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, epigenec data, protein level and modificaon status, metabolite profiles

• Proliferaon of tools Databases, visualizaon, and analysis Difficulty of geng tools to work together Access, analyze, visualize each data type separately Integrave Genomics Use Case

GenePattern 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 “connecon layer” for a wide variety of integrave genomic analyses o Support for all types of resource: Web-­‐based, desktop, etc. o Automac conversion of data formats between tools o Easy access to data from any locaon o Any tool that joins is automacally 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

Cytoscape lincRNAs Galaxy GenePaern Cancer stem cells Genomica IGV Paent Straficaon UCSC Browser

Outreach: new Outreach: new tools www.genomespace.org DPBs GenomeSpace Principles

• Aimed towards non-­‐programming users

• Support interoperability through automac cross-­‐tool data transfer

• Requires 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 GenomeSpace

Tools and Data Sources Actions

Cloud- based filesystem GenomeSpace Acons GenomeSpace Tool Enablement: IGV GenomeSpace Tool Enablement: Galaxy GenomeSpace Data Source Integration: InSilico DB Other collaborang projects

• Cistrome (Dana Farber Cancer Instute) • Reactome (Ontario Instute for Cancer Research) • (Columbia University) • Taverna/MyExperiment (University of Manchester) • ArrayExpress (European Bioinformacs Instute) • Naonal Center for Biomedical Ontology (Stanford University) • ISA-­‐TOOLS (Oxford University) • Archon Genomics X-­‐Prize 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

Galaxy Simple DB

History REST UCSC REST Data Manager (DM) External REST Data Sources

S3 File transfers 28 Adding it to your Galaxy hp://wiki.g2.bx.psu.edu/GenomeSpace

1. Pull the changesets 2. Add GenomeSpace to your toolbox 3. Enable OpenID in your config file 4. Restart Join the GenomeSpace community

We’re looking for Researchers with driving biological projects Developers & Data providers – Add your tools – Contribute format converters – Build new 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 Quesons?