protein-protein interaction networks
TRANSCRIPT
Protein‐ProteinInterac-onNetworksPredic-on,Visualiza-onandAnalysis
VijayarajNagarajanPhDComputa4onalMolecularBiologySpecialist
Bioinforma4csandComputa4onalBiosciencesBranch
Na4onalIns4tuteofAllergyandInfec4ousDiseasesOfficeofCyberInfrastructureandComputa4onalBiology
Outline• Introduc4ontoInterac4onNetworks
• Basiccomponentsofaninterac4onnetwork
• Typesofinterac4onnetworks• Predic4ngProtein‐ProteinInterac4onNetworks
• Methods» Logicandconcept
• AvailableInterac4ondata• Integratedprotein‐proteininterac4ondatabases• Searchingforinterac4ondata
• NetworkVisualiza4onandAnalysistools• Popularvisualiza4ontools• Networkanalysis
• Demonstra4on• Predic4onofinterac4on(PPI…?)networkfrommicroarray(ARACNE)
• Visualiza4onandanalysisofthepredictednetwork(Cytoscape)
• Nodes– DNA/RNA/Protein/Metabolite
• EdgesDirected
– Dis4nc4onbetweensourceandtarget» Ac4va4on(direct/indirect)» Repression(direct/indirect)
Undirected
– Nodis4nc4onbetweensourceandtarget» Co‐expression(indirect)» Binding(direct)
Interac-onNetworks–BasicComponents
Interac-onNetworks‐BasicFeatures• Degree
• Numberofconnec4onsthatanodehas
• Distance• Numberofconnec4onsbetweentwonodes,inashortestpath
• Path• Asequenceofconnec4ons• Isthereapath(reachability)• MeanShortestPathdistance(closeness)• Inhowmanyshortestpaths(betweenness)
• Sizeofanetwork(Numberofnodes)• Densityofanetwork(Propor4onoftheconnec4ons)
• Mo4fs/Cliques/Clusters/Sub‐networks
Loops
Chains
Parallels
Multi-input Single input
Interac-onNetworks‐BasicFeatures
TypesofInterac-onNetworks• DNA‐Protein
» Transcrip4onalregulatorynetworks» Methyla4onnetworks
• RNA‐RNA» miRNAregulatorynetworks
• RNA‐Protein» Splicingregulatorynetworks
• Protein‐Protein» Co‐expressionnetworks» Co‐localiza4onnetworks» Co‐evolu4onnetworks» Structurenetworks» Pathwaynetworks» Proteaseregulatorynetworks» Signaltransduc4onnetworks» GeneOntologynetworks
Singlegene
– Regulators/Co‐regulators– Upstream/Downstreamelementsinthenetwork
– Globalconnec4vity/interconnec4vity– Func4onalfeatures– Differen4allyexpressedsubnetworks– Onegene–onedisease:bunchofgenes–pathways– Nextgensequencingdata
List of genes
WhyBuild/AnalyzeInterac-onNetworks?
Outline• Introduc4ontoInterac4onNetworks
• Basiccomponentsofaninterac4onnetwork
• Typesofinterac4onnetworks• Predic4ngProtein‐ProteinInterac4onNetworks
• Methods» Logicandconcept
• AvailableInterac4ondata• Integratedprotein‐proteininterac4ondatabases• Searchingforinterac4ondata
• NetworkVisualiza4onandAnalysistools• Popularvisualiza4ontools• Networkanalysis
• Demonstra4on• Predic4onofinterac4on(PPI…?)networkfrommicroarray(ARACNE)
• Visualiza4onandanalysisofthepredictednetwork(Cytoscape)
HowtoBuildInterac-onNetworks?• Search/Retrievefromknowledgebases• Predictfromgenomesequences
• Predictfrom“omics”data
• Predictfromliterature• Integrateandanalyze
Protein Engineering, Vol. 14, No. 9, 609-614, September 2001
Predic-onfromgenomesequences• Geneneighbor(genecluster,geneorder)• Genefusion(Rose\astone)• Phylogene4cprofiling• Co‐evolu4on• Mirrortree
Predic-onfrom“omics”data• Co‐expression(Correla4on,MutualInforma4on)
• Integrated(Classifica4on)• Literaturemining(NaturalLanguageProcessing)
Outline• Introduc4ontoInterac4onNetworks
• Basiccomponentsofaninterac4onnetwork
• Typesofinterac4onnetworks• Predic4ngProtein‐ProteinInterac4onNetworks
• Methods» Logicandconcept
• AvailableInterac4ondata• Integratedprotein‐proteininterac4ondatabases• Searchingforinterac4ondata
• NetworkVisualiza4onandAnalysistools• Popularvisualiza4ontools• Networkanalysis
