《英漢對(duì)照分子生物學(xué)導(dǎo)論》課件 王勇 Chapter 9 Mutations and Mutation Repair、Chapter 10 Recombination、Sample Nucleic acids

Chapter9/第9章Chapter9MutationsandMutationRepair9.1DNADamageandMutations9.2PointMutations9.3InsertionsandDeletions9.4Large-ScaleDNAchanges9.5ConsequencesofDNAMutations9.6MutationRepair9.7Experiments第9章突變與突變修復(fù)9.1DNA損傷與突變9.2點(diǎn)突變9.3插入和缺失9.4大規(guī)模DNA變化9.5DNA突變的后果9.6突變修復(fù)9.7實(shí)驗(yàn)研究MutationsandMutationRepair

突變與突變修復(fù)Chemicals化學(xué)物質(zhì)Radiation輻射Transposons轉(zhuǎn)座子Replicationerrors復(fù)制錯(cuò)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(shù)時(shí)候突變一詞用來(lái)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(diǎn)突變Mutationsaffectingonlyonebasepairarecalledpointmutations.Usually,pointmutationsinvolvesubstitutionofonebasewithanotherbase.Ifapyrimidineisreplacedwithaotherpyrimidine,orapurinebyanotherpurineitiscalledatransition.Ifapurineisreplacedbyapyrimidineorvice-versa,itiscalledatransversion.只影響到一個(gè)堿基對(duì)的突變叫做點(diǎn)突變。通常，點(diǎn)突變涉及到一個(gè)堿基被另一個(gè)堿基替換。如果一個(gè)嘧啶被另一個(gè)嘧啶、或一個(gè)嘌呤被另一個(gè)嘌呤取代，這樣的點(diǎn)突變稱為轉(zhuǎn)換。如果一個(gè)嘌呤被一個(gè)嘧啶取代或反之，這樣的點(diǎn)突變稱為顛換。Transitionvs.TransversionT→CG→AT→GG→TTransition

轉(zhuǎn)換Transversion

顛換9.2.1MismatchedBase/錯(cuò)配的堿基dMismatchedbase→Pointmutation9.2.2SpontaneousMutation/自發(fā)突變1.Deamination

/脫氨基2.Depurination

/脫嘌呤3.Tautomerization

/互變異構(gòu)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(gòu)化TautomericformsoftheDNAbases9.2.3InducedMutations/誘發(fā)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(diǎn)突變的另一類分子是烷化劑。這些化合物能夠?qū)⑼榛拥狡渌肿由希拥紻NA的堿基上。如果烷化作用改變了堿基的配對(duì)性質(zhì)，它就很可能會(huì)導(dǎo)致點(diǎn)突變。EMS:ethylmethane

sulfonate

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(lián)/Archive.html

/index.cfm?fuseaction=user...

SCH2H2CH2CCH2ClCl芥子氣Injuriescausedbymustardgas/.../chemweapons/blister.html

/.../onlinedisplay/1910s.html

/.../hospital_hazmat_index.htm

9.3InsertionsandDeletions

插入和缺失9.3.1StrandSlippage/鏈滑動(dòng)9.3.2Transposons/轉(zhuǎn)座子9.3.3IntercalatingAgents/嵌入劑9.3.1StrandSlippage/鏈滑動(dòng)MSI:microsatellite

instability

微衛(wèi)星不穩(wěn)定性/.../MDGF/technology.shtml?MDGF

HereditaryNon-PolyposisColorectalCancer,HNPCC遺傳性非息肉型結(jié)腸癌9.3.2Transposons

/轉(zhuǎn)座子InsertionsanddeletionsmayalsobecausedbyDNAelementscalledtransposons.Whenatransposonrelocatestoanotherareaofthegenomeitcausesaninsertion.插入和缺失也可能由稱為轉(zhuǎn)座子的DNA元件引起。當(dāng)轉(zhuǎn)座子再次定位到基因組的另一個(gè)區(qū)域時(shí)，它就會(huì)引起一個(gè)插入突變。9.3.3IntercalatingAgents/嵌入劑AbasepairIntercalation→Mutation9.4Large-ScaleDNAchanges

