Ontologies and vocabularies supporting data integration: emphasis on mouse phenotypes and disease model Control C3H/HeJ Homozygous Fasl gld /Fasl gld 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. Eppig PATO Meeting, Dec. 2006

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

short domed skull short-limbed dwarfism malocclusion bulging abdomen as adults respiratory problems shorted lifespan Achondroplasia Homozygous achondroplasia mouse mutant and control …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.

…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 Objective

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.

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

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

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

Clone Library Names Inbred Strain Names Gene Symbols

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

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) DAGs

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

enlarged brain ventricles L1cam tm1Mtei /Y129/SvEvnone affected C57BL/6Jhigh percentage affected postnatal deathGnas tm1Kel-pat /Gnas + 129/Sv * C57BL/6Jmost die by P2; all by P9 129/Sv * C57BL/6J * CD-1 most die by P9; 10-20% survive past P21 TMEV viral susceptibility Cd8a tm1Mak /Cd8a tm1Ma k C57BL/6Inflammation after infection resolves by 45 days; disease is absent by 10 mo. PL/Jviral infection persists Genotype = allele combinations carried in the context of a specific genetic background (strain)

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

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

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

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

osteopetrosis Human-mouse disease relationships OMIM terms6,113 Genotypes associated w/ OMIM1,847 OMIM associated w/ genotypes 720 to Human Disease and Mouse Model Page

Vocabularies in MGI DAGs Definition Synonyms MP:1956 Strain: AEJ Alleles:bd/bd Genotype Strain: C57BL/6 Alleles: Ppp1r3a tm1Adpt / Ppp1r3a tm1Adpt Terms … Respiratory failure Postnatal lethality Dilated renal tubules Growth retardation Vocabulary Note … J:65378TAS J:62648IDA J:65322EE Annotations

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

Terms in MP MP termEntityQualityOther Info microphthalmiaeyesmall size hydrocephalycerebro- spinal fluid increasedexcessive brainlarge size (dilated) traumaobservedbrain increased blood pressure ?increased

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.)

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

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

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