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Session outline

Session outline. Standards and the problem of data integration Example: PSICQUIC and the PSICQUIC game Introduction to ontologies. Exploring the Gene Ontology -Coffee break- Introduction to protein-protein interactions (PPIs) IntAct : the molecular interactions database at the EBI

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Session outline

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  1. Session outline • Standards and the problem of data integration • Example: PSICQUIC and the PSICQUIC game • Introduction to ontologies. • Exploring the Gene Ontology • -Coffee break- • Introduction to protein-protein interactions (PPIs) • IntAct: the molecular interactions database at the EBI • -Lunch break- • Introduction to pathways • Reactome: a database of human biological pathways • -Coffee break- • Network representation and analysis: strategies and limitations • Network generation and analysis through Cytoscape and PSICQUIC

  2. Introduction to pathways

  3. What are pathways? • A set of bio-molecules that interact is called a: network > pathway > reaction > interaction/complex • Biologists have been studying and modeling living systems for decades (physiology) • Q. What underlies the physiology? • A. Interactions between the molecules (and cells) • A biological pathway is a model or abstraction of the functionalrelationships between the molecules that take part in a biological event.

  4. What are pathways? vs Protein interaction network Pathway reflects scientific consensus reflects potential physical relation

  5. What are pathways? • “Model or abstraction of the functional relationships between the molecules that take part in a biological event” • Generally pathways are a simple cascade of reactions leading to information flow • e.g. adrenaline signalling, • JAK-STAT pathway

  6. Canonical Pathways • The details of a named and characterized process • Is it complete? • Is it accurate? • Does it show all the details? • Can I see the evidence? • Is this up to date? • Can I export and reuse the steps?

  7. Identifying New Pathways • Mine existing data • Text or manually mine the literature • Annotate (manually or computationally) • Store in a useful way (database, exportable format) • e.g. KEGG, Ingenuity, Reactome • Analysis and interpretation of new high-throughput data • Bioinformatics approaches for mining large datasets • Highly varied, no ‘right’ method, results often subjective! • e.g. Reactome Functional Interaction network Pathways Protein interaction networks

  8. Pathway Databases • KEGG – by subscription • Reactome – free • Ingenuity - commercial • Metacore (GeneGO) – commercial • Related databases • The Gene Ontology Project – free • TRANSFAC – commercial • BioModels- free

  9. Pathway standards and tools • Data exchange formats (XML based) • BioPax • SBML • CellML • Modeling platforms • Cell Designer • BioUML • Graphical representation • SBGN

  10. A Database of human biological pathways Steve Jupe - sjupe@ebi.ac.uk

  11. Rationale – Journal information Nature 407(6805):770-6.The Biochemistry of Apoptosis. “Caspase-8 is the key initiator caspase in the death-receptor pathway. Upon ligand binding, death receptors such as CD95 (Apo-1/Fas) aggregate and form membrane-bound signalling complexes (Box 3). These complexes then recruit, through adapter proteins, several molecules of procaspase-8, resulting in a high local concentration of zymogen. The induced proximity model posits that under these crowded conditions, the low intrinsic protease activity of procaspase-8 (ref. 20) is sufficient to allow the various proenzyme molecules to mutually cleave and activate each other (Box 2). A similar mechanism of action has been proposed to mediate the activation of several other caspases, including caspase-2 and the nematode caspase CED-3 (ref. 21).” How can I access the pathway described here and reuse it?

  12. Rationale - Figures A picture paints a thousand words… • but…. • Just pixels • Omits key details • Assumes • Fact or Hypothesis? Nature. 2000 Oct 12;407(6805):770-6. The biochemistry of apoptosis.

  13. Reactome is… Free, online, open-source curated database of pathways and reactions in human biology Authored by expert biologists, maintained by Reactomeeditorial staff (curators) Mapped to cellular compartment

  14. Reactome is… Extensively cross-referenced Toolsfor data analysis – Pathway Analysis, Expression Overlay, Species Comparison, Biomart… Used to infer orthologous events in 20 other species

  15. BINDING DEGRADATION DISSOCIATION DEPHOSPHORYLATION PHOSPHORYLATION CLASSIC BIOCHEMICAL TRANSPORT Theory - Reactions Pathway steps = the “units” of Reactome = events in biology

  16. Reaction Example 1: Enzymatic

  17. Reaction Example 2: Transport Transport of Ca++ from platelet dense tubular system to cytoplasm REACT_945.4

  18. Other Reaction Types Dimerization Binding Phosphorylation

  19. Reactions Connect into Pathways CATALYST CATALYST CATALYST INPUT OUTPUT INPUT OUTPUT OUTPUT INPUT

  20. Evidence Tracking – Inferred Reactions Direct evidence PMID:5555 PMID:4444 Human pathway Indirect evidence PMID:8976 mouse PMID:1234 cow

  21. Species Selection • Human-based • 20 additional species computationally predicted

  22. Data Expansion – Projecting to Other Species Human B A A + ATP -P + ADP Mouse B A A + ATP + ADP -P Drosophila Reaction not inferred B + ATP A No orthologue - Protein not inferred

  23. Data Expansion - Link-outs From Reactome GO Molecular Function Compartment Biological process KEGG, ChEBI – small molecules UniProt – proteins Sequence dbs – Ensembl, OMIM, Entrez Gene, RefSeq, HapMap, UCSC, KEGG Gene PubMed references – literature evidence for events

  24. Exportable Protein-Protein Interactions Inferred from complexes and reactions (more on this later) Interactions between proteins in the same complex, reaction, or adjoining reaction Lists available from Downloads See Readme document for more details

  25. Coverage – Content, TOC And many more...

  26. Planned Coverage – Editorial Calendar

  27. Reactome Tools • Interactive Pathway Browser • Analysis • Pathway Mapping • Over-representation • Expression overlay • Molecular Interaction overlay • Biomart

  28. Tutorial Tutorial handouts in your info packages…

  29. Front Page http://www.reactome.org

  30. Exercise 1 …see the Tutorial handouts

  31. The Pathway Browser

  32. Pathway Hierarchy Panel Pathway Reaction Black-box

  33. Exercise 2 …see the Tutorial handouts

  34. The Pathway Browser - Pathway Diagrams Boxes are proteins, protein sets, mixed sets or complexes. Ovals are small molecules (or sets of) Green boxes are proteins or sets, blue are complexes. Regulation +ve -ve Input Reaction node Catalyst Outputs Compartment Transition Binding Dissociation Omitted Uncertain

  35. Exercise 3 …see the Tutorial handouts

  36. Navigating in the Pathway Browser I Home button Click here Highlights Details here Click here to open pathway diagram...

  37. Navigating in the Pathway Browser II Highlights Details here Click here Zoom

  38. Exercise 4 …see the Tutorial handouts

  39. The Details Panel

  40. Exercise 5 …see the Tutorial handouts

  41. Analysis – identifier list

  42. Overrepresentation P-vals

  43. Exercise 6 …see the Tutorial handouts

  44. Expression overlay I

  45. Expression overlay II

  46. Yellow = high Blue = low Expression overlay III Step through Data columns

  47. Exercise 7

  48. Species Comparison I Tools > Compare species

  49. Species Comparison II Yellow = human/rat Blue = human only No colour = no data

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