Working in real time building ontologies while annotating the mouse from genotype to phenotype
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Working in Real Time: Building Ontologies While Annotating the Mouse from Genotype to Phenotype. Judith Blake, Ph.D . Mouse Genome Informatics The Jackson Laboratory Bar Harbor, ME 04609. Mouse Genome Informatics. Genotype. Expression. Phenotype. Mouse Genome Database Project (MGD)

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Working in Real Time: Building Ontologies While Annotating the Mouse from Genotype to Phenotype

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Working in real time building ontologies while annotating the mouse from genotype to phenotype

Working in Real Time: Building Ontologies While Annotating the Mouse from Genotype to Phenotype

Judith Blake, Ph.D.

Mouse Genome Informatics

The Jackson Laboratory

Bar Harbor, ME 04609


Mouse genome informatics

Mouse Genome Informatics

Genotype

Expression

Phenotype

  • Mouse Genome Database

    Project (MGD)

    • Genes and Gene Products

    • Comparative Analysis

    • Alleles and Phenotypes

  • Gene Expression DB Project (GXD)

    • Embryonic gene expression

    • Extensive experimental data

  • Mouse Genome Sequence Project (MGS)

    • Connecting sequence & biology

Objective:

Facilitate the use of the mouse as a model for human biology by furthering our understanding of the relationship between genotype and phenotype.


Mgi integration efforts

MGI Integration Efforts

  • Integrated experimental and consensus views

    • Mapping, molecular, alleles, expression, phenotypes

    • Gene to GO associations

  • Canonical gene and sequence

    • Collaborations with SWISS-PROT and LocusLink

    • Nomenclature standards, gene groupings

  • Curated mammalian orthologies

    • used in collaborations with RatDB, NCBI and others

  • Index of primary literature

  • Share knowledge from mouse disease models with medical informatics resources

  • All data associations supported with evidence and citation


    Common issues for model organism databases

    Common Issues for Model Organism Databases

    • Data Integration

      • From Genotype to Phenotype

      • Experimental and Consensus Views

    • Incorporation of large datasets

      • Whole genome annotation pipelines

      • Large scale mutagenesis projects

    • Computational vs. Literature-based data collection and evaluation

    • Data Mining…extraction of new knowledge


    Challenges

    Challenges

    • Genotype

      • Mouse and Human genome sequences

      • Integrating genes/models with existing biological information

      • Updates, emerging knowledge

    • Phenotype

      • Mega-mutagenesis programs

      • Phenome project / baselines

      • Standard screens

      • Integration of mutant information, targeted mutations, transgenes, expression arrays

    jblake-Manchester BioInform Wk


    Numbers 20 march 2002

    Numbers (20 March 2002)

    No. of References70,874

    No. of Genes35,404

    No. of Markers54,834

    Genes w/ NT Seq31,386

    Genes w/ AA Seq12,875

    Genes w/ Orthologs 7,051

    Genes Mapped19,058

    jblake Manchester BioInfor Wk


    Access to mgi resources

    Genes and Markers

    Mammalian Homology

    Sequences and Maps

    Strains and Polymorphisms

    Embryonic Expression

    mouse BLAST, molecular segments

    References, AccID,

    Access to MGI resources

    Alleles and Phenotypes


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Enable Complex Queries

    “Show me all genes with their human orthologs located between cM 5 and 7 on Chr. 3 whose gene products localize to the mitochondrial membrane and whose associated mutant phenotypes include ‘skeletal dysmophology”

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    GOannotations

    Gene detail page in MGD for the vitamin D receptor gene, Vdr


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Sets of Orthologs

    Data associations supported by evidence and citation

    Orthologs of Vdr


    Multiple keyword sets

    Gene/Marker Type

    Allele Type

    Assay Type

    Expression

    Mapping

    Molecular Mutation

    Inheritance Mode

    Nomenclature

    Evidence Codes

    Tissue

    Cell Lines

    Units

    Cytogenetic

    Molecular

    ES Cell Line

    Strain

    Multiple Keyword Sets

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Allele Query Form

    Controlled Vocabularies for Describing Alleles


    Structured vocabularies and ontologies

    Structured Vocabularies and Ontologies

    • Anatomy

    • GO:

