Congenic Mice: What's in a Name? | Taconic Biosciences

Mutations of interest can be moved from one background strain to another through backcrossing, which generates congenic mice primarily derived ... 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MeganM.MacBride,PhDThursday,August18,2016 Facebook  Twitter  Linkedin  print  rss Researchersunfamiliarwithmousegeneticscanbeconfusedbycomplexstrainnomenclature,leavingthemunsurehowtoselectcontrolsforaparticularteststrain.Thenomenclatureof congenicmicerecordsawealthofusefulinformation,includingbothdonorandrecipientstrainsandmutationsofinterest. OnecommonexampleofthisisconfusionaroundbackgroundstrainforGEMandmutantlines.Whileitiscommonnowtomakeadesiredmutationdirectlyinastrainofinterest- suchasthepopularC57BL/6(B6)inbredstrain--duringtheearlydaysofmurinegeneticengineering,mostmutationsweremadeonbackgroundschosenfortheireaseof geneticmanipulationandnotnecessarilyfortheirvalueasastrainofinterest.Forexample,manymutationsweremadeinembryonicstem(ES)cellsderivedfromthe129P2inbredstrain, whichproducedrobustEScells.ButresearcherspreferredtostudythosemutationsontheB6background,notthe129P2background. Sohowcanthosemutationsbetransferredtoanewstrain? BackcrossingtoGenerateCongenicMice Mutationsofinterestcanbemovedfromonebackgroundstraintoanotherthroughbackcrossing,whichgeneratescongenicmiceprimarilyderivedoftherecipientbackground- B6,forexample-containingthemutationofinterestandalinkedsectionofitschromosomederivedfromthedonorstrain.Repeatedlymatingthedonortotherecipientstrainand selectingforoffspringwiththedesiredmutation,typicallythroughgenotyping, removes~50%ofthedonorgenomewitheachsuccessivegeneration.Fivegenerationsofbackcrossingwillproducealine~94%derivedfromtherecipientgenome. Fivegenerationsistheminimumnumberofcrossestogenerateacongenicmousemodel.Atthetenthbackcross,approximately99.9%ofthegenomeisderivedfromtherecipientstrain. Whiletraditionalbackcrossingisstillused,thisprocesscanbeacceleratedviaselectingbreedersineachbackcrossgenerationwhichhavethehighestpercentageofrecipientgenome. Thisiscommonlycalledspeedcongenics. CongenicMouseNomenclature Allofthisbackgroundinformationisencodedincongenicstrainnomenclature,allowinginformedresearcherstorapidlyassesstheutilityofagivenrodentmodeltotheir preciseareaofstudy. Forexample,considertheRAGN12model.TheoriginalRag2knockoutmutationwasmadein CCEEScellsderivedfromthe129S6inbredstrain.Theresultingmutantmicewereonthe 129S6background.AsresearcherswantedtobeabletostudythismutationonthepopularB6background,thelinewasbackcrossed12generationstoC57BL/6NTactomakea congenicstrain.Over99.9%ofthegenomeoftheRAGN12lineisderivedfromtheC57BL/6NTacinbredstrain,withsomesmallresidualgenomecontributionfromthe129S6strain, primarilyflankingtheRag2mutation. Thenomenclatureforthisline-B6.129S6-Rag2tm1FwaN12-tellsthisstoryquitewell.Hereisthebreakdown: InstantOriginInformation Taconicpostsorigininformationforallofourcongeniclines,butresearchersshouldbecarefultoreadthroughthefulloriginbeforeassessingamodel.Forexample, hereistheoriginfortheRAGN12line: "TheRag2mousewasdevelopedinthelaboratoryofFrederickW.AltatColumbiaUniversity.ThemodelwascreatedbytargetingtheRag2geneinCCEEScellsandinjectingthe targetedcellsintoblastocysts.ThislineoriginatedfrommodelRAG2-Mona129S6/SvEvbackground.Themicewerebackcrossedtwelvegenerations(N12)toa C57BL/6NTacinbredbackground.Heterozygoteswereintercrossedtogeneratehomozygoustargetedmutationmice.Thelineismaintainedbyincrossinghomozygousmice." Ifyoustoppedat"ThemodelwascreatedbytargetingtheRag2geneinCCEEScellsandinjectingthetargetedcellsintoblastocysts.ThislineoriginatedfrommodelRAG2-Mona 129S6/SvEvbackground."youmightassumethatthislinewasona129S6background. Researchersfamiliarwithcongenicstrainnomenclature,ontheotherhand,getthefullpictureataglance. MouseModelNomenclatureGuidesControlSelection WildtypecontrolsforGEMmiceshouldbeascloseaspossibletotheGEMlineofinterestintermsofbackgroundgenetics.Forcongeniclineswherebothwildtypeand transgenicmiceareproducedfromthesamematings,thewildtypesproducedinthatmannerareoftenthebestcontrols.ManyGEMlinesaremaintainedviamatingsof homozygousfemalesandmales,however,meaningnowildtypelittermatesareproduced.Inthatcase,areviewofthenomenclatureandoriginisinordertodeterminethe bestwildtypecontrol. Asanexample,let'slookattheCETPline:B6.SJL-Tg(APOA-CETP)1DsgN11. ThenomenclatureindicatesthelineiscongeniconB6,butdoesnotprovidesufficientinformationtodeterminewhichB6subline.AsB6sublinesdifferquiteabit, itisimportanttochoosetheclosestsubline.Areviewoftheoriginprovidesclarity: "TheCETPmousewasdevelopedinthelaboratoryofDr.DavidGrassatXenogenBiosciences,nowTaconic.ThemodelwascreatedbymicroinjectingthehumanCETPgeneinto (C57BL/6JxSJL)F2zygotes.TaconicreceivedstockinApril1996atthesecondbackcrossfromthefounderline.ThemicewerethenbackcrossedonegenerationtoC57BL/6priorto intercrossingforhomozygosity.BackcrossingtoC57BL/6NTacrecommencedatTaconicin2004.Thelinewasbackcrossedatotalof10generations(N10)andthenintercrossedto homozygosity.AhomozygouscolonyismaintainedfortheproductionofhemizygotesthroughmatingtoC57BL/6NTac(N11)." TheoriginindicatesthelinewasbackcrossedtoC57BL/6NTac,makingthatinbredstrainthemostappropriatewildtypecontrol. ReadtheRelatedTaconicBiosciences'Insights:AMousebyAnyOtherName-NomenclatureTutorialConfusedAboutLy5,Cd45,andPtprc? ←UsingCRISPRtochange"A"to"T"and"C"to"G"ImprovingLivesbyModelingRareGeneticDisorders→ TaconicInsights ADMET Alzheimer'sDisease AnimalWelfare CardiovascularDisease ColonyManagementSolutions Cryopreservation Genetics Immunology InfectiousDisease Inflammation MetabolicDisease MicrobiomeandGerm-Free ModelGenerationSolutions Neuroscience OncologyandImmuno-Oncology Parkinson'sDisease Quality TACONICINSIGHTS SUBSCRIBE NevermissanInsight! MostPopularInGeneticsCongenicMice:What'sinaName? OhTransgene,WhereArtThou?MappingTransgeneInsertion BuildorBuy:AnimalModelLicensingintheAgeofCRISPR GeneticVariationinC57BL/6ESCellsandKnockoutMice RNATherapeutics:siRNA VariationswithinOutbredStrains:KnowYourStrainsandStocks Close Welcome!Tellusalittleaboutyourself Hereweshowthechatwindow.