Linking Animal Models and Human Diseases

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

2. Yvonne Bradford Melissa Haendel Kevin Schaper Erik Segerdell Amy Singer Sierra Taylor Michael Ashburner Rachel Drysdale George Gkoutos David Sutherland BBOP Mark Gibson Suzi Lewis Chris Mungall Nicole Washington

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

4. EYA gene mutants zebrafish zebrafish fly human

5. Animal disease models Humans Animal models Mutant Gene Mutant or missing ProteinMutant Phenotype (disease) Mutant Gene Mutant or missing ProteinMutant Phenotype (disease model)

6. Sequence analysis (BLAST) can connect animal genes to human genes Humans Animal models Mutant Gene Mutant or missing ProteinMutant Phenotype (disease) Mutant Gene Mutant or missing ProteinMutant Phenotype (disease model)

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

8. Annotation of eyamutant phenotype entity + Phenotype = quality EQ1 eye + small =

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

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

12. Experimental design • Annotate phenotypes in human, zebrafish, and fly • Annotate human phenotypes triple blind • Compare annotations + FlyBase OBD BBOP + ZFIN

13. Results: Number of annotations added to OBD Human Curate OMIM gene and disease data into OBD using EQ syntax Zebrafish Curate zebrafish mutant phenotype data into OBD using EQ syntax

14. Results: Number of annotations added to OBD Human Curate OMIM gene and disease data into OBD using EQ syntax 10 genes 677 EQ annotations from ZFIN 314 EQ annotations from Flybase 507 EQ annotations from BBOP Zebrafish Curate zebrafish mutant phenotype data into OBD using EQ syntax 4,355 genes and genotypes into OBD 17,782 EQ annotations into OBD

16. ~10% of the annotations for 1 gene

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

18. Example phenotype annotation influences Query: Gene variant E = facial ganglion + Q = morphology

19. Terms are related by ontologies epibranchial ganglion is_a influences Query: Gene variant E = facial ganglion + Q = morphology

20. Terms are related by ontologies cranial ganglion is_a epibranchial ganglion is_a influences Query: Gene variant E = facial ganglion + Q = morphology

21. Terms are related by ontologies ganglion Similar annotations have the same or more general entity types is_a cranial ganglion is_a epibranchial ganglion is_a influences Query: Gene variant E = facial ganglion + Q = morphology

22. Similarity calculated by reasoning across ontologies ganglion Similar annotations have the same or more general entity types is_a cranial ganglion is_a epibranchial ganglion is_a influences Query: Gene variant E = facial ganglion + Q = morphology is_a shape structure size Similar annotations have the same or more specific PATO qualities is_a convex folded wavy

23. Ontologies support comparisons Curator 1 Curator 2 Curator 3

24. Ontologies support comparisons Curator 1 Curator 2 Curator 3

25. Subsumption in similarity scoring

26. Average annotation consistency among curators total annotations similar annotations # Annotations EYA1 SOX10 SOX9 PAX2 congruence 0.78 0.71 0.61 0.72

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

28. Phenotypes identify other alleles of the same gene Example: A search for phenotypes similar to each human EYA1 allele returns other human EYA1 alleles

29. Phenotypes identify other alleles of the same gene Example: A search for phenotypes similar to each human EYA1 allele returns other human EYA1 alleles Allele number Allele number (The smaller the number, the more similar)

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

31. Human phenotypes identify mutations in orthologous model organism genes 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 andEya1tm1Rilm/tm1Rilm E = Sensory perception of sound Q = decreased

32. Problem: different terms are used in different species mouse:EYA1 MGI MP:abnormal vestibulocochlear nerve morphology MGI:nnn eya1 variant nn Homologene: EYA1 human:EYA1 NCBO inheres_in PATO:decreased thickness FMA:cochlear nerve OMIM:601653.nn EYA1 variant zebrafish:eya1 ZFIN inheres_in PATO:decreased thickness ZFIN:geno-nnn Eya1 variant nn ZFA:cranial nerve VIII

33. Searches across species utilize homology annotations mouse:EYA1 MGI MP:abnormal vestibulocochlear nerve morphology MGI:nnn eya1 variant nn mammalian phenotype decomposed into EQ = Homologene: EYA1 inheres_in PATO:morphology MA:vestibulocochlear VIII nerve human:EYA1 NCBO inheres_in PATO:decreased thickness FMA:vestibulocochlear nerve FMA:cochlear nerve OMIM:601653.nn EYA1 variant zebrafish:eya1 ZFIN inheres_in PATO:decreased thickness homology annotations ZFIN:geno-nnn Eya1 variant nn ZFA:cranial nerve VIII

34. Animal annotations can identify human diseases Human, SOX9 (Campomelic dysplasia) Zebrafish, sox9a (jellyfish) Scapula: hypoplastic Scapulocorocoid: aplastic Lower jaw: decreased size Cranial cartilage: hypoplastic Heart: malformed or edematous Heart: edematous Phalanges: decreased length Pectoral fin: decreased length Long bones: bowed Cartilage development: disrupted

35. Annotations can identify other pathway members Similarity search for zebrafish shhat4/t4identifies pathway members Shha Disp1 Gli1

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