      • Molecular function,

      • Biological process,

      • Cellular component

    • Phenotypes

    • Disease Models

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Anatomical Dictionary

    Theiler stage 10 (7 dpc)

    http://genex.hgu.mrc.ac.uk/Databases/Anatomy/

    Collaboration with MRC / Edinburgh 3D-Atlas project


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Links between anatomical structures at successive stages of mouse development enable the analysis of differentiation pathways


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Alternative anatomical hierarchies

    - describe and view anatomy from different anatomical, physiological, and disease perspectives (not just ‘geographical location’, but systems (circulatory) that ‘span geography’

    - integrated analysis of expression and phenotype / disease data


    Consolidated anatomical dictionary

    94 lines

    Consolidated Anatomical Dictionary

    | heart

    | %cardiogenic plate

    | %primitive heart tube

    | | <myocardium

    | | <endocardium

    | | <cardiac jelly

    | <aortic sinus

    | <atrio-ventricular canal (ependymal canal)

    | <atrio-ventricular cushion tissue (bulbar cushion,ependymal cushion tissue)

    | <atrium

    | | %primitive atrium

    | | %common atrial chamber

    | | | <common atrial chamber bulbous cordis

    | | | <common atrial chamber, left part

    | | | | <common atrial chamber, left part, cardiac muscle (myocardium)

    | | | | <common atrial chamber, left part, endocardial lining

    | | | | <common atrial chamber, left part, cardiac jelly

    | | | <common atrial chamber, right part

    | | | | <common atrial chamber, right part, cardiac muscle (myocardium)

    | | | | <common atrial chamber, right part, endocardial lining

    | | | | <common atrial chamber, right part, cardiac jelly

    | | <left atrium

    | | | < left atrium auricular region

    | | | | <left atrium auricular region cardiac muscle (myocardium)

    | | | | < left atrium auricular region endocardial lining

    | | | <left atrium cardiac muscle (myocardium)

    | | | <left atrium endocardial lining

    | | <right atrium

    | | | <right atrium auricular region

    | | | | <right atrium auricular region cardiac muscle (myocardium)

    | | | | <right atrium auricular region endocardial lining

    | | | <right atrium cardiac muscle (myocardium)

    | | | <right atrium endocardial lining

    | | | <right atrium valve

    | | | | % right atrium venous valve

    | | < interatrial septum

    | | | < foramen ovale

    | | | < septum primum

    | | | | < foramen primum (ostium primum)

    | | | | < foramen secundum (ostium secundum)

    | | | < septum secundum

    | <endocardial tissue

    | | <endocardial cushion tissue (bulbar cushion)

    | | <bulboventricular groove

    | | <bulbus cordis

    | | | < bulbus cordis caudal half (myocardium)

    | | | | <bulbus cordis caudal half cardiac muscle (myocardium)

    | | | | <bulbus cordis caudal half endocardial lining

    | | | | <bulbus cordis caudal half cardiac jelly

    | | | < bulbus cordis rostral half (conotruncus)

    | | | | < bulbus cordis rostral half cardiac muscle (myocardium)

    | | | | < bulbus cordis rostral half endocardial lining

    | | | | < bulbus cordis rostral half cardiac jelly

    | < heart mesentery

    | | <dorsal mesocardium (dorsal mesentery of heart)

    | | | <dorsal mesocardium transverse pericardial sinus

    | <outflow tract

    | | <outflow tract aortic component

    | | <outflow tract aortico-pulmonary spiral septum

    | | | <outflow tract future ascending aorta

    | | <outflow tract pulmonary component


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Biol. Process

    Phenotype

    Anatomy

    Gene expression

    jblake Manchester BioInfor Wk


    Beyond mouse

    Mouse Heart Development

    From The Heart by Margaret Kirby in “Embryos, Genes

    and Birth Defects”. Edited by Peter Thorogood

    Beyond mouse

    • Data integration depends on indexing to defined sets of objects.

    • Speaking the same language

      • ‘Development’

      • ‘Heart’

    • Comparisons between model organisms


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    http://www.geneontology.org


    Goals of the consortium

    Goals of the Consortium

    • Develop structured vocabularies (ontologies)

      • Unique ID, Definition, Defined relationships

    • Annotate genes /gene products to vocabularies

      • Evidence and citation

    • Support common data resource for integrated queries across multiple organisms


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Opens browser


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Search returns children


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Returns annotated terms


    First pass phenotype set

    First-Pass Phenotype Set

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Query: genes with mutants classified with term ‘eye dysmorphology’

    Ey


    Genotype phenotype

    Genotype/Phenotype

    A genotype consists of zero, one or more allele pairs on a defined genetic background. The genetic background may be an inbred strain, or it may be unknown.


