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Using Ontologies to Annotate Phenotypic Data Mouse Genome Informatics www.informatics.jax.org Janan T. Eppig December 2008 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 8 known phenotypic mutations in mouse for the forkhead box N1 gene. Data Integration Primary literature Centers: mutagenesis, gene trap, etc • Gather data from multiple sources • Factor out common objects • Assemble integrated objects Data Loads: GenBank, SNPs, clone collections, UniProt, RIKEN, etc Processing, QC, and curation Electronic Submissions (individual labs) Integration is hard…not just a matter of combining data sources… • Data from multiple sources can be of differing quality • The same data can enter the system via various paths • Naming conventions may or may not be to standards • Some data sources don’t maintain unique accession numbers (or allow them to change) • Periodic updates from data sources can cause problems • if objects have disappeared… (or reappear) • If objects have split in two Data integration is hard • “Bucketizing” establishe types of correspondence between objects in the input sets. • Allows immediate incorporation of 1:1 corresponding data. • Sorts conflicting data into bins that allow prioritization for curator resolution. Literature & Loads New Gene, Strain or Sequence? Controlled Vocabularies Evidence & Citation Co-curation of shared objects and concepts Annotation Pipeline • Data Acquisition • Object Identity • Standardizations • Data Associations • Integration with other bioinformatics resources 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 and more… ….. organized as lists or simple hierarchies 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) • Trait Ontology ….. organized as directed acyclic graphs (DAGs) DAGs Vocabularies in MGI Definition Vocabulary Synonyms MP:1956 Note DAGs Terms Growth retardation Dilated renal tubules Postnatal lethality Respiratory failure Genotype EE J:65322 IDA J:62648 TAS J:65378 Strain: AEJ Alleles:bd/bd … … Annotations Strain: C57BL/6 Alleles: Ppp1r3atm1Adpt/ Ppp1r3atm1Adpt Common software for users to access vocabularies in MGI Mammalian Phenotype Ontology Synonyms • Structured as DAG • >6,250 terms covering physiological systems, behavior, survival, and development • Available in web browser and in OBO and text formats from MGI ftp and OBO sites • Each term linked to all annotations to the term or its children • >133,00 annotations genotype - MP Term in context Links to all mouse genotypes with this phenotype behavior/ neurological phenotype abnormal Involuntary movement abnormal reflex tremors muscle phenotype abnormal muscle physiology opisthotonus myoclonus Mammalian Phenotype (MP) Ontology …make phenotype & disease model data robust & accessible to researchers & computational biologists • semantically consistent search methods • integrated access to all phenotypic variation sources (single-gene, genomic mutations, engineered mutations, QTL, strains) • data on human disease correlation • access to mouse models from various approaches - Genetic - Phenotypic - Computational MP Ontology Growth Developing the Mammalian Phenotype Ontology 7000 6000 5000 4000 • New terms from ongoing curation process 3000 • Collaborative community efforts 1000 2000 • identify new terms 0 2004 2005 2006 2007 • suggest improved organization of terms • Rat Genome Database • Mutagenesis Centers • Human (NCBI) • OMIA (Online Mendelian Inheritance in Animals) • Proprietary Databases • Future (International Mouse Knockout Projects) • Comparisons among Ontologies (GO Process, Mouse Anatomy, FMA, Cell Type, MPath, etc.) • Systematic review by domain experts 2008 Making Mammalian Phenotype Ontology Work • accommodate bio-specific terms • computationally useful • human accessible DAGs • practical for curation • cross-reference to other ontologies MP term Terms in MP Entity microphthalmia eye hydrocephaly PATO Quality MP def small size reduced average size of the eyes cerebroincreased, excessive accumulation spinal fluid excessive, of cerebrospinal fluid accumulated in the brain, especially the cerebral ventricles, often leading to increased brain size and other brain trauma brain large size (dilated) trauma of brain observed Complex Examples: id: MP:0006159 ! ocular albinism intersection_of: PATO:0001558 ! lacking processual parts intersection_of: inheres_in MA:0000261 ! eye intersection_of: towards GO:0006582 ! melanin metabolic process MP definition: absence of melanin (pigment) production in the eye with identifiable melanocytes present id: MP:0006110 ! ventricular fibrillation !intersection_of: PATO:0000688 ! asynchronous !intersection_of: inheres_in CL:0000746 ! cardiac muscle cell !intersection_of: towards GO:0060048 ! cardiac muscle contraction !intersection_of: located_in MA:0000079 ! ventricle endocardium !intersection_of: located_in MA:0000082 ! ventricle myocardium MP definition: asynchronous contraction or quivering of individual cardiac muscle fibers in the ventricles Status of Phenotype & Disease Data Nov 2008 Phenotype terms in MP ontology 6,355 Phenotypic alleles cataloged number of genes represented targeted alleles number of genes targeted 21,996 8,225 13,549 5,547 Alleles with MP annotation Genotypes with MP annotation Total MP annotations 19,458 27,261 137,577 Genotypes with OMIM associations OMIM with associated genotypes 2,520 882 QTLs 4,015 Strains >10,500 Current QTL Display Current QTL display + + Changes planned for QTL Display Genome coordinates: 132851306-135646474 (MGI Mouse GBrowse) Need for a trait ontology • What is measured – Blood pressure – % body fat – Coat color • Annotation of – QTL – Strain characteristics / baseline – Measurements Some issues • specificity vs broad • synchronizing wih MP • “how much” cross-species? OBO-Edit, curation tool for building ontologies Working on Trait Ontology • MGI • IMPC • MPD • RGD • Domestic Species (Animal QTL) Currently: approx. 3600 terms, built initially by stripping MP working systematically on branches MGI Phenotype Data Staff Anna Anagnostopoulos Randal P. Babiuk Susan M. Bello Donna L. Burkart Howard Dene Michelle Knowlton Ira Lu Hiroaki Onda Cynthia L. Smith Monika Tomczuk Linda L. Washburn Jonathan S. Beal Kim L. Forthofer Peter Frost NHGRI grant HG000330 The End