Chapter9/第9章Chapter9MutationsandMutationRepair9.1DNADamageandMutations9.2PointMutations9.3InsertionsandDeletions9.4Large-ScaleDNAchanges9.5ConsequencesofDNAMutations9.6MutationRepair9.7Experiments第9章突變與突變修復9.1DNA損傷與突變9.2點突變9.3插入和缺失9.4大規模DNA變化9.5DNA突變的后果9.6突變修復9.7實驗研究MutationsandMutationRepair

突變與突變修復Chemicals化學物質Radiation輻射Transposons轉座子Replicationerrors復制錯誤9.1DNADamageandMutations

DNA損傷與突變AheritablechangeinDNAsequenceiscalledamutation.Mostfrequently,thewordmutationisappliedtoheritablealterationsthataffectthefunctionofagene.DNA序列中可遺傳的改變稱為突變。大多數時候突變一詞用來指影響到基因功能的可遺傳改變。Mutationcanbefavorable

突變可以是有利的MUTAtiOn9.2PointMutations/點突變Mutationsaffectingonlyonebasepairarecalledpointmutations.Usually,pointmutationsinvolvesubstitutionofonebasewithanotherbase.Ifapyrimidineisreplacedwithaotherpyrimidine,orapurinebyanotherpurineitiscalledatransition.Ifapurineisreplacedbyapyrimidineorvice-versa,itiscalledatransversion.只影響到一個堿基對的突變叫做點突變。通常，點突變涉及到一個堿基被另一個堿基替換。如果一個嘧啶被另一個嘧啶、或一個嘌呤被另一個嘌呤取代，這樣的點突變稱為轉換。如果一個嘌呤被一個嘧啶取代或反之，這樣的點突變稱為顛換。Transitionvs.TransversionT→CG→AT→GG→TTransition

轉換Transversion

顛換9.2.1MismatchedBase/錯配的堿基dMismatchedbase→Pointmutation9.2.2SpontaneousMutation/自發突變1.Deamination/脫氨基2.Depurination/脫嘌呤3.Tautomerization/互變異構化1.Deamination/脫氨基C→UReplicationG–C→A–TUU2.Depurination/脫嘌呤AAATTTCCGGAAATTTCCGDepurinate(>5000nt)Repair(most)Depurination/脫嘌呤Depurination→Mutation“HowcanIcontinuemywork?”DNApolAAATCG–C→A–T→C–G→T-A3.Tautomerization/互變異構化TautomericformsoftheDNAbases9.2.3InducedMutations/誘發突變1.BaseAnalogues/堿基類似物2.AlkylatingAgents/烷化劑3.NitrousAcid/亞硝酸4.UltravioletRadiation/紫外輻射1.BaseAnalogues/堿基類似物BU*→MutationA:TA:BUTautome-rizationA:BU*ReplicationG:BU*ReplicationA–T→G–C2.AlkylatingAgents/烷化劑Anotherclassofmoleculeswiththeabilitytocausepointmutationsisalkylatingagent.Thesecompoundscanaddalkylgroupstoothermolecules,includingDNAbases.Whenaklylationchangesbasepairingproperties,itwillmostlikelyleadtopointmutations.能夠引起點突變的另一類分子是烷化劑。這些化合物能夠將烷基加到其它分子上，包括加到DNA的堿基上。如果烷化作用改變了堿基的配對性質，它就很可能會導致點突變。EMS:ethylmethanesulfonate

乙基甲磺酸G:CmG:CEMSReplicationmG:TG–C→A–T3.NitrousAcid/亞硝酸Pickledfood腌制食品Nitrousacid亞硝酸Cancer癌癥Adenine→Hypoxanthine

腺嘌呤→次黃嘌呤A:TH:THNO2ReplicationH:CA–T→G–CCytosine→Uracil

胞嘧啶→尿嘧啶C:GU:GHNO2ReplicationU:AC–G→T–A4.UltravioletRadiation/紫外輻射Pyrimidinedimer/嘧啶二聚體Cross-linking/交聯/Archive.html

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9.3InsertionsandDeletions

插入和缺失9.3.1StrandSlippage/鏈滑動9.3.2Transposons/轉座子9.3.3IntercalatingAgents/嵌入劑9.3.1StrandSlippage/鏈滑動MSI:microsatelliteinstability