• Demonstra4on• Predic4onofinterac4on(PPI…?)networkfrommicroarray(ARACNE)
• Visualiza4onandanalysisofthepredictednetwork(Cytoscape)
AvailableInterac-onData• MINT
• MolecularInterac4onDatabase
• BIND• BiomolecularInterac4onNetworkDatabase
• DIP• DatabaseofInterac4ngProteins
• IntAct• InterAc4onDatabaseatEBI
IntegratedDataSources
• PathwayCommons• BioGRID
• MiMI(MichiganMolecularInterac4ons)
• STRING(SearchToolforRetrievalofInterac4ngGenes/Proteins)• Genes2Network
• VisANT(Integra4veVisualAnalysisTool)
• BIOBASE• IPA(IngenuityPathwayAnalysis)
• MetaCore
Open Source
Proprietary
IP3Rs• Inositoltriphosphatereceptor
• ip3r1• ip3r2• ip3r3
» Calciumionchannels
» ER• s4m1(stromalinterac4onmolecule1)
» PM» Calciumsensorprotein
• orai1(calciumreleaseac4vatedcalciummodulator)» PM
» Accessoryproteindownstreamofs4m1
SearchingforInterac-onData
STRING
IPA
IPA
Outline• Introduc4ontoInterac4onNetworks
• Basiccomponentsofaninterac4onnetwork
• Typesofinterac4onnetworks• Predic4ngProtein‐ProteinInterac4onNetworks
• Methods» Logicandconcept
• AvailableInterac4ondata• Integratedprotein‐proteininterac4ondatabases• Searchingforinterac4ondata
• NetworkVisualiza4onandAnalysistools• Popularvisualiza4ontools• Networkanalysis
• Demonstra4on• Predic4onofinterac4on(PPI…?)networkfrommicroarray(ARACNE)
• Visualiza4onandanalysisofthepredictednetwork(Cytoscape)
• Cytoscape• VisANT(Integra4veVisualAnalysisTool)• Osprey• BioLayout
PopularVisualiza-onTools
VisANT
AnalysisTools• Phunkee(PairingsubgraphsUsingNetworkEnvironmentEquivalence–finds
similarsubnets)
• mfinder(mo4fdetec4on)
• MAVisto(Mo4fAnalysisandVisualiza4ontool–explora4onofmo4fs)
• GraphMatch(Searchforsimilarsub‐nets)
• NeAT(NetworkAnalysisTools–mo4ffinding,nodesta4s4cs)
• Cfinder(Findsclusters–densegroupofnodes)• NetworkBLAST(Comparesmul4plenetworkstoinfercomplexes&paths)
Outline• Introduc4ontoInterac4onNetworks
• Basiccomponentsofaninterac4onnetwork
• Typesofinterac4onnetworks• Predic4ngProtein‐ProteinInterac4onNetworks
• Methods» Logicandconcept
• AvailableInterac4ondata• Integratedprotein‐proteininterac4ondatabases• Searchingforinterac4ondata
• NetworkVisualiza4onandAnalysistools• Popularvisualiza4ontools• Networkanalysis
• Demonstra4on• Predic4onofinterac4on(PPI…?)networkfrommicroarray(ARACNE)
• Visualiza4onandanalysisofthepredictednetwork(Cytoscape)
PPIPredic-onUsingMicroarrayData• Co‐expressionconcept
• Correla4onCoefficient» SIMoNE(Sta4s4calInferenceforModularNetworks)‐R
• MutualInforma4on» ReferenceNetworks» ARACNE(AlgorithmforReconstruc4onofAccurateCellular
Networks)–R,geWorkbench» CLR(ContextLikelihoodofRelatedness)–R» MRNET(MaximumRelevance/MinimumRedundancy)–R
» MONET(ModularizedNETworkLearning)‐Cytoscape
• BayesianNetwork
PPIPredic-onUsingMicroarrayData• Melanomametastasis
• 83samples
• Affymetrix• GEO• ARACNE• geWorkbench• IP3R1,IP3R2,IP3R3,STIM1,ORAI1
GML File
PredictedPPINetwork• Couldformacomplex• Couldbefunc4onallyassociated
• Couldbeinvolvedinasamemetabolicpathway
• Couldbeinvolvedinaspecificsignaltransduc4onpath• Falseposi4ve
Visualiza-onandAnalysisUsingCytoscape• Cytoscape
• Opensource• WorksinWindows,Linux,Mac• Oneofthefirstdevelopedtools• GreatnumberofPLUGINS
• Excellenthelpfromcommunity
LiteratureBasedPPIPredic-onUsingCytoscape
RetrievingPPIUsingCytoscape
DataVisualiza-on,Integra-on,Analysis• ImportARACNEpredictednetwork
• ImportVisANTretrievednetwork• Mergeallnetworks
• Mo4ffinding
NetCirChro(NetworksonCircularChromosomes)‐Citratecycle
B.sub'lisE.coli S.typhi S.aureus
Gram-negative Bacteria Gram-positive Bacteria
ThankYou