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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