微衛星不穩定性/.../MDGF/technology.shtml?MDGF

HereditaryNon-PolyposisColorectalCancer,HNPCC遺傳性非息肉型結腸癌9.3.2Transposons/轉座子InsertionsanddeletionsmayalsobecausedbyDNAelementscalledtransposons.Whenatransposonrelocatestoanotherareaofthegenomeitcausesaninsertion.插入和缺失也可能由稱為轉座子的DNA元件引起。當轉座子再次定位到基因組的另一個區域時，它就會引起一個插入突變。9.3.3IntercalatingAgents/嵌入劑AbasepairIntercalation→Mutation9.4Large-ScaleDNAchanges

大規模DNA變化Translocation

/易位Inversion/倒位Single-strandbreak/單鏈斷裂Peroxides,Fe2+,Cu2+IonizingradiationFreeradicalsDouble-strandbreak/雙鏈斷裂OtherbreaksRepairofDoublestrandbreak/heyerlab/Rooster.htm

ExtremesensitivitytoX-rayModeratesensitivitytoUVHyper-sensitivetomethylmethanesulfonatePhenotypescausedbyaRAD54deletion9.5ConsequencesofDNAMutations

DNA突變的后果11.5.1ConsequencesofPointMutations

點突變的后果11.5.2ConsequencesofInsertionsandDeletions

插入和缺失的后果11.5.3ConsequencesofTranslocations

易位的后果9.5.1ConsequencesofPointMutations/點突變的后果1.Silentmutation

沉默突變2.Missensemutation

錯義突變3.Nonsensemutation

無義突變1.Silentmutation/沉默突變2.Missensemutation/錯義突變Leakymutation/滲漏突變NormalredbloodcellsSicklecells3.Nonsensemutation/無義突變9.5.2ConsequencesofInsertionsandDeletions

插入和缺失的后果Readingframe:Theorganizationofbasesinacodingregionintogroupsofthree,markedatthebeginningandendbystartandstopcodons.讀碼框：編碼區中堿基以三個一組形成的結構，以起始密碼子和終止密碼子為開始和結束的標志?！癟hecatateitsrat.”“Thecatateitsrat.”“Txhecatateitsrat.”/index.php?module=pagemaste...

Frameshiftmutation/移碼突變9.5.3ConsequencesofTranslocations

易位的后果Chronicmyelogenousleukemia

慢性骨髓性白血病

Burkitt’slymphoma非洲淋巴瘤

ChronicMyelogenousLeukemia

慢性骨髓性白血病

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/Courses/BI279/Lec12/Lec12-D.htm

WhatcausesexcessWBCs?Burkitt’slymphoma/

非洲淋巴瘤

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WhatcausesBurkitt’slymphoma?Functionofgenec-myc/Omegaman_UK/apoptosi.html

Apoptosisbegins1234CelldividesCelldiesGenebci-2Genec-MycChromosomeNowshowing

OverviewofEukaryoticGeneExpressionFile:biophoto7\

Genetics:AConceptualApproach\Overviewofeukaryoticgeneexpression(15’)9.5.4MutationHotSpots/突變熱點前方500米事故多發地段MutationHotSpots/突變熱點9.6MutationRepair/突變修復MutationRepair/突變修復9.6.1DirectReversal/直接回復UVlightVisiblelightPhotolyaseTCATTGCCAGTAACGG......光復活主要是原核生物中的一種修復方式。（《遺傳學》教材第451頁）9.6.2MismatchRepair/錯配修復MMR:MismatchRepair(1/2)MMR:MismatchRepair(2/2)11.6.3NucleotideExcisionRepair

核苷酸切除修復NER:NucleotideExcisionRepair

(1/2)NER:NucleotideExcisionRepair

(2/2)MMRvs.NERMMR

MismatchNER

Damagedbases9.6.4BaseExcisionRepair

堿基切除修復DamagetoC(e.g.deamination)BER:BaseExcisionRepair

(1/2)BER:BaseExcisionRepair

(2/2)9.6.5Double-StrandedBreakRepair

雙鏈斷裂修復ExtremesensitivitytoX-rayModeratesensitivitytoUVNHEJ:non-homologousendjoining(1/3)NHEJ:non-homologousendjoining(2/3)NHEJ:non-homologousendjoining(3/3)Homologousrecombination

同源重組

9.7Experiments