Challenges for the study of disease in the 21 st century

1. 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

2. 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

3. 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

4. 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)

5. The European Conditional Mouse Mutagenesis ProgramEUCOMM • 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 • Gene Bridges, Dresden, Germany G. Stevens • Institute Clinique de la Souris (ICS), Strasbourg, France P. Chambon • EMBL, Monterotondo, Italy N. Rosentahl • Medical Research Council, Harwell, UK S. Brown • National Research Council, Monterotondo, Italy G. Tocchini-Valentini • German Rsesource Center of Genome Research (RZPD), Heidelberg B. Korn

6. 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)

7. 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

8. 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

9. The importance of standardisation • Better reproducibility of test outcome • Better comparability of test outcome • Sharing of phenome results Across Time Across Labs Unified Database

10. EumorphiaPhenotype screens for miceDeveloping an integrated platform

11. 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

12. 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

13. 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

14. www.eumorphia.org

15. 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 Additional validation between centres Review and sign-off by Eumorphia scientist outside working group

16. 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)

17. EMPReSS to date • WP groups established March 2003 • All relevant WPs have contributed • Over 150 SOPs and associated documents and annexes

18. Global % PPI Open field % Centre Time 35 100 30 80 25 60 20 CNR 40 15 10 20 5 0 0 C57BL/6 100 35 80 30 25 60 GSF 20 40 C3HeH 15 10 20 5 0 0 BALB/c 100 40 35 80 30 129/Sv 60 25 MRC 20 40 15 20 10 5 0 0 15 100 80 12 60 9 ICS 40 6 20 3 0 0 1st round validation results

19. 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

20. 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

21. 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

22. Beyond Eumorphia - EUMODIC EUCOMM Primary Phenotyping EMPReSSslim 650 mouse lines Mouse clinics GSF, Munich ICS, Strasbourg MRC, Harwell Sanger, Hinxton Refinement of SOPs Additional validation Development of new technologies Secondary Phenotyping Specialist Centres Bioinformatics Statistical analysis Community Databases

23. M 14 weeks 8 weeks 9 weeks 10 weeks 12 weeks Clinical Chemistry Dysmorphology Simplified IPGTT Calorimetry Dysmorphology / Blood / Metabolism 10 10 10 10 10 10 Haematology Repeat Chemistry 10 10 10 10 Pipeline 1 X ray Bone DEXA 10 10 3 3 FACS analysis of peripheral blood cells Allergy / Immune 10 10 EMPReSSslim Immunoglobin concentration 10 10 13 weeks 14 weeks Echo Cardiography ANP Non-invasive Blood Pressure Cardio 10 10 10 10 10 10 8 weeks Open field Pipeline 2 10 10 9 weeks Acoustic Startle Modified SHIRPA 10 10 Sensory /Behaviour 10 weeks 10 10 Grip Strength Tail suspension Tail flick 10 Number of males 10 10 10 10 10 10 12 weeks Y-maze Number of females 10 Opthalmoscope & Slit Lamp Swim Ability 10 10 Elevated Platform 10 10 5 5 10 10

24. Beyond Eumorphia - EUMODIC EUCOMM Primary Phenotyping EMPReSSslim 650 mouse lines Mouse clinics GSF, Munich ICS, Strasbourg MRC, Harwell Sanger, Hinxton Refinement of SOPs Additional validation Development of new technologies Secondary Phenotyping Specialist Centres Bioinformatics Statistical analysis Community Databases

25. 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

26. 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