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Presentation pathway extensions using knowledge integration and network approaches presented at the Systems Biology Institute in Luxembourg on November 28 2012.
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Analysis with biological pathways:
using biological network approaches for dynamic pathway extension with regulatory information.
Chris EveloDepartment of Bioinformatics - BiGCaTMaastricht UniversityThe Netherlands
PathVisio
• Data modeling and visualization on biological pathways• Uses gene expression, proteomics and metabolomics data • Can identify significantly changed processes
www.pathvisio.org
Martijn P van Iersel, Thomas Kelder, Alexander R Pico, Kristina Hanspers, Susan Coort, Bruce R Conklin, Chris Evelo (2008) Presenting and exploring biological pathways with PathVisio. BMC Bioinformatics 9: 399
Faculty of Health, Medicine and Life Sciences
Understandinggenomics
ExampleWikiPathways Pathway
Pathway on glycolysis. Using modern systems biology (MIM) annotation.
And genes and metabolites connected to major databases.
Faculty of Health, Medicine and Life Sciences
Faculty of Health, Medicine and Life Sciences
adding data =adding colour
ExamplePathVisio result
Showing proteomics and transcriptomics results on the glycolysis pathway in mice liverafter starvation.
[Data from Kaatje Lenaerts and Milka Sokolovic, analysis by Martijn van Iersel]
Download PathwaysWeb services
SPARQL endpoint
How to do data visualization?
Connect to Genome Databases
Faculty of Health, Medicine and Life Sciences
Backpages link to databases
Faculty of Health, Medicine and Life Sciences
You could do this for gene lists
BridgeDB: Abstraction Layer
interfaceIDMapper
classIDMapperRdb
relational database
class IDMapperFile
tab-delimited text
classIDMapperBiomart
web service
The BridgeDb Framework: Standardized Access to Gene, Protein and Metabolite Identifier Mapping Services. Martijn P van Iersel, Alexander R Pico, Thomas Kelder, Jianjiong Gao, Isaac Ho, Kristina Hanspers, Bruce R Conklin, Chris T Evelo. BMC Bioinformatics 2010, 11: 5.
Faculty of Health, Medicine and Life Sciences
Pathway Loom, weaving pathways
RDF 3
Nanopub
Data 1
RDF 1
Descriptor
Data 2
RDF 2
Descriptor
Data 3
Descriptor
RDF 4
Nanopub
Data 4
Descriptor
RDF Data Cache
Semantic Data Workflow Engine
SparqlWeb Service API WebServices
OPS GUIOPS FrameworkArchitecture. Dec 2011
App Framework
Identity & Vocabulary
Management
Note: Things may change!
Public Vocabularies
Chemistry Normalisation &
Registration
OPS Data Model
Feed in WikiPathwaysrelationships, use BioPAXto create the RDF
Faculty of Health, Medicine and Life Sciences
Extending pathways, how to do it?
Network approaches to extend pathwaysE.g. most pathways don’t have miRNA’s
Adding miRNA’s clutters
PathVisio RI plugin provides backpage info
microRNAs in pathway analysis. The Regulatory Interaction plugin offers a suitable middle-ground between not including any miRNAs in pathways, which misses this regulatory information, and including all validated miRNA-target interactions, which clutters the pathway. After loading interaction file(s), selecting a pathway element shows the interaction partners of this element and their expressions in a side panel. This allows for the detection of potential active regulatory mechanisms in the study at hand.
http://www.bigcat.unimaas.nl/wiki/images/f/f6/VanHelden-poster-nbic2012.pdf
Faculty of Health, Medicine and Life Sciences
Or consider pathway as a network
GPML Cytoscape Pluginhttp://www.pathvisio.org/wiki/Cytoscape_plugin
PPS1Liver
All pathways
Pathways with high z-score grouped together.
Explains why there are relatively few significant genes, but many pathways with high z-score.
