terry meehan scientific curator mouse genome informatics the jackson laboratory logical definitions...
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Terry MeehanScientific Curator
Mouse Genome InformaticsThe Jackson Laboratory
Logical Definitions for Hematopoietic Cell Terms
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A Brief History of Hematopoietic Cell Terms in the CL
• CL initially developed in 2003 by Jonathan Bard, David States, Michael Ashburner, and Seung Rhee
• 1st round of revisions to hematopoietic cell terms in 2006• adjunct to major improvements to the Gene
Ontology• 80 new cell types• Is_a parentage provided for all
hematopoietically derived cells• Develops_from parentage provided for all major
hematopoietic lineages
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A Brief History of Hematopoietic Cell Terms in CL
• 2nd round, 2008 - 2009 – NIAID Cell Ontology Workshop (May 2008).
• Gathering of NIAID experts on immune system cells with an interest in ontology
• Two day meeting focusing on:• Focus on T cells, B cell, dendritic cells, macrophages• Ontology best practices
• Two publications• “An improved ontological representation of dendritic
cells as a paradigm for all cell types” Masci et al., BMC Bioinformatics 2009
• “Hematopoietic cell types: Prototype for a revised cell ontology” Diehl AD et al., J Biomed Inform. 2010
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Current Development of Hematopoietic Cell Terms
• 3rd round, 2009 - present – ARRA funded improvements to Cell Ontology as supplement to GO grant
• Building upon outcome of the NIAID Cell Ontology Workshop
• 1st year focus is upon using the hematopoietic cells as a test case for redevelopment of the entire Cell Ontology• Create “Hemo_CL” sub-ontology• Provide logical definitions based on cross-products
using OBO Foundry candidate ontologies
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Hemo_CL subontology
Also:- removed insect cell types- DC_CL = dendritic cell ontology- Granulocyte ontology- New terms from literature
Within a couple of weeks, we started generating logical definitions for this sub-ontology
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Logical Definitions (cross-product)• Genus-differentia approach• “an X is a G that D”• X = class we are defining • G = genus (is_a parent) • D = differentia, the characteristics that
discriminate instances of X from other instances of G
“CD4+, alpha-beta T cell” is a “alpha-beta T cell” that has_plasma_membrane_part CD4X G D
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Ontologies & Relationships used in Differentia
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Generating Logical Definitions“Platelet” as it appears in CL
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Generating Logical DefinitionsReduce is_a parent count to 1
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Generating Logical Definitions
Portion of the OBO stanza
intersection_of: CL:0000763 ! myeloid cellintersection_of: capable_of GO:0007596 ! blood coagulationintersection_of: capable_of GO:0008015 ! blood circulationintersection_of: has_quality PATO:0001405 ! anucleateintersection_of: has_quality PATO:0001874 ! discoid
”Platelet: A non-nucleated disk-shaped cell formed by extrusion from megakaryocytes, found in the blood of all mammals, and mainly involved in blood coagulation.”
Use free text for cross-product formation
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Generating Logical DefinitionsInfer relationships with reasoner
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Benefits of Using Logical Definitions
Ontology engineer need only place term along one axis of differentia
? ??
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Benefits = Connections to Other Ontologies
OntologyRelationshipYellow = PATO D = develops_fromGreen = GO-bp C = capable_ofBlue = Hemo_CL Q = has_quality P = part_of
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Red = GO-cellular componentBlue = Hemo_CL
= has_plasma_membrane_part
Benefits = Reasoner flags errors
Declared disjoint_from each other
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Benefits = Reasoner flags errors
Corrected logical definition
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Benefits = Unexpected associations
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Conclusion I
• Hematopoietic cell types have been given logical definitions using terms from other OBO Foundry candidate ontologies
• Logical Definitions allow use of automated reasoners to • infer relationships along other axes of differentia
within CL• infer relationships to other OBO Foundry
candidate ontology• Flag potential errors in logic• Find unexpected associations between terms
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Problems Solved- Species differences
• Hematopoietic cell types described by cell surface markers
• Cell types characterized by presence, absence, or differing levels of expression of cell surface markers
• Cell surface markers differ between species
• Solution: Issues encountered in the DC_CL• new relationships (next talk)• creation of species-specific (-biased?) terms
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New Developmental Cell Types
22 new developmental cell types added
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Problems Solved–Different Viewpoints
Flow cytometry= Diwan A et al. PNAS 2007;104:6794-6799histology = http://www.som.tulane.edu/classware/pathology/Krause/Blood/Blood.html
minimal information needed to substantiate a cell typevs different ways of identifying cell type
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Problems Solved–Different Viewpoints
• Soln:• Protein and protein complexes found on cell
surface is main axis of differentia• amendable with flow cytometry
• Some terms (macrophages) anatomical location is important• logical definition using UBERON terms
• Histological characteristics captured by new terms that are GO-cell components x PATO terms• ex- Basophilic cytoplasm• 8 terms given cellular-phenotype namespace (CP:)
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Problems Solved–Different Viewpoints
• Potential issues • What ontology to put CP terms?• Expression arrays, RNA-seq used to
identify cell types• Moving into neurons• number of CP terms will greatly increase• differing anatomy nomenclature within the
same species and across species
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Problems Not Solved–True path violation with high level termsT cell:“A type of lymphocyte whose defining characteristic is the expression of a T cell receptor complex.”
Thymocyte is_a pro-T cell?Pro-T cells are cells “not fully committed to theT cell lineage”
Currently (not completely satisfactory):T cells are lymphocytes capable_of “T cell mediated immunity”
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Problems Not Solved- Ontological Gaps• Terms needed for logical definitions
missing• many cases just need to request term• -20+ new terms requested for the GO
• Not clear what ontology should cover the following:• Invariant T cell receptors• Type I NK T cells and mucosal invariant T cell
• carbohydrate/lipid/protein complexes• alpha-gal Cer/ Cd1D• tetramers- OBI?
Ontological groups are currently discussing these issues
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Conclusion II
• Generated species-specific cell type terms• Included minimal information for different
points of view• Be aware of true-path violations with high
level terms• Work with other groups on the “ontological
gaps”
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Future Steps
• Logical definitions for high level terms• Add back in insect immune cell types• Incorporate into CL• Neurons!