分子生物学Chapter-9

Chapter9/第9章,Chapter9MutationsandMutationRepair9.1DNADamageandMutations9.2PointMutations9.3InsertionsandDeletions9.4Large-ScaleDNAchanges9.5ConsequencesofDNAMutations9.6MutationRepair9.7Experiments,第9章突变与突变修复9.1DNA损伤与突变9.2点突变9.3插入和缺失9.4大规模DNA变化9.5DNA突变的后果9.6突变修复9.7实验研究,MutationsandMutationRepair突变与突变修复,Chemicals化学物质,Radiation辐射,Transposons转座子,Replicationerrors复制错误,9.1DNADamageandMutationsDNA损伤与突变,AheritablechangeinDNAsequenceiscalledamutation.Mostfrequently,thewordmutationisappliedtoheritablealterationsthataffectthefunctionofagene.,DNA序列中可遗传的改变称为突变。大多数时候突变一词用来指影响到基因功能的可遗传改变。,Mutationcanbefavorable突变可以是有利的,9.2PointMutations/点突变,Mutationsaffectingonlyonebasepairarecalledpointmutations.Usually,pointmutationsinvolvesubstitutionofonebasewithanotherbase.Ifapyrimidineisreplacedwithaotherpyrimidine,orapurinebyanotherpurineitiscalledatransition.Ifapurineisreplacedbyapyrimidineorvice-versa,itiscalledatransversion.,只影响到一个碱基对的突变叫做点突变。通常，点突变涉及到一个碱基被另一个碱基替换。如果一个嘧啶被另一个嘧啶、或一个嘌呤被另一个嘌呤取代，这样的点突变称为转换。如果一个嘌呤被一个嘧啶取代或反之，这样的点突变称为颠换。,Transitionvs.Transversion,TC,GA,TG,GT,Transition转换,Transversion颠换,9.2.1MismatchedBase/错配的碱基,d,MismatchedbasePointmutation,9.2.2SpontaneousMutation/自发突变,1.Deamination/脱氨基2.Depurination/脱嘌呤3.Tautomerization/互变异构化,1.Deamination/脱氨基,CU,Replication,GCAT,U,U,2.Depurination/脱嘌呤,A,A,A,T,T,T,C,C,G,G,A,A,A,T,T,T,C,C,G,Depurinate(5000nt),Repair(most),Depurination/脱嘌呤,DepurinationMutation,“HowcanIcontinuemywork?”,DNApol,A,A,A,T,C,GCATCGT-A,3.Tautomerization/互变异构化,TautomericformsoftheDNAbases,9.2.3InducedMutations/诱发突变,1.BaseAnalogues/碱基类似物2.AlkylatingAgents/烷化剂3.NitrousAcid/亚硝酸4.UltravioletRadiation/紫外辐射,1.BaseAnalogues/碱基类似物,BU*Mutation,A:T,A:BU,Tautome-rization,A:BU*,Replication,G:BU*,Replication,ATGC,2.AlkylatingAgents/烷化剂,Anotherclassofmoleculeswiththeabilitytocausepointmutationsisalkylatingagent.Thesecompoundscanaddalkylgroupstoothermolecules,includingDNAbases.Whenaklylationchangesbasepairingproperties,itwillmostlikelyleadtopointmutations.,能够引起点突变的另一类分子是烷化剂。这些化合物能够将烷基加到其它分子上，包括加到DNA的碱基上。如果烷化作用改变了碱基的配对性质，它就很可能会导致点突变。,EMS:ethylmethanesulfonate乙基甲磺酸,G:C,mG:C,EMS,Replication,mG:T,GCAT,3.NitrousAcid/亚硝酸,Pickledfood腌制食品,Nitrousacid亚硝酸,Cancer癌症,AdenineHypoxanthine腺嘌呤次黄嘌呤,A:T,H:T,HNO2,Replication,H:C,ATGC,CytosineUracil胞嘧啶尿嘧啶,C:G,U:G,HNO2,Replication,U:A,CGTA,4.UltravioletRadiation/紫外辐射,Pyrimidinedimer/嘧啶二聚体,Cross-linking/交联,S,CH2,H2C,H2C,CH2,Cl,Cl,芥子气,Injuriescausedbymustardgas,/./onlinedisplay/1910s.html,9.3InsertionsandDeletions插入和缺失,9.3.1StrandSlippage/链滑动9.3.2Transposons/转座子9.3.3IntercalatingAgents/嵌入剂,9.3.1StrandSlippage/链滑动,MSI:microsatelliteinstability微卫星不稳定性,/./MDGF/technology.shtml?MDGF,HereditaryNon-PolyposisColorectalCancer,HNPCC遗传性非息肉型结肠癌,9.3.2Transposons/转座子,InsertionsanddeletionsmayalsobecausedbyDNAelementscalledtransposons.Whenatransposonrelocatestoanotherareaofthegenomeitcausesaninsertion.,插入和缺失也可能由称为转座子的DNA元件引起。