Challenges for the study of disease in the 21st century

• Characterise the function of every gene in the mammalian genome

• Generate mutations in every gene in the mouse genome

• Characterise the phenotype of every mutant mice

• Identify models of human disease

Genome

Function

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

• Generate mutations in every gene in the mouse genome

• Characterise the phenotype of every mutant mice

• Identify models of human disease

Genome

Function

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

EUCOMM1. GSF National Center, Munich, Germany

W. Wurst (coordinator), Hrabe de Angelis2. Wellcome Trust Sanger Institute,

Hinxton, UKA. Bradley (coordinator), W. Skarnes, P. Liu

3. University Frankfurt, GermanyH. von Melchner

4. Max-Planck-Institute of Molecular Genetics, Berlin, GermanyP. Ruiz

5. University Dresden, GermanyF. Stewart

6. Gene Bridges, Dresden, Germany

G. Stevens7. Institute Clinique de la Souris (ICS),

Strasbourg, FranceP. Chambon

8. EMBL, Monterotondo, ItalyN. Rosentahl

9. Medical Research Council, Harwell, UKS. Brown

10. National Research Council, Monterotondo, ItalyG. Tocchini-Valentini

11. German Rsesource Center of Genome Research (RZPD), HeidelbergB. 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

• Generate mutations in every gene in the mouse genome

• Characterise the phenotype of every mutant mice

• Identify models of human disease

Genome

Function

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

• Better comparability of test outcome

• Sharing of phenome results

AcrossTime

AcrossLabs

UnifiedDatabase

Eumorphia Phenotype screens for mice

Developing an integrated platform

EUMORPHIA - the consortium MRC Mammalian Genetics Unit, UK

IGBMC, Strasbourg, France

MRC Human Genetics Unit, UK

MRC Functional Genetics, UK

ANIMAGE, Lyon, France

CNG/CNRS Paris, France

GSF, Munich, Germany

GBF, Braunschwieg, Germany

NKI, Amsterdam, Netherlands

EMBL Monterotondo, Italy

CNR-IBC, Monterotondo, Italy

Karolinska, Stockholm, Sweden

UNIL-IBA, Lausanne, Switzerland

UNIGE, Geneva, Switzerland

Sanger Institute, Hinxton, UK

CNIO, Madrid, Spain

Univ. Manchester, UK

18 centres across Europe

Phenotyping - Workpackages Standardisation - animal handling

Clinical Chemistry/Haematology

Renal systems

Central, peripheral nervous system, muscle

Behaviour and cognition

Imaging

Necropsy, pathology, histology

First-line phenotyping

Cardiovascular

Hormonal/metabolic

Allergy and infection

Sensory systems

Pulmonary

Cancer

Bone, Cartilage

Expression analysis

European Mouse Phenotyping Resource for Standardised Screens - EMPReSS

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

www.eumorphia.org

Working groups establishedSOPs discussed and drafted

Validation between centresDiscussion of validation

resultsRevision of SOPs

Revalidation between centres

Additional validation between centres

Review of SOPs by EMPReSS resource team

Review and sign-off by Eumorphia scientist outside

working group

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)

Inbred strains for validation

EMPReSS to date

• WP groups established March 2003

• All relevant WPs have contributed

• Over 150 SOPs and associated documents and annexes

0

20406080

100

CNR

GSF0

2040

6080

100

02040

6080

100

MRC

ICS0

20406080

100

C57BL/6

C3HeH

BALB/c

129/Sv

Global % PPI

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

40

0

3

6

9

12

15

Open field % Centre Time

1st round validation results

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

• Generate mutations in every gene in the mouse genome

• Characterise the phenotype of every mutant mice

• Identify models of human disease

Genome

Function

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

Primary Phenotyping

EMPReSSslim

Secondary Phenotyping

650 mouse lines

EUCOMM

CommunityDatabases

Mouse clinicsGSF, MunichICS, StrasbourgMRC, HarwellSanger, Hinxton

Specialist Centres

Develo

pm

ent o

f new

techn

olo

giesBioinformatics

Statistical analysis

Refinement of SOPsAdditional validation

M

Dysmorphology / Blood /Metabolism

Bone

Allergy / Immune

Cardio

Sensory /Behaviour

10 weeks 14 weeks

FACS analysis of peripheral blood cells

Immunoglobin concentration

Dysmorphology

8 weeks

Clinical Chemistry

X rayDEXA

12 weeks

8 weeks

Opthalmoscope & Slit Lamp

Acoustic Startle

Tail flick

Open field

Modified SHIRPA

Elevated Platform

Grip Strength

Y-maze

9 weeks

10 weeks

Tail suspension

Swim Ability

Simplified IPGTT

13 weeks 14 weeks

Non-invasive Blood Pressure

Echo Cardiography

ANP

9 weeks

Calorimetry

10

12 weeks

10

10 10

10 10

10 10

10 1010 1010 10

10 10

10 10

10 10

10 10

10 10

10 10

10 10

10 1010 10

10 10

10 10

5 5

10 10 10 10

3 3

HaematologyRepeat Chemistry

10

10

Number of males

Number of females

Pipeline 1

Pipeline 2

EMPReSSslim

Beyond Eumorphia - EUMODIC

Primary Phenotyping

EMPReSSslim

Secondary Phenotyping

650mouse lines

EUCOMM

CommunityDatabases

Specialist Centres

Develo

pm

ent o

f new

techn

olo

giesBioinformatics

Statistical analysis

Refinement of SOPsAdditional validation

Mouse clinicsGSF, MunichICS, StrasbourgMRC, HarwellSanger, Hinxton

Challenges for the study of disease in the 21st century

• Characterise the function of every gene in the mammalian genome

• Generate mutations in every gene in the mouse genome

• Characterise the phenotype of every mutant mice

• Identify models of human disease

Genome

Function

Disease

EUMORPHIA - the consortium MRC Mammalian Genetics Unit, UK

IGBMC, Strasbourg, France

MRC Human Genetics Unit, UK

MRC Functional Genetics, UK

ANIMAGE, Lyon, France

CNG/CNRS Paris, France

GSF, Munich, Germany

GBF, Braunschwieg, Germany

NKI, Amsterdam, Netherlands

EMBL Monterotondo, Italy

CNR-IBC, Monterotondo, Italy

Karolinska, Stockholm, Sweden

UNIL-IBA, Lausanne, Switzerland

UNIGE, Geneva, Switzerland

Sanger Institute, Hinxton, UK

CNIO, Madrid, Spain

Univ. Manchester, UK

18 centres across Europe