Ted Liefeld Cancer Informatics Development Broad Institute of MIT and Harvard Need: Insights through integrave studies Gene mutation causing Leigh Syndrome Discovery of 3 new genes involved in French Canadian Type (LFSC) and 8 Glioblastoma Multiforme (NF1, ERRB2, other mitochondrial diseases PIK3R1); Confirmation of TP53, PTEN, Integrate: candidate genomic region, EGFR, RB1, PIK3CA mitochondrial proteomic data, and cancer Integrate: DNA sequence, copy number, expression compendium methylation aberrations and expression Authors: Mootha et al. 2003, Calvo et al. 2006 profiles in 206 glioblastomas Authors: TCGA Research Network 2008 Subtle repression of oxphos genes in diabetic muscle: role for mitochondrial ~3000 novel, large non-coding RNAs with dysregulation in diabetes pathology; new functions in development, the immune computational approach Gene Set response and cancer Enrichment Analysis Integrate: Genome sequences from 21 Integrate: Gene sets/pathways & processes mammals, epigenomic maps, and with expression profiles expression profiles Authors: Mootha et al. 2003, Subramanian & Tamayo Authors: Guttman, Rinn et al. 2009 et al. 2005 Characterization of disease subtypes and IKBKE as a new breast cancer oncogene improved risk stratification for Integrate: RNAi screens, transformation medulloblastoma patients of activated kinases, and copy number Integrate: Copy number, expression, from SNP arrays of cell lines clinical data for 96 medulloblastoma Authors: Boehm et al. 2007 patients Authors: Tamayo et al., Cho et al. 2011 The Challenges • Flood of high throughput biological data genomic sequence, global mRNA expression profiles, copy number and LOH, epigene.c(data,( ( (protein(level(and(modi?c-.on(status,(( (metabolite(pro?les( 1(Prolifer-.on(of(tools( (Eatabases,(visualiF-.on,(and(analysis(( (EiGculty(of(geng(tools(to(Iork(together(( (Access,(analyFe,(visualiFe(each(data type(separately( Integrave Genomics Use Case GenePattern Cytoscape IGV/UCSC Genomica CMAP iii 1 Compendium Differentially Expressed Genes GCT GXP Load compendium Arrests SIF ODF GMT Show module G2/M 3 map Show i Network 2 GSEA test network GXC GRP enrichment 5 Show Extract HTML 4 module Expand +1 Chromosome Idea (include NA gene list ii Alterations neighbors) 6 Add Transcription Learn p53 atcgcgtttattcgataagg! Factor track site/score on atcgcgttttttcgataagg! Added to GenePattern from UCSC promoter Pathway iv activation v Expression 8 7 Test for Looks closeGFF GXAsimilarity of Conclusion to p53 site p53 and gene location vi 12 steps, 6 tools, 7 transions 1 i GenePattern Cytoscape IGV Genomica 2 3 ii iii CMAP UCSC Browser Analysis step 4 5 iv v Analysis conclusion Within tool Across tools 6 8 The Need( • A(lightweight Kconnec.on(layerL(for(a Iide(variety(of( integr-.ve(genomic(analyses( o Support for(all(types(of(resourceN(OebPbased,( desktop,(,tc. o Autom-.c(conversion(of(data formats(between(tools( o Easy(access(to(data from(any(loc-.on( o Any(tool(that Soins(is(autom-.cally(connected(to(the( community(of(tools( o Ease(of(entry(into(the(environment Cloud-based storage API connectivity layer Online community to share diverse computational tools 3 Driving Biological 6 Seed Tools Projects Tytoscape( lincRNAs( Ualaxy( UenePaern( Tancer(stem(cells( Uenomica IGV( P-.ent Str-.?c-.on( UCST(BroIser OutreachN(neI( OutreachN(neI( tools( www.genomespace.org EDBs( GenomeSpace Principles • ((Aimed(toIards(nonPprogramming(users( • Support