1. Linking Animal Models and Human Diseases Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838 Cambridge University & the University of Oregon

2. Yvonne Bradford Melissa Haendel Barbara Ruef Kevin Schaper Erik Segerdell Amy Singer Michael Ashburner Rachel Drysdale George Gkoutos Paul Schofield David Sutherland Mark Gibson Suzi Lewis Chris Mungall Nicole Washington Sebastian Bauer Sandra D ölken Peter Robinson

3. Develop methods to: Describe phenotypes Compare descriptions (annotations) Search phenotypes within and across species Linking Animal Models and Human Diseases

4. zebrafish fly human zebrafish

5. HumansAnimal models Mutant Gene Mutant or missing Protein Mutant Phenotype (disease) Mutant Gene Mutant or missing Protein Mutant Phenotype (disease model) Animal disease models

6. HumansAnimal models Mutant Gene Mutant or missing Protein Mutant Phenotype (disease) Mutant Gene Mutant or missing Protein Mutant Phenotype (disease model) BLAST

7. HumansAnimal models Mutant Gene Mutant or missing Protein Mutant Phenotype (disease) Mutant Gene Mutant or missing Protein Mutant Phenotype (disease model) Shared ontologies and syntax can connect mutant phenotypes to candidate human disease genes PhenoBLAST

8. OMIM is a free-text disease description source

9. OMIM Query# of records “large bone”785 "enlarged bone"156 "big bones"16 "huge bones"4 "massive bones"28 "hyperplastic bones"12 "hyperplastic bone"40 "bone hyperplasia"134 "increased bone growth"612

10. eyesmall+ Entity Quality + Phenotype EQ 1 = = EQ 2 =kidney+hypoplastic

11. Entity Quality+ Phenotype (clinical sign) = Anatomical ontology Cell & tissue ontology Developmental ontology Gene ontology biological process molecular function cellular component + PATO Ontologies for Phenotype Annotation

12. Develop methods to: Describe phenotypes Compare descriptions (annotations) Search phenotypes within and across species Linking Animal Models and Human Diseases

13. OMIM genes ZFIN mutant genes FlyBase mutant genes Strategy: use shared genes as proof of principle

14. Annotate phenotypes in human, zebrafish, and fly Annotate human phenotypes triple blind Compare annotations + + ZFIN BBOP FlyBase OBD

16. ~10% of the annotations for 1 gene

17. Curator 1 Curator 2 Curator 3 Annotations vary among curators

18. Curator 1Curator 2Curator 3 Ontologies support comparisons

19. Subsumption reasoning for similarity scoring Information content (IC) is calculated based on depth within the ontology and annotation frequency Similarity is calculated based on ratio of IC values

20. EYA1SOX10SOX9PAX2 0.780.710.610.72 # Annotations congruence total annotations similar annotations

21. Develop methods to: Describe phenotypes Compare descriptions (annotations) Search phenotypes within and across species Linking Animal Models and Human Diseases

22. All alleles are significantly more similar to alleles of the same gene than to alleles of other genes p<0.0001

23. shha query against zebrafish returns signaling pathway members Annotations can identify other pathway members Similarity search for zebrafish shha t4/t4 identifies pathway members

24. A search for phenotypes similar to: Human EYA1 variant OMIM:601653 MP:deafness = E = Sensory perception of sound Q = absent Human phenotypes identify mutations in orthologous model organism genes

25. A search for phenotypes similar to: Human EYA1 variant OMIM:601653 MP:deafness = E = Sensory perception of sound Q = absent returns: Mouse Eya1 bor/bor and Eya1 tm1Rilm/tm1Rilm E = Sensory perception of sound Q = decreased Human phenotypes identify mutations in orthologous model organism genes

26. Zebrafish:ZFIN (EQ) Zebrafish:ZFIN (EQ) Human:OMIM (HPO) Human:OMIM (HPO) Human:DECIPHER (LDD) Human:DECIPHER (LDD) Mouse:MGI (MP) Mouse:MGI (MP) Rat:RGD (MP) Rat:RGD (MP) HPO EQ EQ HPO LDD EQ MP Ontology mappings support cross-species comparisons (Funded by NIH R01 HG004838) MP EQ OBD

27. Develop methods to: Describe phenotypes Compare descriptions (annotations) Search phenotypes within and across species Linking Animal Models and Human Diseases

28. Linking Animal Models and Human Diseases Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838 Cambridge University & the University of Oregon

29. Vocabulary Anatomical system Cornea Embryo Eye Nervous system Visual system

30. Ontology Embryo Anatomical system Nervous system Visual system Eye Cornea