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Reactome - a curated knowledgebase of human biological pathways and processes Overview • What is Reactome? • The Reactome Website Browsing and Seaching the Reactome Website Viewing Pathways Viewing Reactions Viewing Proteins • Reactome Use Cases Skypainter 3rd Party Tools • Future Directions and Questions Reactome Rationale A picture paints a thousand words… ...BUT • is not computationally accessible • doesn’t convey enough detail Nature. 2000 Oct 12;407(6805):770-6. The biochemistry of apoptosis. http://www.reactome.org Background • Open source project • Started off as Genome Knowledgebase (GKB) in 2001 • Re-branded as Reactome in 2004 • Reactome is a free, expert-authored, peer-reviewed knowledgebase of pathways and reactions in human biology • Data Analysis and Visualization Tools • Data downloads – interaction, BioPAX, SBML, etc. • Curated human data are used to infer orthologous events in 22 non-human species • Model organism Reactomes: Arabidopsis, Gallus, Drosophila, (Oryzae) Reactome aims to help guide biological research by organising published pathway data and making it freely available Theory - Reactions • Basic “unit” of Reactome • Represents many events and states found in biology. DEGRADATION BINDING DISSOCIATION DEPHOSPHORYLATION PHOSPHORYLATION “CLASSICAL” TRANSPORT BIOCHEMICAL Reactome Reaction & Pathway Regulation Input 1 Output Reaction Input 2 Compartment CatalystActivity Pathway Pathway Reaction Reaction Where the Data Comes From 1) 2) Recruit bench scientists to write modules. Authors use a software tool to describe their pathway. • • 3) 4) 5) 6) 7) All molecules must be identified explicitly. All assertions backed up by literature references. Curators work with authors to ensure consistency and completeness. Module checked by peer review & software before publication. Public Release of Curated data every 3 months. Rolling review every 2 years by expert. Pathways updates. Reactome Pathway Coverage Human 4076 protein 3669 reactions 3032 complexes 1081 pathways Other species in Reactome • Primary focus: manual curation of human reactions • Some human reactions are manually inferred from other species (lack of experimental evidence in human) • For each release, a set of electronically inferred pathways and reactions for non-human species is produced based on orthology data (OrthoMCL system) human (Homo sapiens) rice (Oryza savita) mouse (Mus musculus) chicken (Gallus gallus) rat (Rattus norvegicus) baker’s yeast (Saccharomyces cerevisiae) Model Organism Reactomes Increasing Coverage • Reactome will hit 5000 proteins by end of 2010. – There are ~20,000 genes in genome • To get more coverage, we added non-Reactome data sets to create a “corona” of less reliable data around each pathway. • Corona connected to pathway components by probable functional interaction links. Corona Data Sources & Combined Network • Pathway databases – INOH, PANTHER, KEGG, CellMap, PID • Bimolecular interactions – Human interactions from BioGrid, BIND, IntACT, HRPD – Interlogs from yeast, worm, fly • Shared GO terms • Gene co-expression data – Multiple sources • Transcription factors/targets – TRED • Literature mining – GeneWays 10,956 proteins 209,988 interactions 46% coverage of UniProt Figure: 15% of the combined network The Reactome Website The Reactome Website Exploring the Pathway http://www.reactome.org/cgi-bin/eventbrowser?ID=69278 Understanding the Reaction Reaction diagram Reactants, products, catalyst. http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_6891 Your Favourite Protein Links to other databases Cellular compartment http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70597 Searching Reactome Reactome Use Cases Using Reactome to Explore your Experimental data Curated F.I. SkyPainter • Visualize High Throughput Datasets Using the Reactome “Starry Sky” • Determine which events (reactions and/or pathways) are overrepresented in a list of genes/proteins/small molecules • Many identifiers can be submitted Usable identifiers: NP_000005 NP_001080 NP_005836 NP_005461 NP_009297 •UniProt •RefSeq •Ensembl •OMIM •Entrez Gene •Affymetrix •GO •KEGG COMPOUND •ChEBI http://www.reactome.org/cgi-bin/skypainter2 Overrepresented Events (GBM Sequenced Genes) Decreasing significance Overrepresentation Analysis (with Numerical Values) Step through, stop/start dataset display Using Reactome to Explore Cancer Datasets Applying Reactome to Cancer Challenges in treating cancer: Every tumor is different Every cancer patient is different New Sequencing Technologies • Drastic decrease in costs per genome • Capacity greater than one Gigabase per run Illumina/Solexa • Applications: DNA, RNA, chromatin (i.e. epigenome) ABI/SOLiD Genes and Pathways associated with Cancer Download Reactome Data “MySQL Dump” “Interactions” SBML BioPAX Textbook Local installation Data entry tool API http://www.reactome.org/download/index.html Exploring Experimental Cancer data sets using Cytoscape and Reactome data Reactome - In progress • Website re-design • New Entity-level view for pathway layout based upon SBGN • New “Pathway Analysis” portal incl. overrepresentation analysis • Colouring of Entity-level view with user-supplied data In Progress: Entity Level Viewer Future • Creating Reactomes for model organisms • Active recruitment of authors to create pathway modules • Reactome’s focus is normal human biology – how about pathological pathways? • Integrating Chemoinformatics resources into Reactome Summary Tools Web Data Reactome: an encyclopedia of pathways and provides data mining tools for life scientists Thank you Please email comments and suggestions to [email protected] Follow Reactome at http://www.facebook.com/group.php?gid=244908260192 http://twitter.com/reactome http://www.linkedin.com/groups?gid=2118372 http://mail.reactome.org/mailman/listinfo/reactome-announce