1. Terry Meehan Scientific Curator Mouse Genome Informatics The Jackson Laboratory Logical Definitions for Hematopoietic Cell Terms

2. 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 1 st 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

3. A Brief History of Hematopoietic Cell Terms in CL 2 nd 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

4. Current Development of Hematopoietic Cell Terms 3 rd round, 2009 - present – ARRA funded improvements to Cell Ontology as supplement to GO grant Building upon outcome of the NIAID Cell Ontology Workshop 1 st 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

5. 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

6. 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 CD4 XGD

7. Ontologies & Relationships used in Differentia

8. Generating Logical Definitions “Platelet” as it appears in CL

9. Generating Logical Definitions Reduce is_a parent count to 1

10. Generating Logical Definitions Portion of the OBO stanza intersection_of: CL:0000763 ! myeloid cell intersection_of: capable_of GO:0007596 ! blood coagulation intersection_of: capable_of GO:0008015 ! blood circulation intersection_of: has_quality PATO:0001405 ! anucleate intersection_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

11. Generating Logical Definitions Infer relationships with reasoner

12. Benefits of Using Logical Definitions Ontology engineer need only place term along one axis of differentia ? ? ?

13. Benefits = Connections to Other Ontologies OntologyRelationship Yellow = PATO D = develops_from Green = GO-bp C = capable_of Blue = Hemo_CL Q = has_quality P = part_of

14. Red = GO-cellular component Blue = Hemo_CL = has_plasma_membrane_part Benefits = Reasoner flags errors Declared disjoint_from each other

15. Benefits = Reasoner flags errors Corrected logical definition

16. Benefits = Unexpected associations

17. 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

18. 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

19. New Developmental Cell Types 22 new developmental cell types added

20. Problems Solved –Different Viewpoints Flow cytometry= Diwan A et al. PNAS 2007;104:6794-6799 histology = http://www.som.tulane.edu/classware/pathology/Krause/Blood/Blood.html minimal information needed to substantiate a cell type vs different ways of identifying cell type

21. 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:)

22. 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

23. Problems Not Solved –True path violation with high level terms T 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 the T cell lineage” Currently (not completely satisfactory): T cells are lymphocytes capable_of “T cell mediated immunity”

24. 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

25. 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”

26. Future Steps Logical definitions for high level terms Add back in insect immune cell types Incorporate into CL Neurons!