1. International Mouse Phenotyping Consortium Mark Moore, Ph.D.

2. Why the IMPC Build a resource of KO mice and associated encyclopedia of gene functions Free thousands of researchers from tool generation This resource will be revolutionize research for the next 20-30 years Novel genes will be brought to light that would otherwise be ignored Potential for breakthrough discoveries 3. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice Axel Visel1,2, Yiwen Zhu1, Dalit May1, Veena Afzal1, Elaine Gong1, Catia Attanasio1, Matthew J. Blow1,2, Jonathan C. Cohen3, Edward M. Rubin1,2 & Len A. Pennacchio1,2 Vol 464| 18 March 2010| doi:10.1038/nature08801 4. Variation in distant-acting regulatory sequences required for cardiovascular expression of CDKN2A and CDKN2B provides a plausible mechanistic model for the increased CAD risk associated with the 9p21 region independently of lipid levels and other known risk factors. 5. IMPC Vision IKMC (2006-11) ARRA (2010-11) EUMODIC (2008-11) IMPC (2011-21) PI Driven 6. The IKMC (EUCOMM, KOMP, NorCOMM and TIGM) have produced over 9,000 KO ES cell lines 7. KOMP Customer orders by month Late 2008 early 2010 87 89 92 45 114 98 121 90 85 104 103 115 132 168 139 115 143 160 R2 = 0.6 0 20 40 60 80 100 120 140 160 180 Sep-08 Oct-08 Nov-08 Dec-08 Jan-09 Feb-09 Mar-09 Apr-09 May-09 Jun-09 Jul-09 Aug-09 Sep-09 Oct-09 Nov-09 Dec-09 Jan-10 Feb-10 Numberoforders Each order saves $20,000-50,000 KOMP is already saving more money than it spends 8. Curiosities and Biases Gateway Entry Vectors - pENTR 1 - 17 of 17 products displayed Product Name SKU # Product Size List Price (USD) Qty K2520-02 20 preps $436.00 AmpliTaq Gold 360 DNA Polymerase, 250U Cat. No. 4398823 $250 Why do some people think that $1,000 or $2,000 for a proven ES line or mouse is expensive? 9. The Wellcome Trust (Dr. Michael Dunn) The Medical Research Council (Dr. Nathan Richardson) The Wellcome Trust Sanger Center (Dr. Allan Bradley) MRC Harwell (Dr. Steve Brown) European Commission (OPEN) German Mouse Clinic/InfraFrontiers (Dr. Martin Hrabe de Angelis) Toronto Centre for Phenogenomics (Dr. Colin McKerlie) ICS (Strasbourg) (Dr. Yann Herault) NIH: NHGRI (Dr. Eric Green) NDCD (Dr. James Battey) Australia Phenomics Network (Adrienne McKenzie) Other likely members: The Jackson Labs China Italy (Monterotondo) Czech Republic Japan UAB (Barcelona) Korea?Taipai? The International Mouse Phenotyping Consortium (IMPC) Steering Committee 10. IMPC Progress Addition of new members bringing total to 10 4 Funding Organizations 6 Mouse phenotyping Centers Response to community-wide surveys Development of workshops Embryology Imaging Technologies Working to actively manage the coordination and development of the multiple centres Launch Phase II 2011? 11. IMPC Activities Six mouse clinics so far; anticipate 10-12 worldwide. Phase I (2011-2016) of the preparatory/development period ~4,000 Work to actively manage the coordination and development of the multiple centres Evaluate a final scientific, management and governance plan for the full scale programme to commence in 2016 Launch Phase II 2016-2021 Completion of the Genome 12. IMPC Phenotyping Proposal The proposal will be shaped by: EUMODIC results The Sanger MGP Publicly available data (Lexicon and Deltagen) ENU screens phenotyping results Survey Results from UK, NIH, EU Recommendations from workshops in the UK and US Future workshops in Europe, US, Canada and UK 13. EMPReSSslim Primary Phenotyping Pipelines 20 phenotyping platforms 406 phenotype parameters 155 metadata parameters 14. WTSI Mouse Genetics Program 15. YES 54% NO 46% 1a. Would the current tests reveal phenotypes that would motivate you to shift your own resources and to take mice and begin work on them in your lab? 2009 Mouse Pipeline Survey 16. Tests Superficial and Insensitive Area not covered Limited Challenge Models (e.g. infectious agents) Funding 2009 Mouse Pipeline Survey If No, then why? 17. 0 2 4 6 8 10 12 14 Blood gas analysis Circadian profile Gait analysis 1' & 2' immunization with antigen + adjuvant Neonatal lethals Plasma assays Diet perturbation Gene expression Balance tests Psychotomimetic challenge Organ weight Flow cytometry Blood chemistry Blood pressure Ig titers Infectious challenge Histology Imaging 2009 Mouse Pipeline Survey # of Suggestions 2b. Specifics within Larger Fields 18. Survey Summary Report Immune challenge Cancer EmbryogenesisLearn/memory Histopath Gene expression Urinalysis M/S soft Auditory Fertility Eye/retina Diet challenge CVS Circ/sleep Behavior What is missing? MMRC Survey Conducted by Kent Lloyd >2000 e-mails and ~300 respondents 19. Survey Summary Report Question #2: Thinking beyond your laboratory, what do you see as the 3 essential tests, analyses, and/or examinations that would most likely reveal the utility of a mutant mouse line in your field? Two caveats: the numbers of mice used per test are limited to 5-10 and the tests must be high throughput (100s/y). immunity/infection/inflammation/arthritis/a diabetes/metabolism/mitochondrial/endocri behavior/neurology/sleep histology/morphology hematology/FACS/bleeding embryonic blood chemistry/lipid levels body composition/diet/growth reproduction/litter size/puberty gene expression bone density/bone morhology/bone strength EKG/cardiac defects/cardiovascular cancer proteomics/genotyping/gene retina/vision/ophthalmology imaging/microCT lacZ hypertension