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International Mouse Phenotyping Consortium & MRC MOUSE NETWORK Tom Weaver Director, MRC Harwell Mary Lyon Centre Outline Update on the IMPC Progress Alleles & Gene Selection Production Phenotyping MRC Mouse Network Objectives Expectations Some Ideas For Going Forward Vision For Next 10 Years... An Encyclopaedia of Mammalian Gene Function Create KO mice for ALL GENES Database with associated primary phenotype info; Discover unforeseen gene function; Free and unfettered access to MICE Free thousands of researchers from tool generation; A rich seam for future hypothesis driven research, with the potential for breakthrough discoveries; A transformative project that will underpin the future of biomedical science and the biology of disease systems. 22 Partners, 13 Production Centres, 9 Countries www.mousephenotype.org IMPC Activities Undertake broad based primary phenotyping of 20,000 mutants from the IKMC resource A coordinated effort of mouse clinics worldwide Phase I (2011-2016): phenotype up to 5,000 lines Pipeline development, logistics Phenotyping technology developments e.g. imaging Ramp up Phase II (2016-2021): Phenotype 15,000 mutants Data freely available through a Data Coordination Centre, supported by R&D groups at clinics Value of Program Scientific (Hypothesis Generating) Innovation Bottleneck (SGX) Welfare (NC3R) Financial (Funders) Paradigm Shift in Scientific Culture (MRC MOUSE NETWORK) Traditional “One Gene at a Time” Approach Clone the Gene Knock Create It Out A in Cells Mouse Study Effect Share Publish with Your Other Work Labs 1 Gene, 1 Mutation, 1 Mouse 3-5 Year Investment in Time and Resources Expensive & Inefficient Individual Scientist Driven Alternative “Whole Genome” Approach Create a Sequence Mutate Repository the Genome EVERY gene of Mice Study Effect “Phenotype” Data Release Share Mice with Other Scientists Study Effect “Phenotype” Publish Work All Genes, 20K Mutations and Mouse Strains Highly Parallel (HTP “Factories”) Immediate Access & Sharing Cost Effective Global Networks Required Status: Raised $200M for Phase 1 Launch – Sept 28th 2011 Centre Total for Phase 1 MRC Harwell 330 Sanger Institute NIH - BaSH NIH - DTCC 1000 Baylor, Sanger, MRC Harwell 830 UC Davis, TCP, Children’s Oakland, CR 830 NIH - JAX 830 TCP, Toronto 150 Helmholtz, Munich 250 ICS, Strasbourg 250 Riken BRC 250 MARC, Nanjing 250 CNR, Monterotondo 250 TOTAL 5220 New Homepage for IMPC Portal www.mousephenotype.org (Andy Blake) IMPC Operational Plan Key Team Players @ Harwell They Will Deliver This Project Martin F. Production Lydia T. Deen Q. Sara W. Tertius H. LacZ Profiling Cohort Breeding Archiving Distribution Allele QC Michael C. Necropsy Phenotyping Genotyping Mark G. Quality Assurance Pathology Histology Training LIMS, Data Portal & Bioinformatics Alison W. Andy B. Hugh M. Finance, HR, Engagement Liz M. Hilary G. Nanda R. Annie M. MOUSE PRODUCTION STATUS IKMC Alleles (will be used in IMPC) Knockout-first, conditional ready allele: Promoter-driven selection cassette Francis Stewart (Dresden) Allan Bradley and Bill Skarnes (WTSI) Wolfgang Wurst (Helmholtz) See Skarnes et al. Nature 474, 262-263 (2011) STATUS: From Mouse Production to Cryopreservation Gene selection Gene selection, and tracking from ES QC to MI, iMits successfully launched MRC STRATEGY: MMN SELECTION Delivery of ES Cells KOMP Repository and EUMMCR tm1a=> tm1b allele conversion Different approaches will be applied across IMPC centres (Harwell ActinCRE working well) Cryopreservation strategy tm1a (and tm1b) – sperm freezing IKMC Alleles (will be used in IMPC) Knockout-first, conditional ready allele: We Archive & Promoter-driven selection cassette Distribute These Strains We Phenotype, Archive & Distribute These Strains Conditional Allele Requires Breeding Francis Stewart (Dresden) Allan Bradley and Bill Skarnes (WTSI) Wolfgang Wurst (Helmholtz) See Skarnes et al. Nature 474, 262-263 (2011) Harwell Production Status 444 MMN Genes “Assigned” to MRC and in progress (BaSH & MRC) =>assume 220 GLTS (50% Pass Rate) 53 tm1a alleles (legacy/imported) undergoing cre-deletion 88 Genes Received as ES cells 9 GLTs: first one is “IGF1R” 6 months from MI to access NEUROMOUSE Gene List & Synergies See Handout Progress 28 genes in progress 5 ES cells in Allele QC, rest awaiting receipt! Genes “Overlapping” interest with other members of network 5 with other consortia Neuodegenerative disease and aging, cancer, Development, Vision, Respiratory Synergy w/ Other Production Centres E.g. we nominate, they KO =>50 lines with China (MADD) 8 Genes from NEUROMOUSE (JAX, TCP, ICS,…) PHENOTYPING STATUS Phenotyping Program Has Evolved…. Much Discussion Build on EUMODIC, MGP, NIH K312 Focus Groups Surveys Operational Workshops (London, Toronto, Barca) Munich, Nov 2011 IMPC Adult Phenotyping Pipeline + LacZ Reporter 23 platforms, 100’s of parameters/metadata Protocol Development Working Groups LacZ Fertility & Viability SHIRPA/Dysmorphology Open Field Grip Strength/Startle, PPI ECG/Echo Calorimetry/IPGTT ABR Body Composition/ X-ray Slit lamp/ Ophthalmoscope Hematology/Clin Chem/Insulin Heart Wt./Gross Pathology/Block Banking FACS, IGs IMPReSS – International Mouse Phenotyping Resource of Standardised Screens IMPReSS (Annie Mallon) Now Live www.mousephenotype.org/impress Data Wranglers Protocols and Parameters for 13 Platforms Uploaded to the IMPReSS database In process of organizing calls for other SOPs SEE HANDOUT Phenotyping Progress @ MRC (Sara Wells & Tertius Hough) Recruiting & Reorg Complete (breeding stations), All Equipment In place SOPs Complete For Agreed Tests (MASSIVE TASK!) Pilot data for echo/ultrasound, challenge plethysmography, ABR 31 TM1A alleles cre-deletion underway (Tm1B) 12 TM1B alleles in cohort production, first full cohort started this month. Data will be in INTERPHENOME INTERPHENOME Mouse Phenotyping Informatics Infrastructure “MPI2” Harwell, Sanger, EBI (Pilot: www.europhenome.org) EuroPhenome (Annie Mallon) (www.europhenome.org) 26,258 mice 8.22M data points 3,416 annotations Gene and Phenotype Search Tools Complex Phenotype Search Result “Increased Circulating Cholesterol” AND “Increased Circulating LDL Cholesterol” EuroPhenome Heatmaps New phenotypes revealed (Steve Brown) Srsf4 (serine/arginine-rich splicing factor 4) Not annotated in MGI Pipeline Screening: Annotations in different systems Reduced RBC count, haemoglobin concentration, haematocrit across sexes and zygosities Much lower Grip Strength in both sexes More subtle changes in Calorimetry and Opthalmoscope 74% (131/176) genes with no prior annotations had significant phenotypes Number of Annotations Under top level term Pipeline Under Constant Review (Role for Networks) 700 600 500 Number of Annotations per top level ontology term 400 300 200 100 0 cardio lung Distribution of Phenotype Annotations Viability 84% of lines have an annotation including viability and fertility Viability % Lethal 34 Sub-viable 11 Reduced life span 2 Viable 53 Proposed IMPC Embryonic Lethal Phenotyping Pipeline viable >40% expected homozygous mutants at weaning Adult Phenotyping Pipeline Draft Pipeline – Under Consultation E12.5 E14.5 (embryos & placentae) Histopathology Embryo μCT (iodine staining) viable (embryos & placentae) Homozygotes Homozygotes Dissection & gross morphology <40% expected homozygous mutants at weaning (embryos & placentae) subviable lacZ staining Heterozygotes (embryos & placentae) Germline transmission Dissection & gross morphology ≥7 Embryos from Sub-viable Lines IKMC mES cells (B6N) IMPC & InfraComp Workshop on Embryonic Lethal Screening Two Day Workshop: April 18th-19th, 2012; Institute of Child Health, UCL Organizers: Andy Copp (UCL, UK), Janet Rossant (Univ Toronto, Canada), Tom Weaver (Harwell, UK), Tim Mohun (NIMR, UK), Monica Justice (Baylor, USA), Michael Raess (HMGU, Germany) Goal: Agree a consensus strategy for embryonic phenotyping & LacZ analysis Topics: Scientific Value of Embryology to Research Community Current Status of Screening – Don’t reinvent the wheel, Funding opportunities Operational Workflow – Not One Single Pipeline, Best Fits LacZ Reporter Analysis – Agree Pipeline Information Technology & Annotation Dev Consortia Input Critical FIRST MAJOR CONTRIBUTION FROM MRC MOUSE NETWORK Engagement Plan: MRC Mouse Network MRC Mouse Network Will Be a Forum to: Communicate about IMPC Encourage Uptake of Resources Promote Use of Resource Facilitate Collaboration 16 Consortia Formed 7/10 Top Therapeutic Areas >400 PIs/25% Clinical “MADD” Consortium Example Novel Drug Target Class 100 Knock Outs Structures/Assays/Industry Collaboration Network Consortia Consortium Principal Investigator Bone and Cartilage