Here's What You Need to Know about the C57BL/6 Substrains

C57BL/6J mice express a mutant Nnt gene, which is involved in glucose-mediated insulin secretion, compared to C57BL/6N substrains (Freeman et , ... genprowebdirectory GENEdge Video&Multimedia LatestNews Login Subscribe News Insights Trendsfor2020 Trendsfor2021 Topics Bioprocessing Cancer DrugDiscovery GenomeEditing InfectiousDiseases OMICs TranslationalMedicine A-Lists Magazine CurrentIssue PastIssues Supplements Subscribe Resources GENProtocols Summits Webinars GENLive eBooks/Perspectives Podcasts Tutorials Peer-ReviewedJournals GENBiotechnology Re:GenOpen NewProducts BestoftheWeb BestApps ConferenceCalendar Subscribe CreateaFreeAccount GetGENEdge LogIn GetGENMagazine GetGENeNewsletters GettheGENMobileApp GetGENNewsfromAlexa Search Advertising MagazineAdvertising WebsiteBannerAdvertising eNewsletterAdvertising WebinarSponsorship eBookAdvertising EmailNurtureCampaigns AdTermsandConditions AboutGEN ContactGEN CreateaFreeAccount GetGENEdge LogIn Signin Welcome!Logintoyouraccount yourusername yourpassword Forgotyourpassword?Gethelp Createanaccount PrivacyPolicy Createanaccount Welcome!Registerforanaccount youremail yourusername Apasswordwillbee-mailedtoyou. 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GEN–GeneticEngineeringandBiotechnologyNews GENEdge Video&Multimedia LatestNews Login Subscribe News Bioprocessing ContinuousMonitoringwithoutLabels Cancer GeneticallyModifiedImmuneEffectorCellsShowLong-TermSafetyinStudy Cancer PotentialStrategyHaltsCancer’sKeyCellRepairMechanism Antibodies SingleCellAtlasofImmuneDisorderCVIDImplicatesEpigeneticFactors Genomics FirstCompleteHumanGenome,ForRealThisTime Insights AllTrendsfor2020Trendsfor2021 AAV(Adeno-associatedvirus) GeneTherapySectorNeedsBetterCellLinesforVectorProduction Bioprocessing UsingLAMPStoImproveBioprocessing AAV(Adeno-associatedvirus) Cancer-FightingVirusProducts Bioprocessing HPLCSystemsFocusonNewDirections Topics Bioprocessing Cancer DrugDiscovery GenomeEditing InfectiousDiseases OMICs TranslationalMedicine A-Lists A-Lists SevenBiopharmaTrendstoWatchin2022 A-Lists SixoftheBestReportsfromtheFrontLineofBiotechnology A-Lists Top10RNA-BasedBiopharmas Coronavirus Top11BestSellingCOVID-19VaccinesandDrugsofH12021 A-Lists Top10SpatialBiologyCompanies Magazine CurrentIssue PastIssues Supplements Subscribe Resources GENProtocols Summits Webinars GENLive eBooks/Perspectives Podcasts Tutorials Peer-ReviewedJournals GENBiotechnology Re:GenOpen NewProducts BestoftheWeb BestApps ConferenceCalendar Subscribe CreateaFreeAccount GetGENEdge LogIn GetGENMagazine GetGENeNewsletters GettheGENMobileApp GetGENNewsfromAlexa HomeAutoimmuneDisordersHere’sWhatYouNeedtoKnowabouttheC57BL/6Substrains Source:dra_schwartz/GettyImages Source:dra_schwartz/GettyImages Share Facebook Twitter Linkedin ReddIt Email Sponsoredcontentbroughttoyouby   Table3.PrevalenceofcommonC57BL/6substrainsinpublishedliterature.Atthetimeofpublication,thefollowingsearchtermsforindividualC57BL/6substrainswereenteredintothePubMeddatabaseandnumberofreferenceswererecorded. Certainly,substraindifferencesexistinallinbredmousestrains.Byfar,however,theC57BL/6strainsarethemostcommonlypublishedintheworldwithover37,000entriesinPubMed(Table3).Forthisreason,thispaperwillfocusonpublisheddifferencesonlyintheC57BL/6family. Currentlythereareover16,000entriesusingtheoriginalJacksonLaboratoryC57BL/6Jsubstrain.AfewotherentriesexistforsubstrainsderivedfromtheoriginalC57BL/6J.Roughly1200entriesuseC57BL/6Nderivedsubstrains.Inthecomingyears,theuseofC57BL/6Nsubstrainsisexpectedtogrowsignificantly,asall20,000genesinthemousegenomewilleventuallybetargetedinC57BL/6NEScellsthroughtheInternationalKnockoutMouseConsortium(IKMC)project(www.mousephenotype.org).   