Transcript Challenges for the study of disease in the 21st century

High throughput
phenotyping of mutant mice
to identify models of human
disease
Cynthia Smith
RCN Phenotyping Summit
2/25/2011
Mouse Models of Human Disease
Achondroplasia
Homozygous achondroplasia
mouse mutant and control
• short domed skull
• short-limbed dwarfism
• malocclusion
• bulging abdomen as adults
• respiratory problems
• shorted lifespan
Creating new models for the
study of human disease
• Generate mutations in every gene in the
mouse genome
• Characterise the phenotype of every mutant
mouse strain
• Identify models of human disease
European Mouse Programmes
• EUCOMM - European Conditional Mouse
Mutagenesis
• Developing mouse mutants for most of the genes in the
mouse genome
• EUMORPHIA - European Mouse Phenotyping
• Development and standardisation of mouse phenotyping
platforms (EMPreSS)
• EUMODIC - European Mouse Disease Clinic
• Undertake a major pilot programme to utilise
standardised phenotyping platforms for the analysis of
mouse mutants from EUCOMM
• EMMA - European Mouse Mutant Archive
• Archiving and dissemination of mice
European Mouse Programmes
• EUCOMM - European Conditional Mouse
Mutagenesis
• Developing mouse mutants for most of the genes in the
mouse genome
• EUMORPHIA - European Mouse Phenotyping
• Development and standardisation of mouse phenotyping
platforms
• EUMODIC - European Mouse Disease Clinic
• Undertake a major pilot programme to utilise
standardised phenotyping platforms for the analysis of
mouse mutants from EUCOMM
• EMMA - European Mouse Mutant Archive
• Archiving and dissemination of mice
European Conditional Mouse
Mutagenesis program (EUCOMM)
• 20,000 gene trap and targeted
null/conditional ES lines - library archived
at RZPD, Heidelberg for distribution
• 538 mouse lines generated and re-archived
for distribution to the community
• Complementary programs
• Canada - NorCOMM and US - KOMP and TIGM
IKMC
international coordination of knockout projects
European Mouse Programmes
• EUCOMM - European Conditional Mouse
Mutagenesis
• Developing mouse mutants for most of the genes in the
mouse genome
• EUMORPHIA - European Mouse Phenotyping
• Development and standardisation of mouse phenotyping
platforms
• EUMODIC - European Mouse Disease Clinic
• Undertake a major pilot programme to utilise
standardised phenotyping platforms for the analysis of
mouse mutants from EUCOMM
• EMMA - European Mouse Mutant Archive
• Archiving and dissemination of mice
Phenotyping Challenges
• Developing a comprehensive phenotyping
platform able to deliver phenotypic
information for all body systems
• Standardising phenotyping protocols so
that we can share and compare phenotype
data from mouse genetics centres
throughout the world
What is
EMPReSS?
• European Mouse Phenotyping Resource for
Standardised Screens
• The EMPReSS provides a platform for the
systematic and standardised primary
characterisation of mouse mutant models
• It is a comprehensive database of validated
SOPs for systematic screens and tests that
allows us to describe the phenotype of a
mouse
8 weeks
9 weeks
10 weeks
Dysmorphology
Calorimetry
Clinical
Chemistry
10 10
Dysmorphology /
Blood /
Metabolism
10 10
14 weeks
12 weeks
Simplified
IPGTT
10 10
10 10
Haematology
Repeat Chemistry
10 10
Pipeline 1
Bone
X ray
DEXA
10 10
3 3
FACS analysis
of peripheral
blood cells
Allergy / Immune
10 10
Immunoglobin
concentration
10 10
M
ANP
Cardio
13 weeks
Non-invasive
Blood Pressure
10 10
14 weeks
Echo
Cardiography
10 10
10 10
8 weeks
Open field
10 10
Sensory /
Behaviour
Modified
SHIRPA 10 10
Grip
Strength
10 10
Pipeline 2
9 weeks
Acoustic
Startle
10 10
Tail flick
10 10
10 weeks
Tail
suspension
10 10
Y-maze
10 10
Elevated
Platform
10 10
Swim Ability
10 10
10
Number of males
10
Number of females
12 weeks
Opthalmoscope
& Slit Lamp
5 5
European Mouse Programmes
• EUCOMM - European Conditional Mouse
Mutagenesis
• Developing mouse mutants for most of the genes in the
mouse genome
• EUMORPHIA - European Mouse Phenotyping
• Development and standardisation of mouse phenotyping
platforms
• EUMODIC - European Mouse Disease Clinic
• Undertake a major pilot programme to utilise
standardised phenotyping platforms for the analysis of
mouse mutants from EUCOMM
• EMMA - European Mouse Mutant Archive
• Archiving and dissemination of mice
Where is the phenotype data
generated?
primary
secondary
Europhenome Data Resource
Phenotype Ontologies - Informatics
 Continue developing systematic and comprehensive
systems to describing phenotypes - not only phenotype
ontologies, but anatomy, cell, function and behavior
 Phenotype ontologies will be central to the curatorial
annotation and mining of comprehensive animal phenotype
databases
 Integration/annotation of phenotype with other supporting
ontologies - assay, stressors, timepoints, genetic
background, sexual dimorphism
Data Descriptions
• Ontologies: allow linking of different levels of
description e.g. retina/eye
• Include metadata about protocol/assay used
• Existing ontologies for mouse phenotype
description
– Mammalian Phenotype Ontology
– Compositional schema
• Entity Quality (EQ) approaches
Describing Phenotypes with
Combinatorial Ontologies
Core
Entity
+
Quality
+
Value
e.g. Anatomical part
From PATO
associated
(Phenotype and Trait
with phenotype
Ontology)
(incl whole organism)
BLOOD PLASMA
GLUCOSE
CONCENTRATION
+
Units
Unit
ontology
20
mmol.l-1
= PHENOTYPE DESCRIPTION
Future Informatics Challenges
• Generation of detailed descriptions of mouse
phenotypes for every gene
• Continued development of ontologies and
mappings among these resources
• Mapping these phenotype descriptions in
model organisms onto human diseases to
assist with candidate gene identification
• May require a description of diseases as
collections of phenotypes
• Maintain and expand central mouse
phenotype databases
Participants To Date
•
Cambridge University
–
•
•
Valérie Gailus-Durner, Martin Hrabé de
Angelis, Christoph Lengger
Sophie Leblanc, Laurent Vasseur
–
Judy Blake, Molly Bogue, Janan Eppig,
Cynthia Smith
•
Aadya Shukla
RIKEN
–
The Jackson Lab
Elissa Chesler
Oxford University
–
•
Duncan Davidson, Kirsty Lee
ORNL
–
•
Andy Blake , Steve Brown, Chris Duran,
Simon Greenaway, John Hancock, AnnMarie Mallon, Alison Walling, Joe Wood
MRC HGU
–
ICS
–
•
•
Werner Müller
GSF
–
•
–
Eli Reuveni
GBF
–
•
MRC Harwell
Helen Parkinson, Glenn Proctor
EMBL Monterotondo
–
•
•
EBI
–
•
Georgios Gkoutos, Paul Schofield
Hiroshi Masuya, Tetsuro Toyoda,
Shigehara Wakana
Sanger Institute
–
Niels Adams, Dave Melvin, Jacqui White