Raj Thakker, Oxford Cardiovascular Patricia Munroe, QMU Development Andrew Copp, UCL Drug Targets: UK-China (MADD) Dario Alessi, Dundee Haematopoiesis and Cancer Claus Nerlov, Edinburgh Host Response to Pneumonia Peter Andrews, Leicester Immune System Werner Muller, Manchester Innate Immunity David Hume, Edinburgh Liver Disease (UK Gold) Raj Thakker, Oxford Models of Diabetes and Obesity (MODO) Tony Vidal-Puig; Anthony Coll, Camb Neurodegenerative Disease & Aging (nPad) Jean Manson, Edinburgh Neuromouse Kay Davies, Oxford; Lizzy Fisher, Prion/UCL Opthamology Ian Jackson, Edinburgh; Marcela Vertruba, Cardiff Renal (RUMP) Robert Unwin, KCL; Matthew Bailey, Edinburgh Respiratory Charlotte Dean, Matthew Hind, Imperial Tissue Recomdelling and Fibroblast Disease (TiReFiC) Chirs Buckley, Birmingham; Jill Norman, UCL 16 Consortia Network; Met January at Ambitions For Network Promote IMPC and Mouse Models: facilitate more road shows, participate in training course(s) Proactive Discussion/Planning: Assign a “Champion” to be main contact with Harwell. Simplify, streamline the communication (gene lists, issues, ideas). Updated/Revised Plan in April. Encourage the network to evolve so that individuals can work together rather than simple info flow from Harwell/Pis. Use the portal as a project management/coordination tool. Direct Participation: Actions with Added Value to Program Pilot Work: Kick-start secondary phenotyping Active Uptake of Lines/Data Feedback: We will ask for a report at end of first year (spring 2013), will influence development of the program. USER CASE SCENARIO => DATA PORTAL On-line Portal (mrcmousenetwork.har.mrc.ac.uk) Individual members of the MRC Mouse Network will be able to communicate directly to one another in a manner similar to “Facebook” Key Functionalities Important Functions Secure Log in (already registered!) General Information News Events Forum => Incredibly Useful for IMPC • Nov 2008, 156 Active Users, 24 Forums, 300 Forum Threads, 8K page views…. My Consortium All Consortia Demo From Andy Blake Today Training For Networks The Network will promote training in the form of workshops, training courses, and site visits. Mouse Genome Browsing, Mutant Mouse Resources Customize to MMN Develop Case Studies, eg GWAS => Candidates => Resources Available 2/3 WEEK OF May 2012, Harwell, 20-40 People Please Update Your Action Plan This Month (Hilary will Email Pis) Champion. Need to get your contact actively linked with our scientists. Hilary/Tom can help coordinate. Access to Mice/Samples. Need feedback and start planning now, but be realistic. Your plans for 2’/3’ phenotyping. Primary Phenotyping Data. Help to evaluate. case input. Use Pathology Network. Cross cutting need. Recruiting a senior pathologist to lead. Join our network? Conditional Alleles. Service will be available. Are you interested? Coordinate Funding. Opportunities to look for technical support, pilots, etc… BHF example. Harwell has an immediate need for an Experienced Pathologist (Permanent B2, sr. lecturer equivalent) Role is to lead the program in animal health and welfare, as well as have overall responsibility for pathology services strategy and management at the Mary Lyon Centre. Opportunity for international collaboration in pathology phenotyping and annotation. Please Contact: Tom Weaver, [email protected] +44(0)778-0666-0922 MRC Mouse Network Timeline of Activity Jan MRC Network Meetings Planning & Reports 2012 Feb Mar Apr May Jun Jul Sep Oct Nov Dec Network Meeting (ops) MMN Launch Final Consortia Project Action Meetings Plan Jan Option for operational training (eg IVF/Cryo, Phenotping). Portal Interim MRC Revise Work Reports Review Plans Bioinfo (MMN Case Study) Portal and iMits on IMPC website Update MRC MTA Harwell & Other Production Centres EUMODIC Now, But InterPhenome with Time. Infra Comp (Emb) UCL MPI2 Wash DC KOMP2 Wash DC Apr May Network Meeting (ops) Consortia Project Meetings Bioinfo (MMN Case Study) Training Project Tracking Access To Mice Access To Data IMPC Specific Meeting Aug 2013 Feb Mar Infra Comp Korea SUMMARY KEY INFO PORTALS: IMPC: http://www.mousephenotype.org MRC MOUSENETWORK PORTAL WEB: http://mrcmousenetwork.har.mrc.ac.uk Email Contact: [email protected] Harwell Contacts Who Can Help Tom Weaver: [email protected] Andy Blake: [email protected] Hilary Gates: [email protected] Thank You