Transcript Mouse Genetics - HGM2006 - Medical Research Council

Challenges for the study of disease in
the 21st century
•
Characterise the function of every gene in the
mammalian genome
Genome
•
Generate mutations in every gene in the mouse
genome
Function
•
Characterise the phenotype of every mutant mice
•
Identify models of human disease
Disease
European Mouse Programmes
• EUCOMM
• Developing mouse mutants for most of the genes in the mouse genome
• EUMORPHIA
• 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 a large number of mouse mutants
Challenges for the study of disease in
the 21st century
•
Characterise the function of every gene in the
mammalian genome
Genome
•
Generate mutations in every gene in the mouse
genome
Function
•
Characterise the phenotype of every mutant mice
•
Identify models of human disease
Disease
European Mouse Programmes
• EUCOMM 2006-2009
• European Conditional Mouse Mutagenesis program
• Major Participants - GSF, Sanger, Univ. Frankfurt, Max
Planck, Berlin, Harwell, Univ. Dresden, Strasbourg, CNR &
EMBL, Monterotondo, RZPD
• 20,000 gene trap and targeted null/conditional ES lines library archived at RZPD, Heidelberg for distribution
• 320 mouse lines generated and re-archived for distribution to
the community
• 20 new Cre expressing mouse strains generated
• Complementary programmes in Canada - NorCOMM
(underway), and US - KOMP (RFA)
The European Conditional Mouse Mutagenesis Program
1.
2.
3.
4.
5.
GSF National Center, Munich, Germany
W. Wurst (coordinator), Hrabe de Angelis
Wellcome Trust Sanger Institute,
Hinxton, UK
A. Bradley (coordinator), W. Skarnes, P.
Liu
University Frankfurt, Germany
H. von Melchner
Max-Planck-Institute of Molecular
Genetics, Berlin, Germany
P. Ruiz
University Dresden, Germany
F. Stewart
EUCOMM
6.
Gene Bridges, Dresden, Germany
G. Stevens
7.
Institute Clinique de la Souris (ICS),
Strasbourg, France
P. Chambon
8.
EMBL, Monterotondo, Italy
N. Rosentahl
9.
Medical Research Council, Harwell, UK
S. Brown
10. National Research Council, Monterotondo,
Italy
G. Tocchini-Valentini
11. German Rsesource Center of Genome
Research (RZPD), Heidelberg
B. Korn
European Mouse Programmes
• EUCOMM 2006-2009
• European Conditional Mouse Mutagenesis program
• Major Participants - GSF, Sanger, Univ. Frankfurt, Max
Planck, Berlin, Harwell, Univ. Dresden, Strasbourg, CNR &
EMBL, Monterotondo, RZPD
• 20,000 gene trap and targeted null/conditional ES lines library archived at RZPD, Heidelberg for distribution
• 320 mouse lines generated and re-archived for distribution to
the community
• 20 new Cre expressing mouse strains generated
• Complementary programmes in Canada - NorCOMM
(underway), and US - KOMP (RFA)
Challenges for the study of disease in
the 21st century
•
Characterise the function of every gene in the
mammalian genome
Genome
•
Generate mutations in every gene in the mouse
genome
Function
•
Characterise the phenotype of every mutant mice
•
Identify models of human disease
Disease
Challenges of Phenotyping
• 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
The importance of standardisation
• Better reproducibility of test
outcome
Across
Time
• Better comparability of test
outcome
Across
Labs
• Sharing of phenome results
Unified
Database
Eumorphia
Phenotype screens for mice
Developing an integrated
platform
EUMORPHIA - the consortium
 MRC Mammalian Genetics Unit, UK
 IGBMC, Strasbourg, France
 EMBL Monterotondo, Italy
 MRC Human Genetics Unit, UK
 CNR-IBC, Monterotondo, Italy
 MRC Functional Genetics, UK
 Karolinska, Stockholm, Sweden
 ANIMAGE, Lyon, France
 UNIL-IBA, Lausanne, Switzerland
 CNG/CNRS Paris, France
 UNIGE, Geneva, Switzerland
 GSF, Munich, Germany
 Sanger Institute, Hinxton, UK
 GBF, Braunschwieg, Germany
 CNIO, Madrid, Spain
 NKI, Amsterdam, Netherlands
 Univ. Manchester, UK
18 centres across Europe
Phenotyping - Workpackages
 Standardisation - animal handling
 First-line phenotyping
European
Mouse Phenotyping
Resource for Standardised Screens EMPReSS
