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 InformaticsThe Jackson LaboratoryBar Harbor, ME 04609

24Mar2002

Genotype

Objective:

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

PhenotypeExpression

Mouse Genome Informatics

Mouse Genome DatabaseProject (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

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MGI Integration Efforts

Integrated experimental and consensus views

Mapping, molecular, alleles, expression, phenotypesGene to GO associations

Canonical gene and sequenceCollaborations with SWISS-PROT and LocusLinkNomenclature standards, gene groupings

Curated mammalian orthologiesused 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

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Common Issues for Model Organism

DatabasesData 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 evaluationData Mining…extraction of new knowledge

24Mar2002 jblake-Manchester BioInform Wk

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

24Mar2002 jblake Manchester BioInfor Wk

Numbers (20 March 2002)

No. of References 70,874

No. of Genes 35,404

No. of Markers 54,834

Genes w/ NT Seq 31,386

Genes w/ AA Seq 12,875

Genes w/ Orthologs 7,051

Genes Mapped 19,058

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Strains and Polymorphisms

Access to MGI resources

Genes and Markers

Sequences and Maps

Embryonic Expression

Mammalian Homology

mouse BLAST, molecular segments

Alleles and Phenotypes

References, AccID,


“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”

Enable Complex Queries

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GO annotations

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

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Orthologs of Vdr

Sets of OrthologsData associations supported by evidence and citation


Multiple Keyword Sets

Gene/Marker TypeAllele TypeAssay Type• Expression• Mapping

Molecular MutationInheritance ModeNomenclature

Evidence CodesTissueCell LinesUnits • Cytogenetic• Molecular

ES Cell LineStrain

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Controlled Vocabularies

for Describing Alleles

Allele Query Form


AnatomyGO: • Molecular function, • Biological process, • Cellular component

PhenotypesDisease Models

Structured Vocabularies and Ontologies

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Stage 10* embryo

• cavity• proamniotic canal

• embryonic component• ectoderm

• primitive ectoderm• primitive streak

• node• endoderm

• primitive endoderm• mesoderm• nervous system

• neural ectoderm* extraembryonic tissue

• allantois• amniotic fold

• anterior amniotic fold• ectoderm• mesoderm

• posterior amniotic fold• ectoderm• mesoderm

• cavity• amniotic cavity• ectoplacental cavity• exocoelomic cavity• proamniotic canal

• extraembryonic component• yolk sac cavity

• ectoderm• endoderm

• parietal endoderm• visceral endoderm

• mesoderm• primordial germ cells

• Reichert's membrane• trophectoderm

• mural trophectoderm• primary trophoblast giant cells

• polar trophectoderm• cytotrophoblast• ectoplacental cone• syncytiotrophoblast

• yolk sac• endoderm

Anatomical Dictionary Theiler stage 10 (7 dpc)

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

Collaboration with MRC / Edinburgh 3D-Atlas project

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

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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

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Biol. Process

Anatomy

Phenotype

Gene expression

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Data integration depends on indexing to defined sets of objects.Speaking the same language• ‘Developmen

t’• ‘Heart’

Comparisons between model organisms

Beyond mouse

From The Heart by Margaret Kirby in “Embryos, Genes and Birth Defects”. Edited by Peter Thorogood

Mouse Heart Development

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http://www.geneontology.org

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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

Goals of the Consortium

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Opens browse

r

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Search returns children

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Returns annotated

terms


First-Pass Phenotype Set

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Ey

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

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Genotype/Phenotype

Classification Term Ref

Allele Pair 1

Allele Pair 2

Background

Growth/weight abnormalitypostnatal

1 ApcTm1Rfc/

Tm1Rfc

B6;129F2

Survival: postnatal lethality

1 ApcTm1Rfc/

Tm1Rfc

B6;129F2

Reproductive system: dysmorphology

1 ApcTm1Rfc/

Tm1Rfc

B6;129F2

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

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


a phenotype can be characterized by many traits &a trait can help characterize many phenotypes

Phenotype a Phenotype b Phenotype c

Trait 1 Trait 2 ….. Trait n

Leprdb-3J/Leprdb-3J


• 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

Developing structured descriptors for traits

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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

Concept Examples

DCS = dolichostenomelia = disproportionally long limbs,

due to long bone overgrow

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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

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Relationship to human genes and disease

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Test Results1676 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

Goal: Query Mouse Data by Human

Disease


SummaryIntegration • 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

24Mar2002

Acknowledgments - MGI

Carol BultBen KingRichard Baldarelli

Dirck BradtSridhar RamachandranDeborah ReedDiane DahmanSophia ZhuDonnie QiLongLong Yang

Pat GrantNancy Butler

Janan EppigJoel Richardson

Martin RingwaldJim Kadin

Lois MaltaisLouise McKenzieHarold DrabkinTom WeigersJon BealLori CorbaniCathy LutzCynthia SmithTeresa ChuSharon CousinsDonna BurkartIra LuLi NiCarroll GoldsmithMoyha Lennon-PierceAntonio Planchart

David HillDale BegleyTerry HayamizuIngeborg McCrightConnie Smith

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

www.informatics.jax.org


Mouse Genome Informatics

http://www.informatics.jax.org

Gene Ontologyhttp://www.geneontology.org

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

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