当转座子再次定位到基因组的另一个区域时，它就会引起一个插入突变。,9.3.3IntercalatingAgents/嵌入剂,Abasepair,IntercalationMutation,9.4Large-ScaleDNAchanges大规模DNA变化,Translocation/易位,Inversion/倒位,Single-strandbreak/单链断裂,Peroxides,Fe2+,Cu2+IonizingradiationFreeradicals,Double-strandbreak/双链断裂,Otherbreaks,RepairofDoublestrandbreak,/heyerlab/Rooster.htm,ExtremesensitivitytoX-ray,ModeratesensitivitytoUV,Hyper-sensitivetomethylmethanesulfonate,PhenotypescausedbyaRAD54deletion,9.5ConsequencesofDNAMutationsDNA突变的后果,9.5.1ConsequencesofPointMutations点突变的后果9.5.2ConsequencesofInsertionsandDeletions插入和缺失的后果9.5.3ConsequencesofTranslocations易位的后果,9.5.1ConsequencesofPointMutations/点突变的后果,1.Silentmutation沉默突变2.Missensemutation错义突变3.Nonsensemutation无义突变,1.Silentmutation/沉默突变,2.Missensemutation/错义突变,Leakymutation/渗漏突变,Normalredbloodcells,Sicklecells,3.Nonsensemutation/无义突变,9.5.2ConsequencesofInsertionsandDeletions插入和缺失的后果,Readingframe:Theorganizationofbasesinacodingregionintogroupsofthree,markedatthebeginningandendbystartandstopcodons.读码框：编码区中碱基以三个一组形成的结构，以起始密码子和终止密码子为开始和结束的标志。,“Thecatateitsrat.”,“Thecatateitsrat.”,“Txhecatateitsrat.”,/index.php?module=pagemaste.,Frameshiftmutation/移码突变,9.5.3ConsequencesofTranslocations易位的后果,Chronicmyelogenousleukemia慢性骨髓性白血病Burkittslymphoma非洲淋巴瘤,ChronicMyelogenousLeukemia慢性骨髓性白血病,/Courses/BI279/Lec12/Lec12-D.htm,WhatcausesexcessWBCs?,Burkittslymphoma/非洲淋巴瘤,www.gfmer.ch/./Maroua_case_presentation.htm,WhatcausesBurkittslymphoma?,Functionofgenec-myc,Apoptosisbegins,1,2,3,4,Celldivides,Celldies,Genebci-2,Genec-Myc,Chromosome,9.5.4MutationHotSpots/突变热点,MutationHotSpots/突变热点,9.6MutationRepair/突变修复,MutationRepair/突变修复,9.6.1DirectReversal/直接回复,UVlight,光复活主要是原核生物中的一种修复方式。（遗传学教材第451页）,9.6.2MismatchRepair/错配修复,MMR:MismatchRepair(1/2),MMR:MismatchRepair(2/2),9.6.3NucleotideExcisionRepair核苷酸切除修复,NER:NucleotideExcisionRepair(1/2),NER:NucleotideExcisionRepair(2/2),MMRvs.NER,MMRMismatch,NERDamagedbases,9.6.4BaseExcisionRepair碱基切除修复,DamagetoC(e.g.deamination),BER:BaseExcisionRepair(1/2),BER:BaseExcisionRepair(2/2),9.6.5Double-StrandedBreakRepair双链断裂修复,ExtremesensitivitytoX-ray,ModeratesensitivitytoUV,NHEJ:non-homologousendjoining(1/3),NHEJ:non-homologousendjoining(2/3),NHEJ:non-homologousendjoining(3/3),Homologousrecombination同源重组,9.7Experiments/实验研究,11.7.1NucleotideExcisionRepairandHumanDisease核苷酸切除修复与人类疾病11.7.2TheAmesTest埃姆斯测验法,9.7.1NucleotideExcisionRepairandHumanDisease核苷酸切除修复与人类疾病,/./imagepages/image161.htm,Xerodermapigmentosum/着色性干皮病,Inmammaliancells,excisionrepairinvolvesmanymoreenzymes.AtleastadozendifferentgenesareinvolvedinrecognizingandexcisingthedamagedDNAsegment.Individuals