TheoriginalC57BL/6JsubstrainfromTheJacksonLaboratorywassentto theNationalInstitutesofHealth(NIH)in1951.TheNIHsubstrain,C57BL/6N,waslaterdistributedtoseveralinstitutesincludingCharlesRiverLaboratoriesin1974(C57BL/6NCrl), toHarlan(nowEnvigo,C57BL/6NHsd)in1974 and1988,andtoTaconic(C57BL/6NTac)in1991.In2005,theNsubstraincamebacktoTheJacksonLaboratory,andis knownastheC57BL/6NJsubstrain.Currently,atleast100generations ofbreedingseparateC57BL/6JsubstrainsfromallC57BL/6Nsubstrains(Figure3). Figure3.C57BL/6substrainhistory.TheoriginalC57BL/6mousewascreatedbyClarenceCookLittle,founderofTheJacksonLaboratory,in1921.Sincethattime,thestrainhasbeendistributedtohundredsofinstitutesandthousandsoflaboratoriesworldwide.Becauseofspontaneousmutationsleadingtogeneticdrift,eachoftheseC57BL/6substrainsisrelated,butcarriesuniqueknownandunknowndifferencesingenomicsequence. SeveralpublicationsdemonstrateheritablephenotypicdifferencesbetweenJandNsubstrainsthathavearisenduetogeneticdrift.Dependingonthespecificresearchquestion,somesubstrainsmaybepreferredoverothers(Bryant,2011).Someclassicandrecentexamplesarelistedhere: C57BL/6JmiceexpressamutantNntgene,whichisinvolvedinglucose-mediatedinsulinsecretion,comparedtoC57BL/6Nsubstrains(Freemanet,2006). C57BL/6JmicehavestrongpreferencesforalcoholwhileC57BL/6NCrlmicedonot(Mulliganet,2008).QuantitativeTraitLocimappingstudiescomparingthesesubstrainsmayleadtoabetterunderstandingofthegenesinvolvedinaddiction. C57BL/6NsubstrainsharbortheretinaldegenerationalleleCrbrd8whiletheC57BL/6Jsubstraincarriesawildtypeallele(Mattapalliletal.,2012). C57BL/6JOlaHsdmicearehomozygousforaspontaneousdeletioninthegenesencodingalphasynucleinandmultimerin-1(SpechtandSchoepfer,2001,2004).While,alphasynucleinaggregatesinthenervoussysteminParkinson’sDisease,thedeletioninC57BL/6JOlaHsdsubstraindoesnotappeartocontributetopriondiseasemediatedsynaptotoxicity(Asunietal.,2010)butmayhaveeffectsonmotorneurondegenerationingeneral(PelkonenandYavich,2011;Peña-Oliveretal.,2012).C57BL/6JOlaHsdmicealsohavereducedbonedensitycomparedtoC57BL/6JandC57BL/6JRccHsdsubstrains(Lironet,2017). C57BL/6NHsdmicecarryaDock2mutationaffectingBcellsignalingandimmunetolerancethatisnotfoundinothermajorC57BL/6substrains(Mahajanetal.,2016). Inthislastrecentexample,anapproximate10yearstepbackinresearchprogressforonelaboratoryoccurredasaresultofconclusionsdrawnfromusing2distinctC57BL/6substrainsoverthecourseoftheirstudies.(www.jax.org/news-and-insights/jax-blog/2016/may/why-it-took-2-years-for-a-harvard-research-lab-to-get-back-to-research).Theoriginalstudieswerepublishedusinganundefined“C57BL/6”substrainasthegeneticbackgroundforcreatingaSiaegeneknockout(Cariappaetal.,2009).SiaewasthoughttocontributetoBcelldevelopmentandsignalingwheninitiallypublishedin2009.TheSiaemutationwaslaterbackcrossedtothespecificC57BL/6JsubstrainfromTheJacksonLaboratory.Surprisingly,theexperimentsontheC57BL/6Jbackgroundfailedtoreproducethelaboratory’spreviouspublication(Mahajanetal.,2016).AfterseveralyearsofadditionalanalysisofseveralcommerciallyavailableC57BL/6substrains,itwasdiscoveredthatacopynumbermutationinadifferentgene,Dock2,hadspontaneouslyariseninastrainofC57BL/6NHsdmice.Dock2wastheactualcausalmutationfortheseBcellfunctions.Thisexampleshouldserveasacautionarytaletocloselymonitorandunderstandtheoriginsofanymiceusedinresearch.Becauseofgeneticdrift,inbredmousesubstrainsshouldnotbeusedinterchangeably. Itshouldbenotedthatinadditiontothespecificresearchquestion,thephenotypiceffectsofspontaneousmutationsthathavearisenduetogeneticdriftmaydependonseveralcontributingexperimentalfactors.Forinstance,theNntmutationinC57BL/6JstrainshasbeenshowntohavereducedinsulinsecretioninvitrocomparedtoC57BL/6JmicerescuedwithtransgenicwildtypeNnt(Freemanetal.,2006).Inanotherstudy,nosignificantdifferencesininsulinsecretionweremeasuredinvitroorinvivoinC57BL/6JandC57BL/6NTacsubstrains(Wongetal.,2010). Furthermore,theNnt mutationalstatusandrelationshipwithdiet-inducedobesityandinsulinresponsivityisnotstraightforward,asitmaydependonthefatcontentofthediet(Nicholsonetal.,2010).Similarly,twoJsubstrains(J,JWehi)andfourNsusbstrains(NTaNHsd,NCrl,NJ)fedalowfatdietwerefoundtohavesimilarinsulinsecretionprofilesinresponsetoglucosechallenge.However,whenfedahighfatdiet,theC57BL/6NJsubstraindemonstratedareducedinsulinresponsetoglucosechallengethatcouldnotbeexplainedbydifferencesinNntstatus,weightgain,fatmass,foodintake,orbetacellarea(Hulletal.,2017). SeveralotherpublisheddifferencesexistbetweenC57BL/6substrains.Differencesinbehaviorsuchasfear,anxiety,pain,andresponsetoamphetamineshavebeennotedintheliterature(summarizedinBryantetal.,2008).Morebroadly,differencesexistacrossmanyotherbaselinemeasures.Inparticular,C57BL/6JandC57BL/6NTacsubstrainswerecomparedinacomprehensive,standardizedphenotypingpipelineof413parameters(EMPReSS)completedbyfourindividualmousecentersoftheEuropeanMouseDiseaseClinic(EUMODIC)consortium(Simonetal.,2013).Acrossthefourphenotypingcenters,theJandNTacmicedifferedinseveralareasincludingstartleresponse,locomotoractivity,gripstrength,cardiovascularcharacteristics,metabolicparameters,andclinicalchemistries. NHsd,NCrl,NJ)fedalowfatdietwerefoundtohavesimilarinsulinsecretionprofilesinresponsetoglucosechallenge.However,whenfedahighfatdiet,theC57BL/6NJsubstraindemonstratedareducedinsulinresponsetoglucosechallengethatcouldnotbeexplainedbydifferencesinNntstatus,weightgain,fatmass,foodintake,orbetacellarea(Hulletal.,2017). SeveralotherpublisheddifferencesexistbetweenC57BL/6substrains.Differencesinbehaviorsuchasfear,anxiety,pain,andresponsetoamphetamineshavebeennotedintheliterature(summarizedinBryantetal.,2008).Morebroadly,differencesexistacrossmanyotherbaselinemeasures.Inparticular,C57BL/6JandC57BL/6NTacsubstrainswerecomparedinacomprehensive,standardizedphenotypingpipelineof413parameters(EMPReSS)completedbyfourindividualmousecentersoftheEuropeanMouseDiseaseClinic(EUMODIC)consortium(Simonetal.,2013).Acrossthefourphenotypingcenters,theJandNTacmicedifferedinseveralareasincludingstartleresponse,locomotoractivity,gripstrength,cardiovascularcharacteristics,metabolicparameters,andclinicalchemistries. Takentogether,geneticbackgroundisonecomponentofexperimentaldesignwhichmayaffectreproducibilityandtheabilitytomakegeneralizationsaboutbiologicalprocesses.Troublingly,ofthenearly37,000entriesinPubMedfor“C57BL/6,”themajorityofthesepublicationsdonotindicateasubstrain. 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