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

A Database of human biological pathways Steve Jupe - sjupe@ebi.ac.uk. Background. Cells contain thousands of molecules, proteins and small chemical compounds They work together to perform tasks.   provide energy produce materials respond to the environment.

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

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

  2. ELLS 2011 Background • Cells contain thousands of molecules, • proteins and small chemical compounds • They work together to perform tasks.   • provide energy • produce materials • respond to the environment. • Processes require coordinated efforts • like a factory production line. • Biologists refer to a chain of connected molecular events as a pathway.

  3. ELLS 2011 Different types of pathways • Metabolic networks – provide the energy and materials • Signaling networks – sense the outside, coordinate activities within and between cells • (Gene) regulatory networks – control processes, set limits, control the molecular composition of cells

  4. ELLS 2011 The scale of pathways • Early pathways were pieced together by studying biochemical reactions of individual proteins, measuring the activity, learning the substrates and products, joining them to the next enzyme in the pathway. • New technologies allow simultaneous measurement of tens of thousands of different molecules. • This reveals that many biological pathways are interconnected, more complicated than the typical textbook examples, with fluid boundaries. They can work together or against each other (feedback and regulation). • Scientists who study or interpret these large scale interactions sometimes refer to the field as ‘systems biology’ • When multiple biological pathways interact = a biological network. • When all possible interactions are added, pathways become extremely difficult to understand • Biologists often work with ‘canonical’ pathways, those that represent the well-understood part of the entire network.

  5. 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?

  6. 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.

  7. 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

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

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

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

  11. Reaction Example 1: Enzymatic

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

  13. Other Reaction Types Dimerization Binding Phosphorylation

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

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

  16. Species Selection

  17. 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

  18. 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

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

  20. Planned Coverage – Editorial Calendar

  21. Reactome Tools • Interactive Pathway Browser • Pathway Mapping and Over-representation • Expression overlay onto pathways • Molecular Interaction overlay • Biomart

  22. Tutorial Tutorial handouts in your info packages…

  23. Front Page http://www.reactome.org Navigation bar Sidebar Main text

  24. Exercise 1 …see the Tutorial handouts

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

  26. Pathways tab – pathway hierarchy Pathway Reaction Black-box

  27. Exercise 2 …see the Tutorial handouts From the homepage, search for ‘PDGF 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. How many sub-pathways does this pathway have? How many reactions are in the first of these sub-pathways? What reaction follows Processing of classical PDGFs? Hint: If it’s not visible, open the Details pane at the bottom of the page by clicking on the blue triangle.

  28. 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

  29. Exercise 3 …see the Tutorial handouts

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

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

  32. Exercise 4 …see the Tutorial handouts

  33. The Details Panel

  34. Exercise 5 …see the Tutorial handouts

  35. Pathway Analysis

  36. Pathway Analysis – Overrepresentation ‘Top-level’ Reveal next level P-val

  37. Exercise 6 …see the Tutorial handouts Check this!

  38. Species Comparison I

  39. Species Comparison II Yellow = human/rat Blue = human only Grey = not relevant Black = Complex

  40. Exercise 7 …see the Tutorial handouts

  41. Expression Analysis I

  42. ‘Hot’ = high ‘Cold’ = low Expression Analysis II Step through Data columns

  43. Exercise 8

  44. Molecular Interaction Overlay

  45. Exercise 9 …see the Tutorial handouts

  46. New Look Browser

  47. End

  48. BioMart – selecting your dataset

  49. BioMart – filters

  50. BioMart – attributes Check to get attribute

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