小鼠表型分析国际合作计划

小鼠表型分析国际合作计划高翔南京大学模式动物研究所国家遗传工程小鼠资源库小鼠基因功能百科全书•基础2002，小鼠基因组计划完1982，小鼠基因剔除技术•资源国际合作2006，KOMP，EuCOMMNorCOMM，ChCOMM2008，日本KOprogram2009，韩国KOprogram2010，台湾KOprogram•功能分析国际合作基因功能Theavailabilityofthefullmousegenomesequencewillimmeasurablyadvanceboththecharacterandthepaceofdiscovery.Nature420,515-516(2002)人类重大疾病的动物模型：现代生物医药研发的核心条件基因组改造：建立疾病动物模型的核心技术小鼠等模式动物：开展基因组改造的最佳对象2007年诺贝尔生理医学奖CappechiEvansSmithies基因组改造转基因/基因剔除/诱发突变肿瘤/代谢/心血管/免疫疾病（大、小动物结合）疾病模型分子机理研究与医药研发建立模型分析与运用模型KnockoutMouseProjectConsortiumNatureGenetics36,921(2004)NorthAmericanConditionalMouseMutagenesisprojectTheTexasA&MInstituteforGenomicMedicineEuropeanConditionalMouseMutagenesisProgramTheKnockoutMouseProject大规模小鼠突变：小鼠基因剔除国际联盟CHCOMM，2006,MARC&MORCPBproject,2006,FudanAMMRA测序(2002)IKMC(2006-11)IMPC(2012-22)独立实验室大规模小鼠突变计划1999~RIKENGSC,ENUmutagenesis・Phenotype,Gene-driven1999~ANU,ENUmutagenesis・Phenotype-driven2001KoreaKITENUmutagenesis・Phenotype-driven2002~FudaiUnv.ICDpiggyBactransposon・Phenotype-driven2004~AcademiaSinica,ENUmutagenesis・Phenotype-driven2006~ChinaChCOMM2008~,JAPANCARD,Osaka,TokyoUniv..RIKENBRC2009~Korea2010~TaiwanAsia/Oceania1997~MRC,GSFENUmutagenesis・Phenotype-driven・Gene-driven2006〜EUEUCOMMConditionalMutagenesisProgram2000~TMGCJacksonLaboratoryBaylorCollegeofMedicineMcLaughlinResearchInstCMHDENUmutagenesis・Phenotype-driven2006~NIH,KOMP2006~GenomeCanadaNorCOMMNorthAmericanConditionalMouseMutagenesisprojectEuropeUS/CanadaChemicalMutagenesisGeneTargetingKOMPCSDRegeneronEuCOMMNorCOMMTIGMChCOMMGoal(ES)5,0003,5008,000500150Vectors511133274521312197TargetedES26742296244345151TrappedESn/an/a45,00047,45010,699n/aMice16816027912150~May2010小鼠基因剔除计划进展2005~ANU,AustralianPhenomicsFacility2001~NanjingUniversityMARC2003~NLACNationalAppliedResearchLaboratories2008~RIKENBRCJapanMouseClinic2008~AcademiaSinicaTaiwanMouseClinic2009~GEMKoreaProject2KoreaMouseMetabolicPhenotypingCenter2002~–NGFN-(FormeGSF)GermanMouseClinic(GMC)2004~2006EUMORPHIAEUMORPHIAhasdevelopedanewrobustprimaryscreeningplatformfordeterminingthephenotypeofmice:EMPReSSslim2003~-MRCTheMRCHarwellMouseClinic2006~-ICSInstitutCliniquedelaSourisMouseClinicalInstitute2007~EUMODICEUMODICundertakeaprimaryphenotypeassessmentofmousemutantlinesdevelopedintheEUCOMM2007~Sanger-MouseGeneticsProgrammePhenotyping1999~JacksonLaｂMPD(MousePhenomeProject)2006~US-BCM–MousePhenotypingCoreFacilityBaylorCollegeofMedicine2007~DeltagenandLexicon2007~–CMHD-TorontoCentreforPhenogenomicsphenotypingplatfrorm大规模小鼠模型分析与标准化项目亚洲欧洲美/加ThegoalofEUCOMMistogenerateacollectionofupto13,000mutatedgenesinmouseC57BL/6NEScellsusingconditionalgenetrappingandgenetargetingapproaches.KOmiceDatabaseSOPPhenotypingEUMODICundertakeaprimaryphenotypeassessmentofupto650mouselinesderivedfromtheEUCOMMprojectStandardizedScreens(EMPReSSlim)EUMORPHIAdevelopedarobustprimaryscreeningplatformfordeterminingthephenotypeofmice.EuroPhenomeisaopensourceprojecttodevelopasoftwaresystemforcapturing,storingandanalyzingrawphenotypingdataArchiving“小鼠遗传学正在成为大科学计划，而目前这些国际计划只包括物理领域的大型强子碰撞型加速装置（LHC）和国际热核聚变实验堆计划（ITER）”。小鼠表型分析I期：5年9亿美金，4000小鼠品系。“Noquestion,themouseiswheretheactionis”动物模型分析InternationalMousePhenotypingConsoritumRome2007,Toronto2008，2010讨论议题Feedingthepipelines模型来源及选择・Source/typeofmutants,e.g.KOprojects,CC,HSstrains,ENU,etc・Methodofselectionandcoordinationofselectionofgenes/lines・ProductionofmouselinesPhenotypingpipelinesandStandardisation分析内容及标准化・Multi-systems(primary)andsystem-focused(secondary)phenotyping・Improvementsandreducinganimalnumbers・StandardisationandSOPs・QualitycontrolofreleaseddataInformatics生物信息学・Approachestodatacapture・Dataannotation–ontologicaldevelopmentsandrequirements・Databases–towardsafederatedstructurewithsharedstandards・Dataexchange,SOPdescriptionandontologiesTechnologydevelopment技术开发・Emergingnewtestsandplatforms–・Improvingthetechnologyinexistingtests–raisingefficiencies,reducinganimalnumbersandcostsKOMP表型分析会议October29-302009Bethesda目的:讨论IKMC产出的小鼠的表型分析计划和战略决定：NIH从2010-14年每年拨款$11M，共初步分析1000-1500个品系。讨论议题：1)基因选择2)小鼠的生产3)分析方法和标准化4)数据集成和利用IMPC现状1.现有6个表型分析中心参加，预期最终全球10-12个2.第一期(2011-16):准备和发展期(分析~5,000品系)3.积极协调和发展多中心合作4.对IMPC的科学性、管理制度、管理结构做评估，于2016年推出全面实施计划5.第二期(2016‐2021):完成基因功能诠释(annotation)IMPC战略byMarkMoore,Ph.D(IMPCProjectManager)Informatics（生物信息学）•AftermeetingwithgroupsfromEUMODIC,theEBI,theJAXanddiscussionswithCASIMIRmembers,theemergingpictureistohaveastand‐alonedatabasethatwillcollectdatafromeachcentreandprovideauserinterfacetotheoutsideworld.•TherehavebeensignificanteffortsmadebyEuroPhenomeandtheSangergroupstodevelopthesetoolsbutthereisnotsufficientcriticalmassinanyoneprogramtoaccomplishthelevelofcomplexity,datavolumeandnumberoftasksthatwillberequiredoftheIMPCinthefuture.IMPC战略byMarkMoore,Ph.D(IMPCProjectManager)未来三年(2010-2013)EUMODICprojectwillcometocompletion(500lines).UCDaviswillcreateandanalyze312KOmouselines.WTSIwillanalyze200KOlinesperyear.TCPwillproduceandanalyzes100‐200KOmouselinesperyear.EU’sINFRAFRONTIERisdevelopingthevitalinfrastructuretocontinueandexpandEUcapacity.NewcentresatUAB(Barcelona)andtheCzechRepublicwillbec