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  3 rd Party Tools Future Directions and Questions

Nature Oct 12;407(6805): The biochemistry of apoptosis. A picture paints a thousand words…...BUT is not computationally accessible doesn’t convey enough detail Reactome Rationale

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. BINDING DEGRADATION TRANSPORT PHOSPHORYLATION DEPHOSPHORYLATION “CLASSICAL” BIOCHEMICAL DISSOCIATION

Compartment Reactome Reaction & Pathway Pathway Reaction CatalystActivity Output Reaction Input 1 Input 2 Regulation

1)Recruit bench scientists to write modules. 2)Authors use a software tool to describe their pathway. All molecules must be identified explicitly. All assertions backed up by literature references. 3)Curators work with authors to ensure consistency and completeness. 4)Module checked by peer review & software before publication. 5)Public Release of Curated data every 3 months. 6)Rolling review every 2 years by expert. 7)Pathways updates. Where the Data Comes From

Reactome Pathway Coverage Human 4076 protein 3032 complexes 3669 reactions 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) rat (Rattus norvegicus) mouse (Mus musculus) rice (Oryza savita) chicken (Gallus gallus) baker’s yeast (Saccharomyces cerevisiae )

Model Organism Reactomes

Increasing Coverage Reactome will hit 5000 proteins by end of – 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

Exploring the Pathway

Understanding the Reaction Reaction diagram Reactants, products, catalyst.

Your Favourite Protein Links to other databases Cellular compartment

Searching Reactome

Reactome Use Cases

Using Reactome to Explore your Experimental data Curated F.I.

SkyPainter Usable identifiers: UniProt RefSeq Ensembl OMIM Entrez Gene Affymetrix GO KEGG COMPOUND ChEBI 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 NP_ NP_ NP_ NP_ NP_009297

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

Illumina/Solexa ABI/SOLiD Drastic decrease in costs per genome Capacity greater than one Gigabase per run Applications: DNA, RNA, chromatin (i.e. epigenome) New Sequencing Technologies

Genes and Pathways associated with Cancer

Download Reactome Data SBML Local installation Data entry tool API BioPAX “Interactions” “MySQL Dump” Textbook

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 Web Data Tools Reactome: an encyclopedia of pathways and provides data mining tools for life scientists

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