Transcript Reactome

Reactome
A database of biological pathways and
processes
Steve Jupe
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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 this be represented as
computationally-accessible
reactions and pathways?
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Rationale - Figures
A picture paints a
thousand words…
but….
• Not computer readable
• Omits key details
• Assumes or infers
Nature. 2000 Oct
12;407(6805):770-6.
The biochemistry of apoptosis.
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Reactome is…
• A 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 (but not tissue or
developmental stage)
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Reactome is…
• Extensively cross-referenced
• Used to infer orthologous events
in 20 non-human species
• Tools for data analysis – Pathway
Analysis, Expression Overlay,
Species Comparison, Biomart…
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Theory - Reactions
• Pathway steps - the “units” of Reactome
• Encapsulate events and states found in biology
BINDING
DEGRADATION
DISSOCIATION
DEPHOSPHORYLATION
PHOSPHORYLATION
CLASSIC
TRANSPORT
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BIOCHEMICAL
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Reaction Example 1: Enzymatic
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Reaction Example 2: Transport
REACT_1338.3
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Other Reaction Types
Phosphorylation
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Dimerization
Reactions Connect into Pathways
CATALYST
CATALYST
CATALYST
INPUT
OUTPUT
INPUT
OUTPUT
INPUT
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OUTPUT
Evidence Tracking – Inferred Reactions
PMID:5555
Direct evidence
PMID:4444
Direct evidence
human
Indirect evidence
PMID:8976
mouse
Indirect evidence
PMID:1234
cow
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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
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Species Selection
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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
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Reaction not
inferred
Exportable Protein-Protein Interactions
• Are electronically inferred from complex and reaction data
• Interaction between proteins in the same complex or
reaction
• Lists of interaction data from “downloads” tab
• Visit the Readme document for more details
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Coverage – Current TOC
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Planned Coverage – Editorial Calendar
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Reactome Tools
•
•
•
•
•
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Interactive Pathway Browser
Pathway Mapping and Over-representation
Expression overlay onto pathways
Molecular Interaction overlay
Biomart
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Tutorial
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Front Page
http://reactome.oicr.on.ca
Sidebar
Navigation bar
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Main
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Exercise 1
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The Pathway Browser
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Pathways tab – pathway hierarchy
Pathway
Reaction
Black-box
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Exercise 2
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The Pathway Browser - Pathway Diagrams
Boxes are proteins, sets or complexes.
Ovals are small molecules.
Green boxes are proteins or sets, blue are complexes.
Regulation
+ve
-ve
Input
Reaction node
Catalyst
Outputs
Compartment
Transition
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Binding Dissociation Omitted
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Uncertain
Exercise 3
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Navigating in the Pathway Browser I
Home and Analyze buttons
Search
Click here
Highlights
Details here
Click here to open pathway diagram...
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Navigating in the Pathway Browser II
Click here
Zoom
Highlights
Details here
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Exercise 4
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The Details Panel
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Exercise 5
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Pathway Analysis
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Pathway Analysis – Overrepresentation
P-val, In set/In pathway
Reveal next level
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‘Top-level’
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Exercise 6
Check this!
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Species Comparison I
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Species Comparison II
Yellow = human/rat
Blue = human only
Grey = not relevant
Black = Complex
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Exercise 7
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Expression Analysis I
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Expression Analysis II
Step through
Data columns
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‘Hot’ = high
‘Cold’ = low
Exercise 8
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Molecular Interaction Overlay
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Exercise 9
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BioMart – selecting your dataset
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BioMart – filters
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BioMart – attributes
Check to get
attribute
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BioMart – results
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Exercise 10
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The End
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Where Reactome’s Data Comes From
Author
Curator
Reviewer
2nd expert
Biology expert
Author
details
(literature
and
diagrams)
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Author &
curator
draft
pathway(s)
Curator
structures
data and
enters into
db
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Reviewer
QC checks
Curator
incorporates
QC
comments
release
Data Provision
EXPERT
•
Expert in the field
•
Recruited in various ways
•
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CURATOR
REVIEWER
jamborees, workshops etc.
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Provide information on biological system
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Curators can be experts
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Data Provision
EXPERT
CURATOR
REVIEWER
• Interprets Author input
• Enters data into the database
• Liaises with expert on details – fits to Reactome
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Data Provision
EXPERT
CURATOR
REVIEWER
• Reviewer is another expert in the field
• QC step
• Feeds back to curator
• Curator completes project for release
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Reactome Mart
• Powered by the BioMart engine (www.biomart.org)
• Bulk queries of Reactome and other databases (e.g.
UniProt, ENSEMBL)
• Queries can linked together data from more than one
database e.g. Search Affymetrix IDs associated with a
Reactome pathway; links a Reactome query to an
ENSEMBL query
• Canned queries available e.g. ‘Find all the proteins in
pathway X’.
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Reactome Mart GUI
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