulationKnockout causes down-regulation
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Integration of cause-and-effect interactions with physical networks
Perturbationeffects
TF-promoter bindingPerturbation causes up-regulationProtein-protein bindingPerturbation causes down-regulation
Yeang, Mak et al. Genome Biology 2005
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ExamplesExamples
Suthram et al. Nature/EMBO MSB 2008Silpa Suthram