Ontologies and vocabularies supporting data integration: emphasis on mouse phenotypes

1. Homozygous Faslgld/Faslgld Control C3H/HeJ Ontologies and vocabularies supporting data integration: emphasis on mouse phenotypes and disease model The mouse generalized lymphoproliferative disease (gld) mutation in the FAS ligand (TNF superfamily, member 6) gene. These mice model human Autoimmune Lymphoproliferative Syndrome; ALPS, type IB Janan T. EppigPATO Meeting, Dec. 2006

2. The genetic tools for mouse provide an ideal platform for experimentation: • Mammal : small, easy to breed and maintain, short lifespan • Similar to human genetically & physiologically • genetic engineering techniques to specifically manipulate the genome • high resolution maps • sequenced genome • human disease model • Inbred strains • ES cell lines

3. Achondroplasia …facilitating the use of the mouse as a model for human biology by providing integrated access to data on the genetics, genomics, and biology of the laboratory mouse. Homozygous achondroplasia mouse mutant and control • short domed skull • short-limbed dwarfism • malocclusion • bulging abdomen as adults • respiratory problems • shorted lifespan www.informatics.jax.org

4. Objective • …make phenotype and disease model data robust and accessible to researchers and computational biologists • semantically consistent search methods • integrated access to all phenotypic variation sources • (single-gene and genomic mutations, QTLs, strains) • ability to query across sequence, orthology, expression, • function, phenotype, disease • data on human disease correlation • access to mouse models from various approaches • - Genetic • - Phenotypic • - Computational

5. Existing Wealth of Mouse Phenotype Data in MGI >16,800 phenotypic alleles representing ≈6,830 unique genes. >71,000 annotations associating MP terms to genotypes. >6,550 phenotype records for 3,210 QTL. >9,000 strains catalogued.

6. A few of the challenges • alleles can produce pleiotropic phenotypic effects • non-allelic mutations can produce indistinguishable phenotypes • modifiers and epistasis can influence mutant phenotypes • alleles of different genes can interact to produce unique phenotypes • genetic background can greatly influence mutant phenotypes • imprinted genes/alleles influence phenotype • quantitative trait loci (QTLs) can contribute unequally to phenotypes • genomic mutations can delete or disrupt multiple genes • strains (“whole-genome”) have characteristic phenotypes • complex genetically engineered and multiple mutation stocks are often developed for disease models • environmental influences and age can dramatically affect phenotype

7. Data Challenge • Mouse phenotype data from • publications • electronic submissions • mutagenesis (ENU centers) • (≈ 300 new alleles; ≈ 700 publications per month on phenotypes) • New initiatives to knock-out every gene in the mouse in next 5 years… • Need for efficiency, accuracy, full description of complex observations, storage/analysis of individual and population data

8. Making semantic sense Controlled vocabularies/nomenclatures • Strains • Genes • Alleles (phenotypic or variant) • Classes of genetic markers • Types of mutations • Types of assays • Developmental stages • Tissues • Clone libraries • ES cell lines ….. organized as lists or simple hierarchies

9. Gene Symbols Inbred Strain Names Clone Library Names

10. Assay Gene nomenclature Specimen Results Hbp1 (high mobility group box transcription factor 1) gene expression differences in KitW-e/KitW-e homozygotes vs wild-type

11. DAGs Semantics plus relationship data Ontologies/structured vocabularies • Gene Ontology (GO) • Molecular function • Biological process • Cellular component • Mouse Anatomy (MA) • Embryonic • Adult • Mammalian Phenotype (MP) • Sequence Ontology (SO) ….. organized as directed acyclic graphs (DAGs)

12. 5.Sequence (GBrowse) 1.Gene Page 2.Phenotype Query 3.MP Ontology 4.Disease vocabulary Human/mouse disease relationships Summary: genotype, MP term, & ref Summary: phenotype classes & human disease associated Phenotype detail, including genotypes for mouse models of human diseases Navigating the views of phenotypes & disease

13. Genotype = allele combinations carried in the context of a specific genetic background (strain)

14. Mammalian Phenotype Ontology • Structured as DAG • Over 4,500 terms covering physiological systems, behavior, development and survival • Available in browser and OBO formats from MGI ftp and OBO sites • Each term linked to all annotations to the term or its children

15. Summary Results • Genotypes that are annotated to a term or children of the term • References supporting annotation • Links to allele detail pages for full mutant phenotype

16. Allele Detail Page full phenotype annotations (MP) for each genotype specific detail for MP terms each MP annotation referenced human diseases for which genotype is used as a model

18. Genes associated with phenotypes characteristic of a disease in human, mouse, or both Mouse model genotypes linked to phenotype details

19. to Human Disease and Mouse Model Page osteopetrosis Human-mouse disease relationships OMIM terms 6,113 Genotypes associated w/ OMIM 1,847 OMIM associated w/ genotypes 720

20. Vocabulary Note Terms DAGs Growth retardation EE J:65322 IDA J:62648 Dilated renal tubules MP:1956 Synonyms Definition TAS J:65378 Postnatal lethality … Respiratory failure … Annotations Vocabularies in MGI Genotype Strain: AEJ Alleles:bd/bd Strain: C57BL/6 Alleles: Ppp1r3atm1Adpt/ Ppp1r3atm1Adpt

21. Making Mammalian Phenotype Ontology Work DAG • accommodate bio-specific terms • computationally useful • human accessible • practical for curation • cross-reference to other ontologies

22. Terms in MP

23. 2003 2004 2005 2006 Future MP Ontology Development • New terms from ongoing curation process • Collaborative community efforts • identify new terms • revise organization of existing terms within particular branches • Recruit domain experts for systematic review • Cross-ref and comparison to other relevant ontologies (GO, Anatomy, Cell Type, Mpath, etc.)

24. Collaborators …currently annotating with MP and contributing to MP development Rat Genome Database (RGD) Mouse Mutagenesis Centers Human (NCBI/dbSNP) Online Mendelian Inheritance in Animals (OMIA) …under discussion Teratology Society Animal Traits

25. Summary • Structured vocabularies and ontologies support semantic integration for the MGI system and promote broader integration of mouse knowledge • To meet community needs, practical implementations parallel formal ontological development • MGI has implemented a generalized structure for vocabularies and ontologies in MGI • The Mouse Genome Informatics group continues its strong interest and participation in community bio-ontology efforts

26. www.informatics.jax.org Human FOXN1 forkhead box N1 T-CELL IMMUNODEFICIENY, CONGENITAL ALOPECIA, AND NAIL DYSTROPHY Frank J, et al. Nature 398, 473 - 474 (1999) Mouse Foxn1 Homozygous “nude” mouse. One of eight known phenotypic mutations in mouse (6 spontaneous; 2 engineered) for the forkhead box N1 gene.