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Ontologies and vocabularies supporting data integration: emphasis on mouse phenotypes and disease model Homozygous Faslgld/Faslgld 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 Control C3H/HeJ Janan T. Eppig PATO Meeting, Dec. 2006 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 …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. Achondroplasia 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 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 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 Gene Symbols Inbred Strain Names Clone Library Names 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 Semantics plus relationship data Ontologies/structured vocabularies • Gene Ontology (GO) DAGs • Molecular function • Biological process • Cellular component • Mouse Anatomy (MA) • Embryonic • Adult • Mammalian Phenotype (MP) • Sequence Ontology (SO) ….. organized as directed acyclic graphs (DAGs) 1.Gene Page 2.Phenotype Query Summary: phenotype classes & human disease associated 3.MP Ontology Summary: genotype, MP term, & ref 4.Disease vocabulary 5.Sequence (GBrowse) Human/mouse disease relationships Phenotype detail, including genotypes for mouse models of human diseases Navigating the views of phenotypes & disease Genotype = allele combinations carried in the context of a specific genetic background (strain) enlarged brain ventricles postnatal death TMEV viral susceptibility L1camtm1Mtei/Y Gnastm1Kel-pat/Gnas+ Cd8atm1Mak/Cd8atm1Ma 129/SvEv none affected C57BL/6J high percentage affected 129/Sv * C57BL/6J most die by P2; all by P9 129/Sv * C57BL/6J * CD-1 most die by P9; 10-20% survive past P21 C57BL/6 Inflammation after infection resolves by 45 days; disease is absent by 10 mo. PL/J viral infection persists k 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 Genes associated with phenotypes characteristic of a disease in human, mouse, or both Mouse model genotypes linked to phenotype details osteopetrosis Human-mouse disease relationships OMIM terms Genotypes associated w/ OMIM OMIM associated w/ genotypes 6,113 1,847 720 to Human Disease and Mouse Model Page Vocabularies in MGI Definition Vocabulary Synonyms MP:1956 Note DAGs Terms Growth retardation Genotype EE J:65322 Dilated renal tubules IDA J:62648 Postnatal lethality TAS J:65378 Respiratory failure … … Annotations Strain: AEJ Alleles:bd/bd Strain: C57BL/6 Alleles: Ppp1r3atm1Adpt/ Ppp1r3atm1Adpt 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 term Entity Quality Other Info microphthalmia eye small size hydrocephaly cerebrospinal fluid increased excessive brain large size (dilated) trauma observed brain ? increased increased blood pressure Future MP Ontology Development • New terms from ongoing curation process • Collaborative community efforts • identify new terms • revise organization of existing terms within particular branches MP Ontology Growth 4500 4000 • Recruit domain experts for systematic review • Cross-ref and comparison to other relevant ontologies (GO, Anatomy, Cell Type, Mpath, etc.) 3500 3000 2500 2000 1500 1000 500 0 1/1/00 2003 1/2/00 2004 1/3/00 2005 1/4/00 2006 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 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.