chaitra sarathy denise slenter combining forces for recon and … · 2019-07-05 · chaitra sarathy...
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Chaitra SarathyPhD Candidate, MaCSBio
Genome scale metabolic modeling &
Combining forces for Recon and WikiPathways
13/06/2019
Denise SlenterPhD Candidate,
BiGCAT
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Chaitra SarathyPhD Candidate, MaCSBio
Modelling intra-cellular metabolism of adipocytesOmics data integration using genome-scale metabolic models
13/06/2019
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Genome Scale Metabolic Models• in silico representations of all known metabolic
reactions in an organism and the genes that encode each enzyme
• complete description of an organism’s metabolic capabilities
• assembled from existing database of genes, proteins, enzymes, metabolites and reactions
Adapted in part from Robinson, Jonathan L., and Jens Nielsen. Molecular BioSystems (2016) and Uhlen et al., Mol Sys Bio (2016)
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Genome Scale Metabolic Models - Flux Balance AnalysisStoichiometric Matrix
Adapted from Orth et al., Nat Biotech 2010
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Genome Scale Metabolic Models - Omics Integration
Adapted from O’Brien et al.,. Cell (2015) and Uhlen et al., Mol Sys Bio (2016)
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Genome Scale Metabolic Models - (some) Applications
O’Brien et al.,. Cell (2015)
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▪ Understand role of adipocytes in regulating plasma metabolite levels
▪ Integrate gene expression from adipose tissue + plasma metabolomics data
▪ Identify relevant genes, intracellular metabolites and reactions
▪ Apply GEM-based approaches
Overall Objective
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▪ Understand role of adipocytes in regulating plasma metabolite levels
▪ Integrate gene expression from adipose tissue + plasma metabolomics data
▪ Identify relevant genes, intracellular metabolites and reactions
▪ Apply GEM-based approaches
Overall Objective
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Methods - EFM Analysis• Elementary Flux Modes (EFMs): non-decomposable, steady-state
pathways in metabolic networks• Network exploration method for identifying possible routes
City Map Metabolic Map
Identify parts of the network important for catabolism of specific plasma metabolites
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Approach used: TreeEFM1
• MILP-based tree search for EFM enumeration
• implemented in C++ (source code unavailable)
• Inputs
• Stoichiometry (irreversible reactions & cofactors removed)
• Active reaction – uptake or releases cx
Model compartments
[x] - Blood[s] - Intrastitial space[c] - Cytosol
XSC = uptakeCSX = release
Methods - EFM Generation
1. Pey, Jon, et al., Bioinformatics 2014
Plasma Metabolites Uptake (s 🡪 c)
Uptake EFMs XSC
Release (c 🡪 s)Release
EFMs CSX
leucine leucine[s] => leucine[c] 159 leucine[c] => leucine[s] 483
Table 1: Total number of EFMs identified by TreeEFM
Current work: Identify differential EFMs, Cluster EFMs
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EFM Visualization: Workflow
C. Submodel CreationD. Visualization
B. EFM GenerationA. Model Preprocessing
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EFM Visualization: Example
Model: Recon 2.2
Active reaction = glucose uptake
Data: TCGA breast cancer gene expression + simulated reaction fluxes
25 reactions, 27 metabolites and 56 genes
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EFM Visualization: Challenges
• Identifier mapping
• Several sources – reactions, metabolites, genes
• Network analysis – less explored
• Combine forces with Wikipathways
• Add data from these models to Wikipathways
• Open resources for Metabolic modelling community
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Combining forces for Recon and Wikipathways
Denise Slenter
Twitter: @SMaLLCaT4Sci and @BiGCaT_UMBlog: http://smallcats4science.blogspot.nlORCID: 0000-0001-8449-1318
2019-06-13 Science Cafe BiGCat
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Current status of WikiPathways* for Humans:
*From WikiPathways SPARQL Endpoint [2019-15-10 data]
Item WikiPathways Approved Reactome
# Pathways 531 475
# GeneProducts 8805 928
# Protein 2553 11319
# Metabolites 2586 1776
#Directed Interactions between two metabolites
3239 4377
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Current status of WikiPathways* for Humans:
*From WikiPathways SPARQL Endpoint [2019-15-10 data]
Item WikiPathways Approved Reactome
# Pathways 531 475
# GeneProducts 8805 928
# Protein 2553 11319
# Metabolites 2586 1776
#Directed Interactions between two metabolites
3239 4377
In HMDB: “40,000 metabolites that have already been identified or are likely to be found in the human body”
https://en.wikipedia.org/wiki/Metabolome
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Co-A
Linking metabolomics data to pathways…
L-tyrosine
Nicotine
Cocaine
Structures obtained from Wikidata [2018-11-01]
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Linking metabolomics data to pathways…
Sparseness of Data
[1] Lindner, et al. BMC ophthalmology (2014)
[1]
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Two approaches:
Network approach [1]
[1] DOI: 10.6084/m9.figshare.5234851.v1[2] DOI: 10.6084/m9.figshare.6368921.v1
Shortest path Ontological Mapping
Molecular Interactions
Molecular Entities
Ontological approach [2]
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Two approaches:
Ontological approach [2]Network approach [1]
Shortest path Ontological Mapping
Molecular Interactions
Molecular Entities
[1] DOI: 10.6084/m9.figshare.5234851.v1[2] DOI: 10.6084/m9.figshare.6368921.v1
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Network approach: AIM
• Directed network of metabolites from pathway knowledge bases
• Calculate sub-network between active metabolites
• Visualise directed paths
• Interpret metabolomics datasets
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WORKFLOW
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FUTURE PERSPECTIVE
• Add more pathway knowledge bases (now WikiPathways, Reactome and LipidMaps*)
• Create app for direct visualisation with Cytoscape from Neo4j (first tests have been run)
• Allow for integration with other omics data sources, such as proteomics and transcriptomics
*Not (fully) converted to Human yet.
