Challenges for the study of disease in the 21 st 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 21 st 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 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 EUCOMM 1.GSF National Center, Munich, Germany W. Wurst (coordinator), Hrabe de Angelis 2.Wellcome Trust Sanger Institute, Hinxton, UK A. Bradley (coordinator), W. Skarnes, P. Liu 3.University Frankfurt, Germany H. von Melchner 4.Max-Planck-Institute of Molecular Genetics, Berlin, Germany P. Ruiz 5.University Dresden, Germany F. Stewart 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 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 21 st 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 Across Time Across Labs Unified Database

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

Working groups established SOPs discussed and drafted Validation between centres Discussion of validation results Revision 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

CNR GSF MRC ICS C57BL/6 C3HeH BALB/c 129/Sv Global % PPI Open field % Centre Time 1st round validation results

European Mouse Programmes EUMORPHIA 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 EuroPhenome database - phenotype validation data on inbred strains Nature Genetics, November 2005

Challenges for the study of disease in the 21 st 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 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 Community Databases Mouse clinics GSF, Munich ICS, Strasbourg MRC, Harwell Sanger, Hinxton Specialist Centres Development of new technologies Bioinformatics Statistical analysis Refinement of SOPs Additional 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 ray DEXA 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 weeks Haematology Repeat Chemistry 10 Number of males Number of females Pipeline 1 Pipeline 2 EMPReSSslim

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

Challenges for the study of disease in the 21 st 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