hearing muscle aging GI urinalysis genotoxic sensitivity/radiation biochemistry/cell biology respiratory dermatology/hair karyotype/stem cells oral/teeth olfactory exercise pharmacodynamics renal function vocalization wound healing secretory gland function tests thrombosis 205 181 174 behavior metabolism immuno MMRC Survey Conducted by Kent Lloyd 20. Key Areas of Unmet Need Cancer Need longer time line to study Fits with aging Challenge? Aging Critical need cited in all surveys and workshops Strongly augments: Cancer, Cardiovascular, Metabolic, Neurodegeneration and Bone Research Embryology A rich source of phenotype data ~30% KOs E.L. Very Specialized Skill Sets Req. Need HTP approach Meeting at TCP April 9-10 21. Cost Components: MLC, MRC, Harwell Mouse Production & Archiving: 21,690 Generation of mice from ES Cells Archiving the mouse line Viability and Fertility testing Breeding of cohort of 8M & 8F mutants Housing for phenotyping cohort (8M & 8F mutants & 4 WT controls) Gene Expression: 1100 Adult WM Embryo WM Metabolism: 1300 High Fat Diet Challenge IPGTT DEXA Weight Curve Calorimetry Full Clinical Chemistry Immune: 1,060 FACS of PBL IgG Levels Behaviour: 500 SHIRPA Open Field Grip Strength Rotarod Behavior/Sensory: 400 Hot Plate PPI Opthalmoscope Slit lamp Bones & Development: 350 Dysmorphology Weight Curves Faxitron Cardiovascular: 1100 Non invasive blood pressure ECG Echocardiograph Heart Weights Haematology: 80 RBC WBC Platelet Counts etc Total Cost: 27,580 22. New Areas and Cost Challenges Respiratory: 441 Plethysmograph Challenge Aging: 18,617 New cohort production and cage costs for 18 months Embryology: ?????$$$$$$ Immunology Challenge Infectious vs defined antigen ?????$$$$$$ 23. IMPC Phenotyping Core group of tests at all centres Agreed upon minimum cohort size (7?) Test and recommend additions to or dropping phenotypic tests from the pipeline Groups are encouraged to add tests to the phenotyping platform where possible Each centre is encouraged to incorporate a challenge assay or assays to the platform Each centre should develop networks of collaborators MRI and/or micro CT likely to be added Incorporate study of embryonic lethals 24. Phenotyping Progression Primary Screen (Thousand(s) per years) Second Level Testing (Hundreds per year) Tertiary In-Depth (dozens per year) 25. Mouse Phenotyping and Production/Distribution Centers Mouse Clinics ES to mouse Production (optional) Archiving (optional) Primary Phenotyping Secondary Phenotyping Production Centers Re-animation Mouse production Archiving Distribution Secondary Phenotyping 26. Informatics After meeting with groups from EUMODIC, the EBI, the JAX and discussions with CASIMIR members, the emerging picture is to have a stand-alone database that will collect data from each centre and provide a user interface to the outside world. There have been significant efforts made by EuroPhenome and the Sanger groups to develop these tools but there is not sufficient critical mass in any one program to accomplish the level of complexity, data volume and number of tasks that will be required of the IMPC in the future. 27. Informatics Organization 28. IMPC Next Steps Form Steering Committee Develop Requirements DocumentInformatics Explore new ways to lower mouse costs Continue exploring commercial optionsMice Form Tech Development Group First Tasks: Imaging Recommendation (&Pathology) Embryonic Lethal Analysis Tech Dev Develop final plan for IMPC Pipeline Operating plan for review of pipelinePhenotyping Working groups in each area Devise how to test models at centersChallenge Models 29. IMPC Standing Committees IT Chair Centre Reps Outside experts QA&QC Rotating Chair Center Reps Outside experts Finance InfraFrontiers Funders PIs Animal Assurance Outside Chair Center Reps Outside experts Technology Development Center Reps Outside experts 30. IMPC Cost Projections 31. IMPC Membership Funding Organizations Mouse Clinics and Phenotyping Centres Mouse Production Groups Informatics Groups Secondary Phenotyping Networks (e.g. APN) Other genetic efforts ENU Collaborative Cross Cre Drivers? Open some mouse clinic work as fee for service for investigator driven? 32. What Does $900M Buy 1 new football stadium 2 Airbus 380s 1/3 of the Bay Bridge retrofit 1 new approved pharmaceutical entity (NCE) Production and phenotyping of 20,000 gene KO lines In vivo functional annotation of a mammalian genome Transformative event for biologists Lower ongoing costs of obtaining mice Likely to identify hundreds of new drug targets Employ >450 researchers a year for 10 years (avg) 33. Next 3 years (2010-2013) EUMODIC project will come to completion UC, Davis has funding to support the creation and limited analysis of 312 KO mouse lines The WTSI is funded to analyse 200 KO lines per year MLC Harwell planning to analyse 100 KO lines per year Toronto Centre for Phenotyping (TCP) has capacity to produce and analyse 100-200 KO mouse lines per year. InfraFrontiers is developing the vital infrastructure for the continuation and expansion of mouse Phenotyping New centres at UAB (Barcelona) and the Czech Republic will be constructed and come online NIH has raised funding to launch Phenotyping 34. Acknowledgements The IMPC Steering Committee Tom Weaver Niels Adams Ramiro Ramirez-Solis Colin Fletcher John Hancock Bill Skarnes Damian Smedley Michael Hagn Paul Schofield Janan Eppig Kent Lloyd The IT group