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May 2012 1 A Database of human biological pathways Steve Jupe -

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1 May A Database of human biological pathways Steve Jupe -

2 May 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?

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

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

5 May Extensively cross-referenced Tools for data analysis – Pathway Analysis, Expression Overlay, Species Comparison, Biomart… Used to infer orthologous events in 20 other species Reactome is…

6 May human PMID:5555PMID:4444 mouse cow Direct evidence Indirect evidence PMID:8976 PMID:1234 Using model organism data to build pathways – Inferred pathway events

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

8 May Reaction Example 1: Enzymatic

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

10 May Other Reaction Types Binding Dimerization Phosphorylation

11 May Reactions Connect into Pathways OUTPUT INPUT CATALYST OUTPUT INPUT CATALYST INPUT OUTPUT CATALYST

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

13 May 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

14 May Species Selection

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

16 May Exportable Protein-Protein Interactions Inferred from complexes and reactions Interactions between proteins in the same complex, reaction, or adjoining reaction Lists available from Downloads See Readme document for more details

17 May Coverage – Content, TOC And many more...

18 May Planned Coverage – Editorial Calendar

19 May Reactome Tools Interactive Pathway Browser Pathway Mapping and Over-representation Expression overlay onto pathways Molecular Interaction overlay Biomart

20 May Tutorial

21 May Front Page Sidebar Main text Navigation bar

22 May Exercise 1

23 May The Pathway Browser Species selector Diagram Key Sidebar Pathway Diagram Panel Details Panel (hidden) Zoom/move toolbar Thumbnail

24 May Pathways tab – pathway hierarchy Pathway Reaction Black-box

25 May Exercise 2 From the homepage, search for ‘Notch signaling’. Click on the top pathway hit. This will open it in the Pathway Browser. Ignoring the diagram for now, look at the Pathways tab on the left. 1.How many sub-pathways does this pathway have? 2.How many reactions are in the first of these sub-pathways? 3.What reaction follows Notch 2 precursor transport to Golgi? Hint: If it’s not visible, open the Details pane at the bottom of the page by clicking on the blue triangle.

26 May 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. Catalyst Input Outputs Compartment Reaction node Transition Binding Dissociation Omitted Uncertain Regulation +ve -ve

27 May Exercise 3

28 May Navigating in the Pathway Browser I Click here Highlights Details here Click here to open pathway diagram... Home and Analyze buttons

29 May Details here Navigating in the Pathway Browser II Click hereZoomHighlights

30 May Exercise 4

31 May The Details Panel

32 May Exercise 5

33 May Pathway Analysis

34 May Pathway Analysis – Overrepresentation ‘Top-level’ Reveal next level P-val

35 May Exercise 6 Check this!

36 May Species Comparison I

37 May Species Comparison II Yellow = human/rat Blue = human only Grey = not relevant Black = Complex

38 May Exercise 7

39 May Expression Analysis I

40 May Expression Analysis II ‘Hot’ = high ‘Cold’ = low Step through Data columns

41 May Exercise 8

42 May Molecular Interaction Overlay

43 May Exercise 9

44 May The End

45 May BioMart – selecting your dataset

46 May BioMart – filters

47 May BioMart – attributes Check to get attribute

48 May BioMart – results

49 May Exercise 10


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