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Translational Research in Genet…

上传者: Time_Of_Flight_2013 2013-03-05 评分 0 0 0 0 0 0 暂无简介 简介 举报

简介:本文档为《Translational Research in Genetics and Genomicspdf》,可适用于人文社科领域,主题内容包含TranslationalResearchinGeneticsandGenomicsThispageintentionallyleftblankTr符等。

TranslationalResearchinGeneticsandGenomicsThispageintentionallyleftblankTranslationalResearchinGeneticsandGenomicsMoyraSmith,MD,PhD,MFAOxfordUniversityPress,Inc,publishesworksthatfurtherOxfordUniversity’sobjectiveofexcellenceinresearch,scholarship,andeducationOxfordNewYorkAucklandCapeTownDaresSalaamHongKongKarachiKualaLumpurMadridMelbourneMexicoCityNairobiNewDelhiShanghaiTaipeiTorontoWithofficesinArgentinaAustriaBrazilChileCzechRepublicFranceGreeceGuatemalaHungaryItalyJapanPolandPortugalSingaporeSouthKoreaSwitzerlandThailandTurkeyUkraineVietnamCopyrightªbyOxfordUniversityPress,IncPublishedbyOxfordUniversityPress,IncMadisonAvenue,NewYork,NewYorkwwwoupcomOxfordisaregisteredtrademarkofOxfordUniversityPressAllrightsreservedNopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmitted,inanyformorbyanymeans,electronic,mechanical,photocopying,recording,orotherwise,withoutthepriorpermissionofOxfordUniversityPressLibraryofCongressCataloginginPublicationDataSmith,MoyraTranslationalresearchingeneticsandgenomics=MoyraSmithpcmIncludesbibliographicalreferencesandindexISBN:MedicalgeneticsGenomics,DNLM:Genetics,MedicalGeneticDiseases,InbornGenomicsQZSITitleRBSdcPrintedintheUnitedStatesofAmericaonacidfreepaperTowrestfromnaturethesecretswhichhaveperplexedphilosophersinallages,totracktotheirsourcesthecausesofdisease,tocorrelatethevaststoresofknowledge,thattheymaybequicklyavailableforthepreventionandcureofdiseasetheseareourambitionsTocarefullyobservethephenomenaoflifeinallitsphasesnormalandperverted,tomakeperfectthemostdifficultofallthearts,theartofobservation,tocalltoaidthescienceofexperimentation,tocultivatethereasoningfacultysoastobeabletoknowthetruefromthefalsetheseareourmethodsTopreventdisease,torelievesufferingandtohealthesickthisisourworkWilliamOsler,ThispageintentionallyleftblankPREFACETheunderlyingpremiseofthisbookisthatdiscoveryofthefundamentalmechanismsofaspecificdiseaseleadstoimproveddiagnosticmethodsandtreatment,andinsomecasespointsthewaytodiseasepreventionThegoalofthisbookistoreviewprogressinthetranslationofresearchinmoleculargeneticstoimproveddiagnosisandtherapyofsinglegenedisordersandofdisorderswheregeneticfactorsplayanimportantroleThestudyofhumangenomics,thearchitecture,composition,andfunctionofchromosomesandtheirsegregationandtransmissionfromonegenerationtothenext,hassteadilyprogressed,particularlyoverthelastyears,whentechniquesevolvedtomaphumangenesandgeneticmarkersMappingstudiesandpositionalcloningenabledidentificationandcharacterizationofdiseasegenesAvailabilityofDNAsequenceinformation,througheffortsintheHumanGenomeProject,hasgreatlyexpeditedthisprocessMorerecently,sequenceinformation,characterizationofgeneticvariationandmaplocationsofmanythousandsofgeneticmarkers,andhighthroughputanalysistechnologieshaveprovidedresourcestoapproachtheproblemsofcomplexcommondiseaseswheregeneticriskcontributestotheetiopathogenesisThereareanumberofdifferenthypothesesregardingthegeneticfactorsinvolvedinthesediseasesIexploreseveraloftheseandpresentresultsofpublishedstudiesinsupportofeachhypothesisResearchonthehumangenome,facilitatedbytheavailabilityofrapidsequencingandmicroarraytechnologies,hasproducedanumberofsurprisingresultsOneexampleistherevelationofthehighdegreeofstructuralvariationinthegenomethatispresentinhealthyindividualsHowever,wehavealsocometolearnthatspecificstructuralvariantspredisposetogenomerearrangementsandtodosageimbalancesthatmayleaddirectlytopathologyorpredisposetopathology,insomecasesthroughmodificationofgene–environmentinteractionsFurthermore,informationgainedfromanalysisofDNAsequencesandRNAtranscriptsrequiresthatwenowredefineourlongstandingdefinitionofageneDissectionsofthemolecularbasisofsinglegenedisordershaveledtothedevelopmentofnewtherapiesthatspecificallytargetthegenedefectsorthedownstreameffectsofthegenemutationOnestrikingexampleisthefindingofthehighfrequencyofsplicingdefectsinsinglegenedisordersandtheidentificationoftherapeuticagentsthatsuppresstheseAnotherimportantdevelopmentisthefindingthatspecificchemicalagentsmaysuppresstheeffectsofnonsensemutationsthatgeneratestopcodonsInanumberofdisorders,molecularchaperonescanmitigatethedownstreameffectsofmutationsthatleadtoaberrantproteinfoldingandalteredproteinstabilityKnowledgeofthemoleculardefectsincancerisactivelytranslatedtodevelopspecifictherapiesthattargetmalignantcellsanddefectsinspecificsignalingandmetabolicpathwaysAvailabilityofDNAsequenceinformationandhighthroughputtechnologieshavegreatlyimpactedpharmacogenomicsanddrugdesignAlongwiththisprogress,pharmacogeneticstudiescontinuetorevealthatindividualvariationindrugresponseneedstobetakenintoaccountFortunately,technicaladvancesfacilitateanalysisofthemolecularbasisofadversedrugresponsesinmanycasesAslateonsetneurodegenerativediseaseandcancercontributemorefrequentlytooveralldiseaseburden,itbecomesevenmoreimportanttoconsiderenvironmentalfactorsthatimpactthegenomestructureandfunctionTherolesofreactiveoxygenspeciesingeneratingDNAdamage,somaticmutation,alteredproteinstructure,andmitochondriaareimportantconsiderationsInaddition,theeffectsofsynthetictoxicsubstancesonthegenomerequirevigorousinvestigationThefinalchapterofthisbookisdevotedtothephenome,theanalysisofphenotypiccomplexity,andclinicalservicestopatientsInconsideringwhoshouldprovidegeneticservices,itisclearthattheteamshouldbemultidisviiiPrefaceciplinaryandthatgeneticswillnotremaintheprerogativeofregionaloracademicgeneticcentersAllbranchesofmedicinewillneedtousegeneticknowledgeintheirpracticeTosome,theprogressoftranslationofresearchingeneticsandgenomicstopatientcareseemsremarkabletoothersitseemsslowandinadequateAsLewisThomaswroteininTheLivesofaCell,‘‘Thereisnoquestionaboutourgoodintentionsinthismatter:weallhanker,collectively,tobecomeappliedscientistsassoonaswecan,overnightifpossibleIttakessomedoing,howeverEveryoneforgetshowlongandhardtheworkmustbebeforethereallyimportantapplicationsbecomeapplicable’’PrefaceixThispageintentionallyleftblankACKNOWLEDGMENTSIthankWilliamLamsbackandNancyWolitzer,editorsatOxfordUniversityPressfortheirguidancewiththisbookIwishtoexpressmygratitudetoSherylRoweandJeanBlackburnfortheirvaluableassistanceinthecopyeditingandfinalstagesofpreparationforpublicationIhavebenefitedgreatlyfromtheresourcesavailablethroughtheUniversityofCaliforniaLibrarysystem,andIamgratefulfortheseIwishtoacknowledgetheencouragementofmycolleaguesintheDepartmentofPediatricsattheUniversityofCalifornia,IrvinexiThispageintentionallyleftblankCONTENTSIsolationofDiseaseGenesThroughGenomics,AdvancesinGenomeAnalysis:DiscoveryofStructuralVariationandGenomicDosageDifferencesinHealthandDisease,SignificanceofDNASequenceChangesforDiagnosisandTherapy,Epigenetics,ComplexDiseases:MolecularGeneticContributionstoElucidationofEtiopathogenesisofLateOnsetNeurodegenerativeDiseases,AdvancesinTreatmentofSingleGeneDisordersThroughTranslationalScience:TreatmentWithSmallMolecules(Chaperones)andGeneBasedTherapies,FromGeneDiscoveryinGeneticSyndromestoIdentificationofTherapeuticAgents,ImpactoftheEnvironmentontheGenome,MolecularDefectsinCancer:ApplicationtoTherapy,xiiiPharmacogeneticsandPharmacogenomics,Phenomes,Phenotypes,andClinicalGeneticServices,References,Index,xivContentsTranslationalResearchinGeneticsandGenomicsThispageintentionallyleftblankISOLATIONOFDISEASEGENESTHROUGHGENOMICSConnectingphenotypewithgenotypeisthefundamentalaimofgeneticsDBotsteinandNRisch,AdvancesinchromosomemappingandDNAsequencinghavegreatlyincreasedourabilitytolocateandcharacterizegenesresponsibleforspecificdiseasesPhysicalmapsofgenesonchromosomesprovideinformationonthepositionofageneormarkeronachromosomerelativetolandmarksonthatchromosome(eg,porqarm,chromosomeband)Sincecompletionofthehumangenomeprojects,thephysicalmaplocationofagenemayalsobebasedondefiningthepositionofageneormarkerrelativetothenucleotidesequenceofthechromosometowhichitmapsLinkagemapsarederivedthroughanalysisofthecosegregationofaseriesofpolymorphicmarkersduringmeiosisandthetransmissionofaseriesofpolymorphicgeneticmarkersfromonegenerationtothenextThepossibilityoffindingageneticmarkerthatiscloselylinkedtoadiseasegeneisgreaterifthereisahighdensityofpolymorphicmarkersoneachchromosome,andifthemarkersarehighlyinformative,thatis,havingmanydifferentallelesWhenhighlyinformativemarkersareanalyzedinapopulationwithrandommating,thereisahighchancethateachparentwillbeheterozygousforeachalleleMethodstoidentifydifferentallelesataspecificlocusbasedonanalysisofDNAsequencehaveyieldedmarkersthataremorereadilyanalyzedandthataremoreinformativeVarioustypesofsequencevariationconstitutethebasisforalleleidentificationDNAsequencevariationmayleadtodifferencesinsensitivitytoDNAcleavagebyaparticularrestrictionendonucleaseThroughsequencingitmaybepossibletoidentifyspecificnucleotidechangesthatgiverisetoapolymorphismKnowledgeofthespecificnucleotidechangesthatgiverisetoapolymorphismmaybeutilizedinthedesignofoligonucleotideprobestobeusedinmicroarraysIntensityofhybridizationofalabeledsampleDNAfragmenttothemicroarraywilldependonthedegreeofmatchtothemicroarraysegmentPolymorphicmarkersincludevariationinthenumberofnucleotiderepeatsinaspecificDNAsegmentorsinglenucleotidedifferencesInthecaseofrarerecessivephenotypesthatoccurinpopulationisolatesorininbredpopulations,homozygositymappingisveryusefulThisformofmappingisbasedonthefactthataffectedmembersofafamilywithaspecificgeneticdiseasealsoinheritaspecificgeneregionAllelesofpolymorphicmarkersthatmapinthisregionareidenticalintheaffectedfamilymembersInrarecases,mappingofadiseasegenelocusmaybefacilitatedbythepresenceofchromosomeabnormalities,includingdeletions,duplications,andtranslocationsIdentificationoftheputativemappositionofadiseasedetermininggeneonthebasisoflinkageanalysisorchromosomebreakpointanalysisrepresentsthefirststepinpositionalcloningandisolationofthediseasegeneKeyelementsindiseasegeneisolationareaccurateassessmentofthephenotypeandaccuratemappingPhenotypicheterogeneity,wheremutationsindifferentgenesgiverisetothesamephenotype,complicatestheprocessFollowingmapping,databaseresourcesmaybeusedtodeterminewhichgenesmapinthatregionandtoconsiderthebiologicalandphysiologicalrelevanceofthesegenestothediseaseprocessThelatterconstitutecandidategenesforthediseaseInmanycases,however,particularlypriortocomprehensivegenomesequencing,thediseasecausinggenewasunknownpriortoitspositionalcloningandtheunderlyingbiologicalmechanismofthediseasewasunknownFollowingfinemappingofthelocus,isolationofthatgeneispossibleTranslationalResearchinGeneticsandGenomicsTRANSLATIONALASPECTSOFGENEMAPPINGANDISOLATIONCharacterizationoftheproductofthediseasegeneleadstounderstandingofthemolecularbasisofdiseasesandelucidationofpathogenesisThroughanalysisofgeneproductfunctionandtheroleofthatproductinbiochemicalandphysiologicalpathways,andthroughidentificationofothergeneproductsthatparticipateinthosesamepathways,itmaybepossibletoidentifygenesthatplayaroleintheetiologyofsimilardiseasephenotypesIdentificationofthediseasedetermininggenegeneratesmaterialthatfacilitatesdiagnosisIdentificationofthegeneproductandelucidationofthepathogenicpathwaymayfacilitatedevelopmentofspecifictherapiesLinkagestudieshaveprovenlesspowerfulintheisolationofgenesinvolvedincommoncomplexdiseasesLinkagedisequilibriumstudiesaremorelikelytobeusefulinidentificationofgenesforthesedisorders(BotsteinandRisch)Beforediscussinglinkagedisequilibriummappingandassociationstudies,itwillbeusefultoconsidertheoriesregardingtheoriginofcommongeneticallycomplex,multifactorialdiseasesCOMPLEXMULTIFACTORIALDISEASESTheoriesRegardingOriginOnetheorycentersontheconceptthatDNAchangesthatpredisposetocomplexmultifactorialdiseasesareevolutionarilyold,thattheythereforeexistathighfrequencyinthepopulations,andthatacomplexdiseasephenotyperesultsfrominteractionbetweengeneticriskfactorsandspecificenvironmentalfactors(RischandMerikangas)Itisthistheorythathasfueledthemultibilliondollarsearchforgeneticvariation(polymorphisms,oftensinglenucleotidepolymorphisms,SNPs)associatedwithorinlinkagedisequilibriumwithcommondiseasesRopers()presentedevidencethatthecomplexityofmultifactorialdiseasesismostlikelyduetogeneticheterogeneityFurthermore,heemphasizedthatnewmutations,includingthosethatleadtodenovocopynumbervariation,likelycontributetotheincidenceofcommoncomplexdiseasesRopersemphasizedfurtherthatcomplexdisordersarenotnecessarilymultifactorialInsomecases,oneorafewgeneticchangesmayleadtothedisorderThesedisordersarethereforecomplexinthesensethatmutationsinanynumberofdifferentgenesmayleadtothediseasephenotypeIsolationofDiseaseGenesThroughGenomicsLinkageDisequilibriumandAssociationStudiesinMappingofComplexDiseasesLinkagedisequilibriummappingisbasedonsearchesforassociationbetweendiseaseandaspecificalleleatamarkerlocusFurthermore,itisbasedontheassumptionthatinaparticularfamily,affectedmemberswillinheritthesamealleleatdiseaseassociatedmarkerlociDNAsequencebasedpolymorphismsAmongthegoalsofprojectsdesignedtodevelopadetailedcatalogofDNAsequencebasedpolymorphismsinthehumangenomewastohaveavailableaplatformtoanalyzetheassociationandcosegregationofspecificDNAvariantswithspecificcommondiseasesTheguidingprinciplewasthatthroughdefinitionandmappingofdiseaseassociatedmarkers,itwouldbepossibletoidentifynewdiseasepathwaysThisinturnwouldleadtoimprovedriskassessmentandopenthewayfordevelopmentofmoreeffectivediseasespecifictherapiesAssociationstudiesarecurrentlybasedlargelyontheanalysisofSNPsInmanystudies,agenomewideanalysisiscarriedout,andthisincludesanalysisofSNPsincodingandinnoncodingregionsofthegenomeOneofthekeystepsinfurtheranalysisofassociationistodeterminethefunctionalsignificanceofthenucleotidevariationinaSNPBotsteinandRisch()proposedthattheanalysisofSNPsingenesismostimportantinassociationassessmentTheyproposedthatfollowinginitialidentificationofanassociatedSNPinagene,resequencingbecarriedouttoidentifyadditionalandpossiblelesspolymorphicSNPsinthecodingregionFurthermore,theyproposedthatifcodingregionSNPsareanalyzed,itispossibletoincludeinformationonthesignificanceofnucleotidechangesthathavebeendevelopedoverthepastseveraldecadesthroughtheanalysisofmutantproteinsindiseasesduetosinglegenedefectsDevelopmentofageneticmapofapproximatelyhighlyinformativemicrosatellitemarkersfacilitateddiseasegenemappingwithinregionsoftomillionbasepairs(Weissenbach)DevelopmentofthemapofSNPsfacilitatedgenemappingbylinkagestudiessincehundredsofthousandsofthesemarkerscanbeanalyzedusingmicroarrayscontainingboundoligonucleotideprobesinacosteffectivemanner(Gundersonetal)LinkagedisequilibriumandHapMapSincepolymorphismsinneighboringsegmentsofDNAoftentraveltogether,thequestionarosetowhatextentitispossibletopredictonepolymorTranslationalResearchinGeneticsandGenomicsphismonthebasisofthepresenceofanotherResearchcarriedoutaspartoftheHapMapprojectledtogenerationofinformationontheassociationofspecificDNApolymorphismsindifferentpopulationsThisprojectalsosoughttodeterminetheminimumnumberofSNPsthatwouldberepresentativeofeachspecifichaplotypeTheseweredesignatedasTagSNPsHaplotypesAhaplotypeisaseriesoflinkedgeneticmarkersthatusuallysegregatesasaunitduringmeiosisHaplotypeblocksoccurasaresultofblocksoflinkagedisequilibriumIfaspecifichaplotype(ie,aseriesofpolymorphisms)isassociatedwithaspecificgenevariant,thatgivesrisetoadisease,thepresenceofaspecifichaplotypeinanatriskindividualmayserveasanindicatorofthepresenceofthediseasepredisposingmutationbeforethesymptomsandsignsofthediseaseareevidentCertainmutationsmaybedifficulttodetectwithcertainty,particularlyinsamplesprovidedforprenataldiagnosisKnowledgeofthehaplotypeonwhichadiseasemutationoccursmaybehelpfulifthehaplotypecanbeanalyzedmorereadilythanthediseasemutationLinkagedisequilibriumPolymorphismsinadjacentsegmentsofDNAoftentraveltogetherReichetal()definedlinkagedisequilibriumas‘‘thecorrelationsamongneighboringallelesthatreflecthaplotypesdescendedfromasingleancestralchromosome’’(p)IntheiranalysisofaUSpopulation,Reichetal()reportedthatlinkagedisequilibriumtypicallyextendsforadistanceofkbfromacommonalleleTheynotedthatinanAfricanpopulation(Nigerian),linkagedisequilibriumextendsovermuchshorterdistancesInconstructinglinkagedisequilibriummaps,Reichetal()focusedoncoreSNPswithingenesandtheSNPschosenbecausetheydemonstratedahighfrequencyofvariationTheyresequencedDNAsegmentsofaboutkbthatwerelocatedatdistanceof,,,,,andkbfromacoreSNPTheirdataindicatedthatlinkagedisequilibriumextendsfurtherthanhadbeenestimatedpriortoth

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