Phenotypes in the Mouse Genome Database: functional screens to precise analysis

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Ontologies and vocabularies supporting data
integration emphasis on mouse phenotypes and
disease model
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
Janan T. EppigPATO Meeting, Dec. 2006
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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
 genetic engineering techniques to specifically
manipulate the genome
high resolution maps
 sequenced genome
 human disease model
Inbred strains
ES cell lines
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Achondroplasia
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.
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
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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

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Existing Wealth of Mouse Phenotype Data in MGI

• gt16,800 phenotypic alleles representing 6,830
  unique genes.
• gt71,000 annotations associating MP terms
• to genotypes.
• gt6,550 phenotype records for 3,210 QTL.
• gt9,000 strains catalogued.

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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

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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

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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

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Hbp1 (high mobility group box transcription
factor 1) gene expression differences in
KitW-e/KitW-e homozygotes vs wild-type
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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)
• .. organized as directed acyclic graphs (DAGs)

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3.MP Ontology
1.Gene Page
4.Disease vocabulary
2.Phenotype Query
5.Sequence (GBrowse)
Human/mouse disease relationships
Summary genotype, MP term, ref
Summary phenotype classes human disease
associated
Phenotype detail, including genotypes for mouse
models of human diseases
Navigating the views of phenotypes disease
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Genotype allele combinations carried in the
context of a specific genetic background (strain)
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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

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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

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• Allele Detail Page
• full phenotype
• annotations (MP) for
• each genotype
• specific detail for MP
• terms
• each MP annotation
• referenced

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Genes associated with phenotypes characteristic
of a disease in human, mouse, or both
Mouse model genotypes linked to phenotype details
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osteopetrosis
Human-mouse disease relationships OMIM
terms 6,113 Genotypes associated w/
OMIM 1,847 OMIM associated w/ genotypes 720
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Vocabularies in MGI
Genotype
Strain AEJ Allelesbd/bd
Strain C57BL/6 Alleles Ppp1r3atm1Adpt/
Ppp1r3atm1Adpt
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Making Mammalian Phenotype Ontology Work

• accommodate bio-specific terms
• computationally useful
• human accessible
• practical for curation
• cross-reference to other ontologies

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Terms in MP
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Future MP Ontology Development

• New terms from ongoing curation process
• Collaborative community efforts
• identify new terms
• revise organization of existing
• terms within particular branches
• Recruit domain experts for
• systematic review
• Cross-ref and comparison
• to other relevant ontologies
• (GO, Anatomy, Cell Type, Mpath, etc.)

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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

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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

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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.
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