The proximal origin of SARS-CoV-2 | Nature Medicine

Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance of pneumonia in humans ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature naturemedicine correspondence article TheproximaloriginofSARS-CoV-2 DownloadPDF DownloadPDF Subjects ComputationalbiologyandbioinformaticsMolecularevolution TotheEditor—Sincethefirstreportsofnovelpneumonia(COVID-19)inWuhan,Hubeiprovince,China1,2,therehasbeenconsiderablediscussionontheoriginofthecausativevirus,SARS-CoV-23(alsoreferredtoasHCoV-19)4.InfectionswithSARS-CoV-2arenowwidespread,andasof11March2020,121,564caseshavebeenconfirmedinmorethan110countries,with4,373deaths5.SARS-CoV-2istheseventhcoronavirusknowntoinfecthumans;SARS-CoV,MERS-CoVandSARS-CoV-2cancauseseveredisease,whereasHKU1,NL63,OC43and229Eareassociatedwithmildsymptoms6.HerewereviewwhatcanbededucedabouttheoriginofSARS-CoV-2fromcomparativeanalysisofgenomicdata.WeofferaperspectiveonthenotablefeaturesoftheSARS-CoV-2genomeanddiscussscenariosbywhichtheycouldhavearisen.OuranalysesclearlyshowthatSARS-CoV-2isnotalaboratoryconstructorapurposefullymanipulatedvirus.NotablefeaturesoftheSARS-CoV-2genomeOurcomparisonofalpha-andbetacoronavirusesidentifiestwonotablegenomicfeaturesofSARS-CoV-2:(i)onthebasisofstructuralstudies7,8,9andbiochemicalexperiments1,9,10,SARS-CoV-2appearstobeoptimizedforbindingtothehumanreceptorACE2;and(ii)thespikeproteinofSARS-CoV-2hasafunctionalpolybasic(furin)cleavagesiteattheS1–S2boundarythroughtheinsertionof12nucleotides8,whichadditionallyledtothepredictedacquisitionofthreeO-linkedglycansaroundthesite.1.Mutationsinthereceptor-bindingdomainofSARS-CoV-2Thereceptor-bindingdomain(RBD)inthespikeproteinisthemostvariablepartofthecoronavirusgenome1,2.SixRBDaminoacidshavebeenshowntobecriticalforbindingtoACE2receptorsandfordeterminingthehostrangeofSARS-CoV-likeviruses7.WithcoordinatesbasedonSARS-CoV,theyareY442,L472,N479,D480,T487andY4911,whichcorrespondtoL455,F486,Q493,S494,N501andY505inSARS-CoV-27.FiveofthesesixresiduesdifferbetweenSARS-CoV-2andSARS-CoV(Fig.1a).Onthebasisofstructuralstudies7,8,9andbiochemicalexperiments1,9,10,SARS-CoV-2seemstohaveanRBDthatbindswithhighaffinitytoACE2fromhumans,ferrets,catsandotherspecieswithhighreceptorhomology7.Fig.1:FeaturesofthespikeproteininhumanSARS-CoV-2andrelatedcoronaviruses.a,MutationsincontactresiduesoftheSARS-CoV-2spikeprotein.ThespikeproteinofSARS-CoV-2(redbarattop)wasalignedagainstthemostcloselyrelatedSARS-CoV-likecoronavirusesandSARS-CoVitself.KeyresiduesinthespikeproteinthatmakecontacttotheACE2receptoraremarkedwithblueboxesinbothSARS-CoV-2andrelatedviruses,includingSARS-CoV(Urbanistrain).b,AcquisitionofpolybasiccleavagesiteandO-linkedglycans.BoththepolybasiccleavagesiteandthethreeadjacentpredictedO-linkedglycansareuniquetoSARS-CoV-2andwerenotpreviouslyseeninlineageBbetacoronaviruses.SequencesshownarefromNCBIGenBank,accessioncodesMN908947,MN996532,AY278741,KY417146andMK211376.ThepangolincoronavirussequencesareaconsensusgeneratedfromSRR10168377andSRR10168378(NCBIBioProjectPRJNA573298)29,30.FullsizeimageWhiletheanalysesabovesuggestthatSARS-CoV-2maybindhumanACE2withhighaffinity,computationalanalysespredictthattheinteractionisnotideal7andthattheRBDsequenceisdifferentfromthoseshowninSARS-CoVtobeoptimalforreceptorbinding7,11.Thus,thehigh-affinitybindingoftheSARS-CoV-2spikeproteintohumanACE2ismostlikelytheresultofnaturalselectiononahumanorhuman-likeACE2thatpermitsanotheroptimalbindingsolutiontoarise.ThisisstrongevidencethatSARS-CoV-2isnottheproductofpurposefulmanipulation.2.PolybasicfurincleavagesiteandO-linkedglycansThesecondnotablefeatureofSARS-CoV-2isapolybasiccleavagesite(RRAR)atthejunctionofS1andS2,thetwosubunitsofthespike8(Fig.1b).Thisallowseffectivecleavagebyfurinandotherproteasesandhasaroleindeterminingviralinfectivityandhostrange12.Inaddition,aleadingprolineisalsoinsertedatthissiteinSARS-CoV-2;thus,theinsertedsequenceisPRRA(Fig.1b).TheturncreatedbytheprolineispredictedtoresultintheadditionofO-linkedglycanstoS673,T678andS686,whichflankthecleavagesiteandareuniquetoSARS-CoV-2(Fig.1b).Polybasiccleavagesiteshavenotbeenobservedinrelated‘lineageB’betacoronaviruses,althoughotherhumanbetacoronaviruses,includingHKU1(lineageA),havethosesitesandpredictedO-linkedglycans13.Giventhelevelofgeneticvariationinthespike,itislikelythatSARS-CoV-2-likeviruseswithpartialorfullpolybasiccleavagesiteswillbediscoveredinotherspecies.ThefunctionalconsequenceofthepolybasiccleavagesiteinSARS-CoV-2isunknown,anditwillbeimportanttodetermineitsimpactontransmissibilityandpathogenesisinanimalmodels.ExperimentswithSARS-CoVhaveshownthatinsertionofafurincleavagesiteattheS1–S2junctionenhancescell–cellfusionwithoutaffectingviralentry14.Inaddition,efficientcleavageoftheMERS-CoVspikeenablesMERS-likecoronavirusesfrombatstoinfecthumancells15.Inavianinfluenzaviruses,rapidreplicationandtransmissioninhighlydensechickenpopulationsselectsfortheacquisitionofpolybasiccleavagesitesinthehemagglutinin(HA)protein16,whichservesafunctionsimilartothatofthecoronavirusspikeprotein.AcquisitionofpolybasiccleavagesitesinHA,byinsertionorrecombination,convertslow-pathogenicityavianinfluenzavirusesintohighlypathogenicforms16.TheacquisitionofpolybasiccleavagesitesbyHAhasalsobeenobservedafterrepeatedpassageincellcultureorthroughanimals17.ThefunctionofthepredictedO-linkedglycansisunclear,buttheycouldcreatea‘mucin-likedomain’thatshieldsepitopesorkeyresiduesontheSARS-CoV-2spikeprotein18.Severalvirusesutilizemucin-likedomainsasglycanshieldsinvolvedimmunoevasion18.AlthoughpredictionofO-linkedglycosylationisrobust,experimentalstudiesareneededtodetermineifthesesitesareusedinSARS-CoV-2.TheoriesofSARS-CoV-2originsItisimprobablethatSARS-CoV-2emergedthroughlaboratorymanipulationofarelatedSARS-CoV-likecoronavirus.Asnotedabove,theRBDofSARS-CoV-2isoptimizedforbindingtohumanACE2withanefficientsolutiondifferentfromthosepreviouslypredicted7,11.Furthermore,ifgeneticmanipulationhadbeenperformed,oneoftheseveralreverse-geneticsystemsavailableforbetacoronaviruseswouldprobablyhavebeenused19.However,thegeneticdatairrefutablyshowthatSARS-CoV-2isnotderivedfromanypreviouslyusedvirusbackbone20.Instead,weproposetwoscenariosthatcanplausiblyexplaintheoriginofSARS-CoV-2:(i)naturalselectioninananimalhostbeforezoonotictransfer;and(ii)naturalselectioninhumansfollowingzoonotictransfer.WealsodiscusswhetherselectionduringpassagecouldhavegivenrisetoSARS-CoV-2.1.NaturalselectioninananimalhostbeforezoonotictransferAsmanyearlycasesofCOVID-19werelinkedtotheHuananmarketinWuhan1,2,itispossiblethatananimalsourcewaspresentatthislocation.GiventhesimilarityofSARS-CoV-2tobatSARS-CoV-likecoronaviruses2,itislikelythatbatsserveasreservoirhostsforitsprogenitor.AlthoughRaTG13,sampledfromaRhinolophusaffinisbat1,is~96%identicaloveralltoSARS-CoV-2,itsspikedivergesintheRBD,whichsuggeststhatitmaynotbindefficientlytohumanACE27(Fig.1a).Malayanpangolins(Manisjavanica)illegallyimportedintoGuangdongprovincecontaincoronavirusessimilartoSARS-CoV-221.AlthoughtheRaTG13batvirusremainstheclosesttoSARS-CoV-2acrossthegenome1,somepangolincoronavirusesexhibitstrongsimilaritytoSARS-CoV-2intheRBD,includingallsixkeyRBDresidues21(Fig.1).ThisclearlyshowsthattheSARS-CoV-2spikeproteinoptimizedforbindingtohuman-likeACE2istheresultofnaturalselection.Neitherthebatbetacoronavirusesnorthepangolinbetacoronavirusessampledthusfarhavepolybasiccleavagesites.AlthoughnoanimalcoronavirushasbeenidentifiedthatissufficientlysimilartohaveservedasthedirectprogenitorofSARS-CoV-2,thediversityofcoronavirusesinbatsandotherspeciesismassivelyundersampled.Mutations,insertionsanddeletionscanoccurneartheS1–S2junctionofcoronaviruses22,whichshowsthatthepolybasiccleavagesitecanarisebyanaturalevolutionaryprocess.ForaprecursorvirustoacquireboththepolybasiccleavagesiteandmutationsinthespikeproteinsuitableforbindingtohumanACE2,ananimalhostwouldprobablyhavetohaveahighpopulationdensity(toallownaturalselectiontoproceedefficiently)andanACE2-encodinggenethatissimilartothehumanortholog.2.NaturalselectioninhumansfollowingzoonotictransferItispossiblethataprogenitorofSARS-CoV-2jumpedintohumans,acquiringthegenomicfeaturesdescribedabovethroughadaptationduringundetectedhuman-to-humantransmission.Onceacquired,theseadaptationswouldenablethepandemictotakeoffandproduceasufficientlylargeclusterofcasestotriggerthesurveillancesystemthatdetectedit1,2.AllSARS-CoV-2genomessequencedsofarhavethegenomicfeaturesdescribedaboveandarethusderivedfromacommonancestorthathadthemtoo.ThepresenceinpangolinsofanRBDverysimilartothatofSARS-CoV-2meansthatwecaninferthiswasalsoprobablyinthevirusthatjumpedtohumans.Thisleavestheinsertionofpolybasiccleavagesitetooccurduringhuman-to-humantransmission.EstimatesofthetimingofthemostrecentcommonancestorofSARS-CoV-2madewithcurrentsequencedatapointtoemergenceofthevirusinlateNovember2019toearlyDecember201923,compatiblewiththeearliestretrospectivelyconfirmedcases24.Hence,thisscenariopresumesaperiodofunrecognizedtransmissioninhumansbetweentheinitialzoonoticeventandtheacquisitionofthepolybasiccleavagesite.Sufficientopportunitycouldhaveariseniftherehadbeenmanypriorzoonoticeventsthatproducedshortchainsofhuman-to-humantransmissionoveranextendedperiod.ThisisessentiallythesituationforMERS-CoV,forwhichallhumancasesaretheresultofrepeatedjumpsofthevirusfromdromedarycamels,producingsingleinfectionsorshorttransmissionchainsthateventuallyresolve,withnoadaptationtosustainedtransmission25.Studiesofbankedhumansamplescouldprovideinformationonwhethersuchcrypticspreadhasoccurred.Retrospectiveserologicalstudiescouldalsobeinformative,andafewsuchstudieshavebeenconductedshowinglow-levelexposurestoSARS-CoV-likecoronavirusesincertainareasofChina26.Critically,however,thesestudiescouldnothavedistinguishedwhetherexposureswereduetopriorinfectionswithSARS-CoV,SARS-CoV-2orotherSARS-CoV-likecoronaviruses.FurtherserologicalstudiesshouldbeconductedtodeterminetheextentofpriorhumanexposuretoSARS-CoV-2.3.SelectionduringpassageBasicresearchinvolvingpassageofbatSARS-CoV-likecoronavirusesincellcultureand/oranimalmodelshasbeenongoingformanyyearsinbiosafetylevel2laboratoriesacrosstheworld27,andtherearedocumentedinstancesoflaboratoryescapesofSARS-CoV28.WemustthereforeexaminethepossibilityofaninadvertentlaboratoryreleaseofSARS-CoV-2.Intheory,itispossiblethatSARS-CoV-2acquiredRBDmutations(Fig.1a)duringadaptationtopassageincellculture,ashasbeenobservedinstudiesofSARS-CoV11.ThefindingofSARS-CoV-likecoronavirusesfrompangolinswithnearlyidenticalRBDs,however,providesamuchstrongerandmoreparsimoniousexplanationofhowSARS-CoV-2acquiredtheseviarecombinationormutation19.TheacquisitionofboththepolybasiccleavagesiteandpredictedO-linkedglycansalsoarguesagainstculture-basedscenarios.Newpolybasiccleavagesiteshavebeenobservedonlyafterprolongedpassageoflow-pathogenicityavianinfluenzavirusinvitroorinvivo17.Furthermore,ahypotheticalgenerationofSARS-CoV-2bycellcultureoranimalpassagewouldhaverequiredpriorisolationofaprogenitorviruswithveryhighgeneticsimilarity,whichhasnotbeendescribed.SubsequentgenerationofapolybasiccleavagesitewouldhavethenrequiredrepeatedpassageincellcultureoranimalswithACE2receptorssimilartothoseofhumans,butsuchworkhasalsonotpreviouslybeendescribed.Finally,thegenerationofthepredictedO-linkedglycansisalsounlikelytohaveoccurredduetocell-culturepassage,assuchfeaturessuggesttheinvolvementofanimmunesystem18.ConclusionsInthemidstoftheglobalCOVID-19public-healthemergency,itisreasonabletowonderwhytheoriginsofthepandemicmatter.Detailedunderstandingofhowananimalvirusjumpedspeciesboundariestoinfecthumanssoproductivelywillhelpinthepreventionoffuturezoonoticevents.Forexample,ifSARS-CoV-2pre-adaptedinanotheranimalspecies,thenthereistheriskoffuturere-emergenceevents.Incontrast,iftheadaptiveprocessoccurredinhumans,thenevenifrepeatedzoonotictransfersoccur,theyareunlikelytotakeoffwithoutthesameseriesofmutations.Inaddition,identifyingtheclosestviralrelativesofSARS-CoV-2circulatinginanimalswillgreatlyassiststudiesofviralfunction.Indeed,theavailabilityoftheRaTG13batsequencehelpedrevealkeyRBDmutationsandthepolybasiccleavagesite.ThegenomicfeaturesdescribedheremayexplaininparttheinfectiousnessandtransmissibilityofSARS-CoV-2inhumans.AlthoughtheevidenceshowsthatSARS-CoV-2isnotapurposefullymanipulatedvirus,itiscurrentlyimpossibletoproveordisprovetheothertheoriesofitsorigindescribedhere.However,sinceweobservedallnotableSARS-CoV-2features,includingtheoptimizedRBDandpolybasiccleavagesite,inrelatedcoronavirusesinnature,wedonotbelievethatanytypeoflaboratory-basedscenarioisplausible.Morescientificdatacouldswingthebalanceofevidencetofavoronehypothesisoveranother.Obtainingrelatedviralsequencesfromanimalsourceswouldbethemostdefinitivewayofrevealingviralorigins.Forexample,afutureobservationofanintermediateorfullyformedpolybasiccleavagesiteinaSARS-CoV-2-likevirusfromanimalswouldlendevenfurthersupporttothenatural-selectionhypotheses.ItwouldalsobehelpfultoobtainmoregeneticandfunctionaldataaboutSARS-CoV-2,includinganimalstudies.TheidentificationofapotentialintermediatehostofSARS-CoV-2,aswellassequencingofthevirusfromveryearlycases,wouldsimilarlybehighlyinformative.IrrespectiveoftheexactmechanismsbywhichSARS-CoV-2originatedvianaturalselection,theongoingsurveillanceofpneumoniainhumansandotheranimalsisclearlyofutmostimportance. ReferencesZhou,P.etal.Naturehttps://doi.org/10.1038/s41586-020-2012-7(2020).Article  