 Clinical Chemistry/Haematology
 Cardiovascular
 Renal systems
 Hormonal/metabolic
 Central, peripheral nervous system,
 Allergy and infection
muscle
 Behaviour and cognition
 Imaging
 Necropsy, pathology, histology
 Sensory systems
 Pulmonary
 Cancer
 Bone, Cartilage
 Expression analysis
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
Working groups established
SOPs discussed and drafted
Validation between centres
Discussion of validation
results
Revision of SOPs
Revalidation between centres
Review of SOPs by
EMPReSS resource team
Review and sign-off by
Eumorphia scientist outside
working group
Additional validation
between centres
Inbred strains for validation
BALB/cByJ
(+ BALB/cAnN)
AnN ENU mutagenesis at Harwell
C57BL/6J
(+ C57BL/6N)
C3H/HeBFeJ
(+ C3H/HeN)
FeJ ENU mutagenesis at GSF/HeN at Harwell
129/SvPas
(+ 129S6/SvEvTac)
EMPReSS to date
• WP groups established March 2003
• All relevant WPs have contributed
• Over 150 SOPs and associated documents and
annexes
Global % PPI
Open field % Centre Time
35
100
80
60
40
20
0
30
25
20
15
10
5
0
35
30
C57BL/6
25
20
15
10
C3HeH
5
0
40
BALB/c
35
30
25
20
129/Sv
15
10
5
0
15
12
9
6
3
0
1st round validation results
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
CNR
GSF
MRC
ICS
European Mouse Programmes
• EUMORPHIA 2003-2006
• European Consortium to develop and standardise mouse
phenotyping platforms - 18 centres across Europe
• Over 150 SOPs developed and validated across laboratories
in Europe
• EMPReSS database, European Mouse Phenotyping
Resource for Standardised Screens
www.eumorphia.org
• EuroPhenome database - phenotype validation data on
inbred strains
• Nature Genetics, November 2005
Challenges for the study of disease in
the 21st century
•
Characterise the function of every gene in the
mammalian genome
Genome
•
Generate mutations in every gene in the mouse
genome
Function
•
Characterise the phenotype of every mutant mice
•
Identify models of human disease
Disease
European Mouse Programmes
• EUMODIC 2007-2010
• European Mouse Disease Clinic - apply EMPReSS protocols
to phenotyping of lines from EUCOMM
• 650 lines from EUCOMM phenotyped through a subset of
primary EMPReSS protocols - EMPReSSslim
• 4 mouse clinics (Harwell, GSF, Sanger, Strasbourg) will carry
out the primary phenotyping
• Subsets of lines will be distributed to a network of secondary
phenotyping centres for in-depth investigation
• Data deposited to EuroPhenome database
Beyond Eumorphia - EUMODIC
650 mouse
lines
Primary
Phenotyping
EMPReSSslim
Refinement of SOPs
Additional validation
Mouse clinics
GSF, Munich
ICS, Strasbourg
MRC, Harwell
Sanger, Hinxton
Secondary
Phenotyping
Bioinformatics
Statistical analysis
Community
Databases
Specialist
Centres
Development of new technologies
EUCOMM
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
EMPReSSslim
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
Beyond Eumorphia - EUMODIC
650
mouse lines
Primary
Phenotyping
EMPReSSslim
Refinement of SOPs
Additional validation
Mouse clinics
GSF, Munich
ICS, Strasbourg
MRC, Harwell
Sanger, Hinxton
Secondary
Phenotyping
Bioinformatics
Statistical analysis
Community
Databases
Specialist
Centres
Development of new technologies
EUCOMM
Challenges for the study of disease in
the 21st century
•
Characterise the function of every gene in the
mammalian genome
Genome
•
Generate mutations in every gene in the mouse
genome
Function
•
Characterise the phenotype of every mutant mice
•
Identify models of human disease
Disease
EUMORPHIA - the consortium
 MRC Mammalian Genetics Unit, UK
 IGBMC, Strasbourg, France
 EMBL Monterotondo, Italy
 MRC Human Genetics Unit, UK
 CNR-IBC, Monterotondo, Italy
 MRC Functional Genetics, UK
 Karolinska, Stockholm, Sweden
 ANIMAGE, Lyon, France
 UNIL-IBA, Lausanne, Switzerland
 CNG/CNRS Paris, France
 UNIGE, Geneva, Switzerland
 GSF, Munich, Germany
 Sanger Institute, Hinxton, UK
 GBF, Braunschwieg, Germany
 CNIO, Madrid, Spain
 NKI, Amsterdam, Netherlands
 Univ. Manchester, UK
18 centres across Europe