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Recon vs Wikipathways• Recon3D – Most recent human reconstruction• Wikipathways – 2019-05-10 RDF data
Genes Metabolites Reactions Pathways
ID format Entrez Recon/Wikidata Metabolic conversions only
Humans only
Recon 3,288 4,140 13,543 111
Wikipathways (Approved + Reactome) 11,869 2,650 7,616 1,006
Recon metabolite IDs
ReconMap 2024PdMap 169
ChEBI 1276PubChemID 1408KEGG ID 1682HMDB ID 721
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Recon vs WikipathwaysSubsystems
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Recon – Subsystem visualized: Citric acid cycle
Recon vs Wikipathways
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Overlap in genes
Recon vs Wikipathways
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Recon vs Wikipathways
Red = Recon
Blue = WPs
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Overlap in metabolites
Recon vs Wikipathways
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Overlap in metabolites
Recon vs Wikipathways
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Proposed workflow for integration:Genes
Find unique genes
Create GPML for (unique) genes (per
subsystem)
Perform Pathway Analysis on
Transcriptomics data
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Proposed workflow for integration:Genes
Find unique genes
Create GPML for (unique) genes (per
subsystem)
Perform Pathway Analysis on
Transcriptomics data
Proof of Principle
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Proposed workflow for integration:Genes Metabolites
Find unique genes
Create GPML for (unique) genes (per
subsystem)
Add Recon-IDs to BridgeDb
Find unique metabolites
Perform Pathway Analysis on
Transcriptomics data
Proof of Principle
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Proposed workflow for integration:Genes Metabolites Reaction (IDs)
Find unique genes
Create GPML for (unique) genes (per
subsystem)
Add Recon-IDs to BridgeDb
Find unique metabolites
Create Datasource for Recon reaction ID
Perform Pathway Analysis on
Transcriptomics data
Proof of Principle
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Proposed workflow for integration:Genes Metabolites Reaction (IDs)
Find unique genes
Create GPML for (unique) genes (per
subsystem)
Add Recon-IDs to BridgeDb
Find unique metabolites
Create Datasource for Recon reaction ID
Create GPML for reactions and (unique) substrate+product-combinations (per subsystem)
Perform Pathway Analysis on
Transcriptomics data
Proof of Principle
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Proposed workflow for integration:Genes Metabolites Reaction (IDs)
Find unique genes
Create GPML for (unique) genes (per
subsystem)
Add Recon-IDs to BridgeDb
Find unique metabolites
Create Datasource for Recon reaction ID
Create GPML for reactions and (unique) substrate+product-combinations (per subsystem)
Perform Pathway Analysis on
Transcriptomics data
Create complete GPML for (all/unique?) reactions, substrate+product, catalysing enzyme (per subsystem),
literature etc.
Proof of Principle
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Challenges
Besides the ones already mentioned:
- Layout of subsystems (coordinates for DataNode boxes).
- Add location (cellular and tissue level) → Not possible in PathVisio (yet).
- Map Recon metabolite IDs to more then InchiKey (for example, to Wikidata).
- Mappings from Rhea to Recon-Reaction IDs currently not possible; therefore fluxomics is difficult.
- Do we need GPMLs in WPs? Or do we (only) want info in RDF?
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Acknowledgements, questions, discussion
Ilja ArtsMarian BreuerMichael Lenz
Michiel AdriaensChris T Evelo
Jonathan MeliusRyan Miller
Georg SummerChris T Evelo
Egon L Willighagen
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Acknowledgements, questions, discussion
Ilja ArtsMarian BreuerMichael Lenz
Michiel AdriaensChris T Evelo
Jonathan MeliusRyan Miller
Georg SummerChris T Evelo
Egon L Willighagen
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Recon vs Wikipathways (Extra)
Transport, extracellular 2851Exchange/demand reaction 1972Fatty acid oxidation 1146Drug metabolism 573Transport, mitochondrial 530Miscellaneous 374Transport, endoplasmic reticular 364Fatty acid synthesis 340Cholesterol metabolism 321Glycerophospholipid metabolism 316Eicosanoid metabolism 284Peptide metabolism 242Bile acid synthesis 232Transport, lysosomal 208Transport, peroxisomal 182Nucleotide interconversion 178Tyrosine metabolism 151Sphingolipid metabolism 141Xenobiotics metabolism 137
Subsystems Arachidonic acid metabolism 135Steroid metabolism 116Transport, golgi apparatus 116Glycosphingolipid metabolism 115N-glycan synthesis 108Vitamin A metabolism 107Transport, nuclear 92Inositol phosphate metabolism 90Androgen and estrogen synthesis and metabolism 85Tryptophan metabolism 77Keratan sulfate degradation 76Urea cycle 69Folate metabolism 62Phosphatidylinositol phosphate metabolism 60Keratan sulfate synthesis 59Methionine and cysteine metabolism 55Valine, leucine, and isoleucine metabolism 52Arginine and proline metabolism 51Phenylalanine metabolism 50R group synthesis 50Glycine, serine, alanine, and threonine metabolism 49