PubMed  PubMedCentral  GoogleScholar  Wu,F.etal.Naturehttps://doi.org/10.1038/s41586-020-2008-3(2020).Article  PubMed  PubMedCentral  GoogleScholar  Gorbalenya,A.E.etal.bioRxivhttps://doi.org/10.1101/2020.02.07.937862(2020).Article  GoogleScholar  Jiang,S.etal.Lancethttps://doi.org/10.1016/S0140-6736(20)30419-0(2020).Article  PubMed  PubMedCentral  GoogleScholar  Dong,E.,Du,H.&Gardner,L.LancetInfect.Dis.https://doi.org/10.1016/S1473-3099(20)30120-1(2020).Article  PubMed  GoogleScholar  Corman,V.M.,Muth,D.,Niemeyer,D.&Drosten,C.Adv.VirusRes.100,163–188(2018).Article  GoogleScholar  Wan,Y.,Shang,J.,Graham,R.,Baric,R.S.&Li,F.J.Virol.https://doi.org/10.1128/JVI.00127-20(2020).Article  PubMed  GoogleScholar  Walls,A.C.etal.bioRxivhttps://doi.org/10.1101/2020.02.19.956581(2020).Article  GoogleScholar  Wrapp,D.etal.Sciencehttps://doi.org/10.1126/science.abb2507(2020).Article  PubMed  GoogleScholar  Letko,M.,Marzi,A.&Munster,V.Nat.Microbiol.https://doi.org/10.1038/s41564-020-0688-y(2020).Article  PubMed  PubMedCentral  GoogleScholar  Sheahan,T.etal.J.Virol.82,2274–2285(2008).CAS  Article  GoogleScholar  Nao,N.etal.MBio8,e02298-16(2017).Article  GoogleScholar  Chan,C.-M.etal.Exp.Biol.Med.233,1527–1536(2008).CAS  Article  GoogleScholar  Follis,K.E.,York,J.&Nunberg,J.H.Virology350,358–369(2006).CAS  Article  GoogleScholar  Menachery,V.D.etal.J.Virol.https://doi.org/10.1128/JVI.01774-19(2019).Article  PubMed  GoogleScholar  Alexander,D.J.&Brown,I.H.Rev.Sci.Tech.28,19–38(2009).CAS  Article  GoogleScholar  Ito,T.etal.J.Virol.75,4439–4443(2001).CAS  Article  GoogleScholar  Bagdonaite,I.&Wandall,H.H.Glycobiology28,443–467(2018).CAS  Article  GoogleScholar  Cui,J.,Li,F.&Shi,Z.-L.Nat.Rev.Microbiol.17,181–192(2019).CAS  Article  GoogleScholar  Almazán,F.etal.VirusRes.189,262–270(2014).Article  GoogleScholar  Zhang,T.,Wu,Q.&Zhang,Z.bioRxivhttps://doi.org/10.1101/2020.02.19.950253(2020).Article  GoogleScholar  Yamada,Y.&Liu,D.X.J.Virol.83,8744–8758(2009).CAS  Article  GoogleScholar  Rambaut,A.Virological.orghttp://virological.org/t/356(2020).Huang,C.etal.Lancethttps://doi.org/10.1016/S0140-6736(20)30183-5(2020).Article  PubMed  PubMedCentral  GoogleScholar  Dudas,G.,Carvalho,L.M.,Rambaut,A.&Bedford,T.eLife7,e31257(2018).Article  GoogleScholar  Wang,N.etal.Virol.Sin.33,104–107(2018).Article  GoogleScholar  Ge,X.-Y.etal.Nature503,535–538(2013).CAS  Article  GoogleScholar  Lim,P.L.etal.N.Engl.J.Med.350,1740–1745(2004).CAS  Article  GoogleScholar  Wong,M.C.,JavornikCregeen,S.J.,Ajami,N.J.&Petrosino,J.F.bioRxivhttps://doi.org/10.1101/2020.02.07.939207(2020).Article  GoogleScholar  Liu,P.,Chen,W.&Chen,J.