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DomainGraph – visual analysis of the
biological effects of alternative splicing
Introduction
• Affymetrix Exon Array enables researchers to:
• Identify / classify occurrences of alternative splicing events
• Identify protein isoforms occurring in specific tissues
• Identify protein isoforms occurring in diseased tissues
 Focus mainly on identification of alternative splicing events and
isoforms
But: what about the biological impact?
Introduction
Protein – Protein interaction:
PDB entry: 1OPH
Alpha-1-antitrypsin (red), P01009
Cationic trypsin (yellow), P00760
Serin Protease Inhibitor (red), PF00079
Trypsin (yellow), PF00089
Domain definition:
• structural units of proteins
• fold independently
• specific functions
• may appear in several proteins
Domain – Domain interaction:
• underlies protein interaction
Introduction
• Alternative Splicing
Affymetrix Technical Note:
Identifying and Validating Alternative Splicing Events
PDB entry: 1OPH
DomainGraph 3.0
• Cytoscape plugin
• Main functionalities:
I.) Analysis of AltAnalyze statistics (without prior biological knowledge)
a) Gene / Transcript / Protein / Functional Groups Analysis
b) Pathway Analysis
II.) Analysis of specific interaction networks
a) Visualization of protein interaction networks with underlying
domain interactions
b) Visualization of gene interaction networks and their encoded
proteins with domain composition
c) Integration of AltAnalyze statistics
DomainGraph Visualization
• Graph representation of genes, proteins, and domains and their connections
• Nodes:
• Genes
Node
• Proteins
• Domains
• Edges:
• Gene interactions
• Protein interactions
• Domain interactions
• Gene – protein linker
• Protein – domain linker
Edge (undirected)
AltAnalyze and DomainGraph Overview
I.) Analysis of AltAnalyze results
(no prior biological knowledge of the data needed)
I.) Analysis of AltAnalyze statistics – Table View
I.) Analysis of AltAnalyze statistics – Gene / Gene Product Analysis
Single-Gene
Network View
Probeset View
I.) Analysis of AltAnalyze statistics – Single-Gene Network View
Domain Node
Protein Node
(regulated)
Gene – protein linker
Protein – domain linker
Gene Node (regulated)
Protein Node
Domain Node
(regulated)
I.) Analysis of AltAnalyze statistics – Probeset View
Gene: FYN
Protein, domain
Exon structure
Probesets, miRNA-BS
II.) Analysis of a specific network – Probeset View
I.) Analysis of AltAnalyze statistics – Table View
I.) Analysis of AltAnalyze statistics – Pathway Selection
I.) Analysis of AltAnalyze statistics – Pathway View
Regulated Genes:
green
WikiPathway Import via GPML-Plugin
II.) Analysis of a specific network
a) Creating a Domain Graph
II.) Analysis of a specific network – PPI network
Network annotated with protein IDs:
•
Decomposition of proteins into constituent domains
•
Inference of domain-domain interactions (DDIs)
 Visualization of protein interactions with constituent domains and DDIs
 Focus on DDIs forming the PPIs
DDI datasets provided with DomainGraph
•
From PDB structures: iPfam, 3did
•
From predictions: InterDom, DPEA, DIMA,…
II.) Analysis of a specific network – PPI network
Input:
•
Protein interaction network
•
Selection of DDI dataset
•
Selection of initial view (more or less detailed)
•
Identifier specification (Ensembl, UniProt)
Internal Computation:
•
Decomposition of proteins into domains
•
Calculation of domain interactions
•
Calculation of initial view
Output:
•
Domain Graph with protein and domain nodes; protein and domain
interactions; protein – domain linkers
II.) Analysis of a specific network – PPI network
PPI network
Protein interaction with
confidence score
Domain interaction
with confidence score
Protein node
Domain node
Protein domain linker
PPI network
Network Views:
• Extended view
• Displays domains for each
protein separately
• Relatively high number of nodes
and edges
• Compact view
• Identical domains occurring in
different proteins are merged
• Decreased number of nodes and
edges
• Protein network view
• Display domain interactions for
user-selected proteins only
• Stepwise exploration of network
possible
Features: Protein and Domain Annotations
II.) Analysis of a specific network – GGI network
Network annotated with gene IDs:
•
Extraction of protein isoforms encoded by the genes
•
Decompositions of protein isoforms into constituent domains
 Visualization of gene interaction with encoded proteins and constituent
domains
 Focus on protein isoforms and their differences
II.) Analysis of a specific network – PPI network
Input:
•
Gene interaction network
•
Selection of initial view (more or less detailed)
•
Identifier specification (Ensembl, Entrez)
Internal Computation:
•
Extraction of all protein isoforms encoded by the genes
•
Decomposition of protein isoforms into domains
•
Calculation of initial view
Output:
•
Domain Graph with gene, protein and domain nodes; gene interactions;
gene – protein and protein – domain linkers
II.) Analysis of a specific network – GGI network
GGI network
Protein – domain linker
Gene – protein linker
Gene node
Gene interaction
Protein node
Domain node
II.) Analysis of a specific network – Domain and Exon Structure Comparison
Gene: FYN
II.) Analysis of a specific network
b) Integrating AltAnalyze Statistics
II.) Analysis of a specific network – AltAnalyze Data Integration
Input:
•
Domain Graph built from PPI or GGI network
•
AltAnalyze probeset statistics file
Internal Computation:
•
Mapping probesets to proteins, exons, domains, miRNAs
•
Calculating positions of regulated probesets
Output:
•
Domain Graph with gene, protein, and domain nodes highlighted
according to occurrences of alternative splicing
II.) Analysis of a specific network – Domain Graph with Integrated AltAnalyze Data
Domain Graph with Integrated AltAnalyze Data
Gene Node
(regulated)
Protein Node
(regulated)
Domain Node (regulated)