interoperability(through( autom-.c(crossPtool(data transfer( • Re9uires(minimal(changes(to(tools( Open Source, LGPL @genomespace www.genomespace.org GenomeSpace Components Galaxy GenePattern Cytoscape Integrative Genomics Viewer GS Enabled Tools 1 Authentication and Authorization 2 3 Analysis and Data Manager Tool Manager Genome Space GenomeSpace Server Project Data … External Data Sources & Tools Seed Tools Cytoscape Galaxy GenePattern Genomica IGV UCSC Genome Browser Using UenomeSpace( Tools and Data Sources Actions Cloud- based filesystem UenomeSpace(=cons GenomeSpace Tool Enablement: IGV GenomeSpace Tool Enablement: Galaxy GenomeSpace Data Source Integration: InSilico DB Other collaborang projects • Tistrome((Dana Farber Cancer Ins.tute1% • Reactome((2ntario%Ins.tute%for%Cancer%Research1% • geOorkbench((Columbia%:niversity1%% • Taverna/MyExperiment((:niversity%of%Manchester1% • ArrayExpress((European%Bioinforma.cs%Ins.tute1% • N-.onal(Tenter(for(Biomedical(Ontology((Stanford :niversity1% • ISAPTOOAS((2Cford%:niversity1% • Archon(Genomics(XPPriFe( DBP3: Studying the regulatory control of human hematopoiesis DBP3: Studying the regulatory control of human hematopoiesis – Overview Part 1: Data pre-processing! Part 3: Studying the! Part 4: cis-regulatory! and quality control" transcriptional program" site analysis" Genomica From 2 From part 3 3 2 4 part 2 GenePattern 2 3 4 1 IGV To part 2 2 2 1 1 1 From part 2 1 Cytoscape Galaxy 1 1 1 1 1 2 2 Manual step 3 2 To part 5 1 2 Analysis section 1 Part 5: Finding new! 4 Analysis step (# steps) transcription factor regulators" 1 1 Analysis conclusion From part 4 Optional choices Part 2: Basic analysis" 1 Currently integrated From part 1 To part 3 3 1 2 3 2 Not yet integrated 2 2 1 2 2 1 3+ 2 1 2 1 To part 4 Part 5: Finding new! transcription factor regulators" From part 4 Step 1 2 3 Step 4 Step 2 2 Step 3 2 Step 1: Create transcription factor dataset in Genomica and save to GenomeSpace Step 2: Send transcription factor datasets into GenePattern Step 2: Perform differential expression analysis in GenePattern Step 3: Send differentially expressed genes to Genomica Step 3: perform module network analysis in Genomica Step 4: Visualize regulators with known SNPs and linkage regions Step 4: Visualize regulators with known SNPs and linkage regions GenomeSpaceDeployment Architecture Architecture Clients Amazon REST GS UI Clustered Identity REST Service IGV (OpenID) Analysis REST CDK Gene- Task Pattern Manager https (ATM) REST REST Galaxy Simple DB History REST REST UCSC REST Data Manager (DM) External REST Data Sources S3 File transfers 28 Adding it to your Galaxy hMpN//Iiki.g2.bx.psu.edu/UenomeSpace( 1. Pull(the(changesets( 2. Add(UenomeSpace('o your('oolbox 3. Enable(BpenID in your(con?g(?3,( 4. Restart Join the GenomeSpace community O,bre(looking(for( Researchers(Iith(driving(biological(proSects( Eevelopers(c(Eata providers( – Add(your tools( – Tontribute(format converters( – Build(neI(infrastructure( Acknowledgements GenomeSpace Collaborators Broad Institute Cytoscape: Trey Ideker Lab, UCSD Michael Reich Galaxy: Anton Nekrutenko Lab, Penn State University Helga Thorvaldsdottir Genomica: Eran Segal Lab, Weizmann Institute Jim Robinson UCSC Browser Team Marco Ocana GenePattern Team Jill Mesirov, PI IGV Team Driving Biological Projects Howard Chang Lab – Stanford University Aviv Regev Lab – Broad Institute Funding [email protected] www.genomespace.org @genomespace Queson#e(.