-P.Viruses11,979(2019).CAS  Article  GoogleScholar  DownloadreferencesAcknowledgementsWethankallthosewhohavecontributedsequencestotheGISAIDdatabase(https://www.gisaid.org/)andanalysestoVirological.org(http://virological.org/).WethankM.Farzanfordiscussions,andtheWellcomeTrustforsupport.K.G.A.isaPewBiomedicalScholarandissupportedbyNIHgrantU19AI135995.A.R.issupportedbytheWellcomeTrust(CollaboratorsAward206298/Z/17/Z―ARTICnetwork)andtheEuropeanResearchCouncil(grantagreementno.725422―ReservoirDOCS).E.C.H.issupportedbyanARCAustralianLaureateFellowship(FL170100022).R.F.G.issupportedbyNIHgrantsU19AI135995,U54HG007480andU19AI142790.AuthorinformationAffiliationsDepartmentofImmunologyandMicrobiology,TheScrippsResearchInstitute,LaJolla,CA,USAKristianG.AndersenScrippsResearchTranslationalInstitute,LaJolla,CA,USAKristianG.AndersenInstituteofEvolutionaryBiology,UniversityofEdinburgh,Edinburgh,UKAndrewRambautCenterforInfectionandImmunity,MailmanSchoolofPublicHealthofColumbiaUniversity,NewYork,NY,USAW.IanLipkinMarieBashirInstituteforInfectiousDiseasesandBiosecurity,SchoolofLifeandEnvironmentalSciencesandSchoolofMedicalSciences,TheUniversityofSydney,Sydney,AustraliaEdwardC.HolmesTulaneUniversity,SchoolofMedicine,DepartmentofMicrobiologyandImmunology,NewOrleans,LA,USARobertF.GarryZalgenLabs,Germantown,MD,USARobertF.GarryAuthorsKristianG.AndersenViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAndrewRambautViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarW.IanLipkinViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarEdwardC.HolmesViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRobertF.GarryViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto KristianG.Andersen.Ethicsdeclarations Competinginterests R.F.G.isco-founderofZalgenLabs,abiotechnologycompanythatdevelopscountermeasurestoemergingviruses. RightsandpermissionsReprintsandPermissionsAboutthisarticleCitethisarticleAndersen,K.G.,Rambaut,A.,Lipkin,W.I.etal.TheproximaloriginofSARS-CoV-2. NatMed26,450–452(2020).https://doi.org/10.1038/s41591-020-0820-9DownloadcitationPublished:17March2020IssueDate:April2020DOI:https://doi.org/10.1038/s41591-020-0820-9SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative Furtherreading SARS-CoV-2:tracingtheorigin,trackingtheevolution KonstantinosVoskarides BMCMedicalGenomics(2022) PredictedcoronavirusNsp5proteasecleavagesitesinthehumanproteome BenjaminM.Scott VincentLacasse NikolajS.Blom BMCGenomicData(2022) ScopeofSARS-CoV-2variants,mutations,andvaccinetechnologies JosephineWambani PatrickOkoth TheEgyptianJournalofInternalMedicine(2022) ReconcilingdifferencespertainingtotheoriginofSARS-CoV-2 YasinAliMuhammad BulletinoftheNationalResearchCentre(2022) GenomicepidemiologyoftheLosAngelesCOVID-19outbreakandtheearlyhistoryoftheB.1.43strainintheUSA LonghuaGuo JamesBoocock LeonidKruglyak BMCGenomics(2022) DownloadPDF Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Podcasts Currentissue Collections FollowusonFacebook FollowusonTwitter Signupforalerts RSSfeed Aboutthejournal Aims&Scope JournalInformation JournalMetrics AbouttheEditors Ourpublishingmodels EditorialValuesStatement EditorialPolicies ContentTypes ClinicalResearch NatureMedicineClassicCollection WebFeeds Posters Contact Publishwithus SubmissionGuidelines ForReviewers Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies Closebanner Close SignupfortheNatureBriefingnewsletter—whatmattersinscience,freetoyourinboxdaily. Emailaddress Signup IagreemyinformationwillbeprocessedinaccordancewiththeNatureandSpringerNatureLimitedPrivacyPolicy. Closebanner Close Getthemostimportantsciencestoriesoftheday,freeinyourinbox. SignupforNatureBriefing