Working%20in%20Real%20Time:%20Building%20Ontologies%20While%20Annotating%20the%20Mouse%20from%20Genotype%20to%20Phenotype

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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

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Mouse Genome Informatics

• 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

Genotype
Phenotype
Expression
Objective Facilitate the use of the mouse as a
model for human biology by furthering our
understanding of the relationship between
genotype and phenotype.
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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
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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 Miningextraction of new knowledge

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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

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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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Access to MGI resources
Alleles and Phenotypes
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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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Sets of Orthologs
Data associations supported by evidence and
citation
Orthologs of Vdr
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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

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Allele Query Form
Controlled Vocabularies for Describing Alleles
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Structured Vocabularies and Ontologies

• Anatomy
• GO
• Molecular function,
• Biological process,
• Cellular component
• Phenotypes
• Disease Models

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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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Consolidated Anatomical Dictionary
94 lines
heart cardiogenic plate primitive
heart tube ltmyocardium
ltendocardium ltcardiac jelly ltaortic
sinus ltatrio-ventricular canal (ependymal
canal) ltatrio-ventricular cushion tissue
(bulbar cushion,ependymal cushion tissue)
ltatrium primitive atrium
common atrial chamber ltcommon
atrial chamber bulbous cordis
ltcommon atrial chamber, left part
ltcommon atrial chamber, left part, cardiac
muscle (myocardium) ltcommon
atrial chamber, left part, endocardial lining
ltcommon atrial chamber, left part,
cardiac jelly ltcommon atrial
chamber, right part ltcommon
atrial chamber, right part, cardiac muscle
(myocardium) ltcommon atrial
chamber, right part, endocardial lining
ltcommon atrial chamber, right part,
cardiac jelly ltleft atrium
lt left atrium auricular region
ltleft atrium auricular region cardiac muscle
(myocardium) lt left atrium
auricular region endocardial lining
ltleft atrium cardiac muscle (myocardium)
ltleft atrium endocardial lining
ltright atrium ltright atrium
auricular region ltright atrium
auricular region cardiac muscle (myocardium)
ltright atrium auricular region
endocardial lining
ltright atrium cardiac muscle
(myocardium) ltright atrium
endocardial lining ltright atrium
valve right atrium venous
valve lt interatrial septum
lt foramen ovale lt septum primum
lt foramen primum (ostium
primum) lt foramen secundum
(ostium secundum) lt septum secundum
ltendocardial tissue ltendocardial
cushion tissue (bulbar cushion)
ltbulboventricular groove ltbulbus cordis
lt bulbus cordis caudal half
(myocardium) ltbulbus cordis
caudal half cardiac muscle (myocardium)
ltbulbus cordis caudal half endocardial
lining ltbulbus cordis caudal
half cardiac jelly lt bulbus cordis
rostral half (conotruncus) lt
bulbus cordis rostral half cardiac muscle
(myocardium) lt bulbus cordis
rostral half endocardial lining
lt bulbus cordis rostral half cardiac jelly lt
heart mesentery ltdorsal mesocardium
(dorsal mesentery of heart) ltdorsal
mesocardium transverse pericardial sinus
ltoutflow tract ltoutflow tract aortic
component ltoutflow tract
aortico-pulmonary spiral septum
ltoutflow tract future ascending aorta
ltoutflow tract pulmonary component
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Biol. Process
Phenotype
Anatomy
Gene expression
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Beyond mouse

• Data integration depends on indexing to defined
  sets of objects.
• Speaking the same language
• Development
• Heart
• Comparisons between model organisms

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http//www.geneontology.org
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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

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Opens browser
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Search returns children
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Returns annotated terms
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First-Pass Phenotype Set
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Query genes with mutants classified with term
eye dysmorphology
Ey
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Genotype/Phenotype
Classification Term Ref Allele Pair 1 Allele Pair 2 Background
Growth/weight abnormality postnatal 1 ApcTm1Rfc/Tm1Rfc B6129F2
Survival postnatal lethality 1 ApcTm1Rfc/Tm1Rfc B6129F2
Reproductive system dysmorphology 1 ApcTm1Rfc/Tm1Rfc B6129F2
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.
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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

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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
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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
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Concept Examples
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
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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 Results
Goal Query Mouse Data by Human Disease

• 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

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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

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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,
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Mouse Genome Informatics http//www.informatics.j
ax.org Gene Ontology http//www.geneontology.org