    Some definitions

    Some Definitions

    • Trait: measurable characteristic of individual or population

      • Blood pressure, coat color, % body fat

      • May be associated with anatomical structure, e.g., an immune response with its site of action

    • Phenotype: name for a group of traits, syndrome, condition

      • e.g., type II diabetes, obesity, lymphocytic leukemia

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    a phenotype can be characterized

    by many traits

    &

    a trait can help characterize

    many phenotypes

    Leprdb-3J/Leprdb-3J

    Phenotype a Phenotype b Phenotype c

    Trait 1 Trait 2 ….. Trait n

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Developing structured descriptors for traits

    • Use existing and develop new controlled vocabularies that cover orthogonal concepts

    • Combine terms from these vocabularies to describe traits

    • Assign phenotype (disease) terms for nomenclature ease

    Joel Richardson, Michael Ashburner, Martin Ringwald

    jblake Manchester BioInfor Wk


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    ConceptExamples

    System:Immune system, cardiovascular system

    Tissue: heart, lung, liver, eye, skin

    Cell type: epithelial, fibroblast, myoblast, melanocyte

    Age: E15, P25

    Biol.Process: apoptosis, growth, cell differentiation, behavior

    Metabolite: Glucose, Calcium

    Qualifier: abnormal, absent, enlarged, increased, disrupted

    DCS = dolichostenomelia = disproportionally long limbs,

    due to long bone overgrow


    Relationships of mouse models to human diseases

    Relationships of Mouse Models to Human Diseases

    • Mouse gene ortholog, same mutation

      • Same phenotype

      • Different phenotype

    • Mouse gene ortholog, different or unknown mutations

      • Same or different phenotypes

    • Mouse phenotype same as human

      • Mouse gene ortholog

      • Another mouse gene

      • Gene unknown

    • Mouse phenotype similar

      • Unknown genetic component

  • Gene same or different


  • Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Relationship to human genes and disease


    Test results

    Goal: Query Mouse Data by Human Disease

    Test Results

    • 1676 disease listings in OMIM

      • 382 have phenotype reports

    • 3187 notated mouse/human orthologs

      • 958 correspond to OMIM entries

    • 305 have phenotype reports

  • 8535 listings in MESH disease tree

    • 709 correspond to orthologs

    • 237 have phenotype reports


  • Summary

    Summary

    • Integration

      • Requires both manual and computational approaches

      • Attention to data modeling, object identity, data migration issues

    • Ontologies and standardized vocabularies

      • Integral component of integration effort

      • Essential for extracting knowledge

    • Parallel development

      • ontology representations

      • data acquisition and integration efforts

    jblake Manchester BioInfor Wk


    Acknowledgments mgi

    Acknowledgments - MGI

    Carol Bult

    Ben King

    Richard Baldarelli

    Dirck Bradt

    Sridhar Ramachandran

    Deborah Reed

    Diane Dahman

    Sophia Zhu

    Donnie Qi

    LongLong Yang

    Pat Grant

    Nancy Butler

    Janan Eppig

    Joel Richardson

    Martin Ringwald

    Jim Kadin

    Lois Maltais

    Louise McKenzie

    Harold Drabkin

    Tom Weigers

    Jon Beal

    Lori Corbani

    Cathy Lutz

    Cynthia Smith

    Teresa Chu

    Sharon Cousins

    Donna Burkart

    Ira Lu

    Li Ni

    Carroll Goldsmith

    Moyha Lennon-Pierce

    Antonio Planchart

    www.informatics.jax.org

    David Hill

    Dale Begley

    Terry Hayamizu

    Ingeborg McCright

    Connie Smith

    Matt, Mike, Leslie, Jeff, Prita, Jill, Diane, DebbieK, Dieter, Lucette, Janice,


    Working in real time building ontologies while annotating the mouse from genotype to phenotype

    Mouse Genome Informatics

    http://www.informatics.jax.org

    Gene Ontology

    http://www.geneontology.org

    jblake Manchester BioInfor Wk


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