Cytoscape visualization used to group
Robert Caesar et al (2010) A combined transcriptomics and lipidomics analysis of subcutaneous, epididymal and mesenteric adipose tissue reveals marked functional differences. PLoS One 5: 7. e11525http://dx.doi.org/doi:10.1371/journal.pone.0011525
Explore pathway interactions
Thomas Kelder, Lars Eijssen, Robert Kleemann, Marjan van Erk, Teake Kooistra, Chris Evelo (2011) Exploring pathway interactions in insulin resistant mouse liver BMC Systems Biology 5: 127 Aug. http://dx.doi.org/doi:10.1186/1752-0509-5-127
What we used
Non-redundant shortest paths in a weighted graph.
1. A set of pathways2. An interaction network3. Weight value for all edges
= experimental expression of connected genes.
Pathway interactions and what causes them
An indirect interaction between the Axon Guidance and Insulin Signaling pathways in the network for the comparison between HF and LF diet at t = 0. Left: Network representation of the identified path between the two pathways, consisting of three proteins Gsk3b, Sgk3 and Tsc1. Right: The location of these proteins in the KEGG pathway diagrams. The newly found indirect interactions have been added in red.
Pathway interactions and detailed network visualization for the interactions with three apoptosis related pathways for the comparison between HF and LF diet at t = 0. A: Subgraph of the pathway interaction network, based on incoming interactions to three stress response and apoptosis pathways with the highest in-degree. Pathway nodes with a thick border are significantly enriched (p < 0.05) with differentially expressed genes. B: The protein interactions that compose the interactions between the three apoptosis related pathways and their neighbors in the subgraph as shown in box A (see inset, included interactions are colored orange). Protein nodes have a thick border when their encoding genes are significantly differentially expressed (q < 0.05).
We tried to make it easier with
The CyTargetLinker Cytoscape PluginExtending pathways on the fly.
Provided databases with the plugin: • miRNAs with targets• Transciption Factors with targets• Drug – Target Interactions• ENCODE derived databases
Extend with your own.
Collection of miRNA-target gene interactions in the miRTarBase database with 1,715 genes,286 miRNAs and 2,817 interactions.
miRTarBase as a target interaction network
MiRNAs of Interest
miRNA target information from mirTarBase
miRNAs associated with colorectal cancer extended with validated target genes
human ErbB signaling pathway extended with validated microRNA regulation
Visualizing fluxes on metabolic pathways 33
Visualizing fluxes on metabolic pathways
Anwesha Dutta
Visualizing fluxes on metabolic pathways 34
Data
Metabolite
Flux
Visualizing fluxes on metabolic pathways 35
File format
Metabolic Data
Reactome
HMDB http://www.pathvisio.org/wiki/DatabasesMapps
Visualizing fluxes on metabolic pathways 36
Data visualized on pathway
Integrating it allVisualizing fluxes, data and annotation
Faculty of Health, Medicine and Life Sciences
SNP pathways look like this….
Gene/Protein Z
Metabolite X
Metabolite Y
mi999
TF
RS00001
RS00003
RS00002
RS00004
Functionalize SNPsUnkown function (attribute to gene)
In miRNA binding site
In TF binding site
Changing protein functionality (coding)
Gene/Protein Y
RS00005
Changing protein interactions (coding)
Thanks!
Funding. Dutch: IOP, NBIC, NuGO, NCSB. Regional: Transnational University. EU: NuGO and Microgennet, IMI: Open Phacts + Agilent thought leader grant and NIH.
WikiPathways team:• Martijn van Iersel (PathVisio,
BridgeDB)• Thomas Kelder (WikiPathways,
networks)• Alex Pico (US team leader)• Brice Conklin (former US team leader)• Kristina Hanspers (US curation)• Martina Kutmon (CyTargetLinker)• Susan Coort (Regulatory plugins)• Lars Eijssen (Data pipelines)• Anwesha Dutta (Flux visualisation)• Andra Waagmeester (LOOM)• Egon Willighagen (Open Phacts)
Thanks!
Funding. Dutch: IOP, NBIC, NuGO, NCSB. Regional: Transnational University. EU: NuGO and Microgennet, IMI: Open Phacts + Agilent thought leader grant.