Download Reactome

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Metabolic network modelling wikipedia , lookup

Mir-92 microRNA precursor family wikipedia , lookup

Transcript
A Database of
human biological
pathways
Steve Jupe - [email protected]
1
June 2011
www.reactome.org
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 membranebound 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?
2
June 2011
www.reactome.org
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.
3
June 2011
www.reactome.org
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
4
June 2011
www.reactome.org
Reactome is…
Extensively cross-referenced
Tools for data analysis –
Pathway Analysis,
Expression Overlay, Species
Comparison, Biomart…
Used to infer orthologous
events in 20 non-human
species
5
June 2011
www.reactome.org
Using model organism data to build
pathways – Inferred pathway events
PMID:5555
Direct evidence PMID:4444
Direct evidence
human
PMID:8976
mouse
Indirect evidence
PMID:1234
cow
6
June 2011
www.reactome.org
Theory - Reactions
Pathway steps = the “units” of Reactome
= events in biology
BINDING
DEGRADATION
DISSOCIATION
DEPHOSPHORYLATION
PHOSPHORYLATION
CLASSIC
TRANSPORT
7
June 2011
BIOCHEMICAL
www.reactome.org
Reaction Example 1: Enzymatic
8
June 2011
www.reactome.org
Reaction Example 2: Transport
Transport of Ca++ from platelet dense tubular system to cytoplasm
REACT_945.4
9
June 2011
www.reactome.org
Other Reaction Types
Dimerization
Binding
Phosphorylation
10 June
2011
www.reactome.org
Reactions Connect into Pathways
CATALYST
CATALYST
CATALYST
INPUT
OUTPUT
INPUT
OUTPUT
INPUT
11 June
2011
www.reactome.org
OUTPUT
Evidence Tracking – Inferred Reactions
Direct evidence
PMID:5555
PMID:4444
Human pathway
PMID:8976
Indirect evidence
mouse
PMID:1234
cow
12 June
2011
www.reactome.org
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
13 June
2011
www.reactome.org
Species Selection
14 June
2011
www.reactome.org
Data Expansion – Projecting to Other Species
Human
B
A
+ ATP
A -P + ADP
Mouse
B
A
A -P + ADP
+ ATP
Drosophila
A
+ ATP
B
No orthologue - Protein not inferred
15 June
2011
www.reactome.org
Reaction not
inferred
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
16 June
2011
www.reactome.org
Coverage – Content, TOC
And many more...
17 June
2011
www.reactome.org
Planned Coverage – Editorial Calendar
18 June
2011
www.reactome.org
Reactome Tools
• Interactive Pathway Browser
• Pathway Mapping and Over-representation
• Expression overlay onto pathways
• Molecular Interaction overlay
• Biomart
19 June
2011
www.reactome.org
Tutorial
20 June
2011
www.reactome.org
Front Page
http://www.reactome.org
Sidebar
Navigation bar
21 June
2011
Main
text
www.reactome.org
Exercise 1
22 June
2011
www.reactome.org
The Pathway Browser
Species selector
Diagram Key
Sidebar
Zoom/move
toolbar
Pathway Diagram Panel
Details Panel (hidden)
Thumbnail
23 June
2011
www.reactome.org
Pathways tab – pathway hierarchy
Pathway
Reaction
Black-box
24 June
2011
www.reactome.org
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.
25 June
2011
www.reactome.org
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
26 June
2011
Binding Dissociation Omitted
www.reactome.org
Uncertain
Exercise 3
27 June
2011
www.reactome.org
Navigating in the Pathway Browser I
Home and Analyze buttons
Click here
Highlights
Details here
Click here to open pathway diagram...
28 June
2011
www.reactome.org
Navigating in the Pathway Browser II
Click here
Highlights
Zoom
Details here
29 June
2011
www.reactome.org
Exercise 4
30 June
2011
www.reactome.org
The Details Panel
31 June
2011
www.reactome.org
Exercise 5
32 June
2011
www.reactome.org
Pathway Analysis
33 June
2011
www.reactome.org
Pathway Analysis – Overrepresentation
P-val
Reveal next level
‘Top-level’
2011
34 June
www.reactome.org
Exercise 6
Check this!
1. What is the most significantly over-represented top-level pathway for this
dataset?
2. How many genes are in this pathway, and how many were represented in the
dataset?
3. Why is the top-level pathway Chromosome Maintenance higher in the list
than Signalling by Wnt when the latter has a more significant probability
score? (Hint – use the Open All button)
4. Can you interpret these results in terms of the underlying biology? (Hint:
good luck, there are many correct answers!)
35 June
2011
www.reactome.org
Species Comparison I
36 June
2011
www.reactome.org
Species Comparison II
Yellow = human/rat
Blue = human only
Grey = not relevant
Black = Complex
37 June
2011
www.reactome.org
Exercise 7
38 June
2011
www.reactome.org
Expression Analysis I
39 June
2011
www.reactome.org
Expression Analysis II
Step through
Data columns
40 June
2011
www.reactome.org
‘Hot’ = high
‘Cold’ = low
Exercise 8
41 June
2011
www.reactome.org
Molecular Interaction Overlay
42 June
2011
www.reactome.org
Exercise 9
43 June
2011
www.reactome.org
BioMart – selecting your dataset
44 June
2011
www.reactome.org
BioMart – filters
45 June
2011
www.reactome.org
BioMart – attributes
Check to get
attribute
46 June
2011
www.reactome.org
BioMart – results
47 June
2011
www.reactome.org
Exercise 10
48 June
2011
www.reactome.org
The End
49 June
2011
www.reactome.org