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Integration and correlation of expression and phenotype data Martin Ringwald The Jackson Laboratory Mouse Genome Informatics (MGI) the community informatics resource for the laboratory mouse Genotype Expression Phenotype MGD GXD MGS MTB GO Function The laboratory mouse: an experimental model for studying human biology and diseases Inbred strain: unique alleleic combination specific characteristics DBA/2 System Immune system Behavior/Neurogenetic Reproduction Pathology hemolytic complement deficient resistant to leishmania infection susceptible to salmonella infection audiogenic seizure prone avoids alcohol high shock avoidance learning low testis weight high frequency deficient mammae leukemia, mammary tumor calcerious deposits around heart Standard Strain Nomenclature approved by the International Committee on Standardized Genetic Nomenclature for Mice provides standardized descriptors for strains and substrains and, implicitly, breeding schemes facilitate data integration and representation of complex biological concepts Examples: B10.129-H12b is a congenic strain with the genetic background of C57BL/10Sn (=B10) which differs from that strain by the introduction of a differential allele H12b derived from strain 129/J. BXD, a set of recombinant inbred strains derived from a cross of C57BL/6J x DBA/2J B = C57BL/6J; maternal progenitor strain X indicates recombinant inbred strain D = DBA/2J; paternal progenitor strain BXD-1, strain 1 from BXD set Expression patterns in segregating RI strains Genetic control of gene expression Experiment by Beverly Paigen et al. NHLBI-PGA From: Lee M. Silver, Mouse Genetics Standard Nomenclature for Alleles approved by the International Committee on Standardized Genetic Nomenclature for Mice Examples: Wnt3avt is the allele symbol for the recessive (indicated by lower case) vestigal tail allele of the Wnt3a gene, Tlx1tm1Sjk , 1st targeted mutation of Tlx1 created in the laboratory of Stanley J Korsmeyer. Genotype (in MGI) Strain (Background) Mutant Alleles Pax6Coop accession_id Record for Pax6Coop, the corneal opacity allele of paired box gene 6 Allele type, strain of origin, mode of inheritance Phenotype classifications, Genotype Molecular defect Additional phenotype terms OMIM links and disease models Gene “Phenoslim” classifications Allele type Molecular Mutation Inheritance Mode Gene Specimens Strain Mutations Results Anatomical dictionary terms Expression of Lhx1 in wild type and Pax6Sey homozygous mutant mice Expression of Pax6 in wild type and different mutant mice Integration of expression and phenotype data by sharing common objects for genes, strains and allelic variants Anatomy is an important integrator for expression and phenotype data Physiology Phenotype Anatomy Pathology Gene expression Biol. Process Anatomical Dictionary for Mouse Development Number of anatomical structures (Total: 13798) 20 00 18 00 16 00 14 00 12 00 10 00 80 0 60 0 40 0 20 0 0 TS 1 TS 2 TS 3 TS 4 TS 5 TS 6 TS 7 TS 8 TS 9 TS 10 TS 11 TS 12 TS 13 TS 14 TS 15 TS 16 TS 17 TS 18 TS 19 TS 20 TS 21 TS 22 TS 23 TS 24 TS 25 TS 26 Edinburgh collaborators: Jonathan Bard, Matthew Kaufman, Duncan Davidson, Richard Baldock GXD Concepts 2. Standardized description of expression patterns Links between anatomical structures at successive stages of mouse development enable the analysis of differentiation pathways Anatomical Dictionary for the adult mouse multiple hierarchies • physiological systems • space / histology • sampling Describe and view anatomy from different anatomical, physiological, and disease perspectives Anatomical Dictionary for the adult mouse multiple hierarchies • physiological systems • space / histology • sampling Describe and view anatomy from different anatomical, physiological, and disease perspectives Anatomical Dictionary for the Adult Mouse 3380 terms (as of 11/14/02) -> put bits and pieces together -> import in DAGedit -> make available via GoBo site -> refinements Evolution of phenotype descriptions in MGI Mouse Locus Catalog Free text “Phenoslim”: high-level phenotype classifications: list of 104 terms Phenotype Ontology: DAG; > 1800 terms Abnormal Lens Induction Qualifier Anatomy Process GO: Developmental Process Ontology Problem: incorporation of anatomical concepts -> pollution with species-specific terms -> explosion of the ontology -> re-inventing the wheel (anatomy ontology) -> disintegration Solution: keep process and anatomy ontology orthogonal and represent developmental processes by combinations of process and anatomy terms -> takes advantage of existing ontologies (terms + relationships) -> more robust and complete representation of developmental processes > normalization and integration Heart development - a detailed case study Extension and Integration of the Gene Ontology (GO): combining GO vocabularies with external vocabularies. David Hill, Judith Blake, Joel Richardson, and Martin Ringwald Genome Research, in Press. Trait: measurable characteristic of individual or population e.g., blood pressure, coat color, % body fat may be associated with anatomical structures, 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 Trait 1 Phenotype c Trait 2 ….. Trait n Developing structured descriptors for traits • Use existing and develop new controlled vocabularies that cover orthogonal concepts • Combine terms from these vocabularies to describe traits Concept Examples System: Immune system, cardiovascular system Tissue: heart, lung, liver, blood, eye, skin, long bone 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 System: Immune system, cardiovascular system Tissue: heart, lung, liver, blood, eye, skin, long bone 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 Increased levels of glucose in the blood Concept Examples System: Immune system, cardiovascular system Tissue: heart, lung, liver, eye, skin, long bone 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 Abnormal growth of melanocytes in the skin Concept Examples System: Immune system, cardiovascular system Tissue: heart, lung, liver, eye, skin, long bone 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 dolichostenomelia -> disproportionally long limbs, due to long bone overgrowth Use of common terms for description of phenotype and expression data • integration and comparison of phenotype data • direct correlation of expression and phenotype data • insights into the molecular mechanisms of disease The Jackson Laboratory MRC Edinburgh Terry Hayamizu Richard Baldock Mary Mangan Duncan Davidson John Corradi Albert Burger David Hill Joel Richardson Judy Blake Cynthia Smith Cathy Lutz Janan Eppig Edinburgh University Jonathan Bard Matthew Kaufman