大規(guī)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-sensitivetomethylmethanesulfonate

PhenotypescausedbyaRAD54deletion9.5ConsequencesofDNAMutations

DNA突變的后果11.5.1ConsequencesofPointMutations

點(diǎn)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(diǎn)突變的后果1.Silentmutation

沉默突變2.Missensemutation

錯(cuò)義突變3.Nonsensemutation

無(wú)義突變1.Silentmutation/沉默突變2.Missensemutation/錯(cuò)義突變Leakymutation/滲漏突變NormalredbloodcellsSicklecells3.Nonsensemutation/無(wú)義突變9.5.2ConsequencesofInsertionsandDeletions

插入和缺失的后果Readingframe:Theorganizationofbasesinacodingregionintogroupsofthree,markedatthebeginningandendbystartandstopcodons.讀碼框：編碼區(qū)中堿基以三個(gè)一組形成的結(jié)構(gòu)，以起始密碼子和終止密碼子為開(kāi)始和結(jié)束的標(biāo)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

/

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

WhatcausesexcessWBCs?Burkitt’slymphoma/

非洲淋巴瘤

/lectures/spleen.htm

www.gfmer.ch/.../Maroua_case_presentation.htm_presentation.htm

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

Apoptosisbegins1234CelldividesCelldiesGenebci-2Genec-MycChromosomeNowshowing

OverviewofEukaryoticGeneExpressionFile:biophoto7\

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

核苷酸切除修復(fù)NER:NucleotideExcisionRepair

(1/2)NER:NucleotideExcisionRepair

(2/2)MMRvs.NERMMR

MismatchNER

Damagedbases9.6.4BaseExcisionRepair

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

(1/2)BER:BaseExcisionRepair

(2/2)9.6.5Double-StrandedBreakRepair

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

同源重組

9.7Experiments/實(shí)驗(yàn)研究11.7.1NucleotideExcisionRepair

andHumanDisease

核苷酸切除修復(fù)與人類疾病11.7.2TheAmesTest

埃姆斯測(cè)驗(yàn)法9.7.1NucleotideExcisionRepair

andHumanDisease

核苷酸切除修復(fù)與人類疾病/.../imagepages/image161.htmXerodermapigmentosum

/著色性干皮病Inmammaliancells,excisionrepairinvolvesmanymoreenzymes.AtleastadozendifferentgenesareinvolvedinrecognizingandexcisingthedamagedDNAsegment.IndividualswhosufferfromXPareextremelysensitivetosunlight./.../imagepages/image161.htmwww.eprints-scd-ulp.u-strasbg.fr:8080/archive/000...9.7.2TheAmesTest/埃姆斯測(cè)驗(yàn)法TheAmesTestforbacteriaTheAmesTestformammalsChemicalANoxioussubstancesLiverNontoxicsubstancesChemicalA’TheAmesTestformammalsChapter10Recombination/重組10.1HomologousRecombination10.1.1MechanismforCrossing-Over10.1.2MechanismforDouble-StrandedBreakRepair10.1.3TheRecBCDpathway10.1.4GeneConversion10.2Non-homologousRecombination10.2.1Transposons10.2.2Retrotransposons10.2.3Bacteriophageλintegration10.1同源重組

10.1.1交換機(jī)理

10.1.2雙鏈斷裂修復(fù)機(jī)理

10.1.3RecBCD途徑

10.1.4基因轉(zhuǎn)換10.2非同源重組

10.2.1轉(zhuǎn)座子

10.2.2反轉(zhuǎn)錄轉(zhuǎn)座子

10.2.3λ噬菌體的整合10.1HomologousRecombination同源重組Diploid(2n)2copiesofeachchromosomeHomologousRecombinationIfthesechromosomeswereleftunchanged…ChildGrand-childIdenticalCrossing-overinmeiosisChildGrand-childDifferentHomologousRecombinationinDNArepairHomologouschromosomes10.1.1MechanismforCrossing-Over/交換機(jī)理Mechanismofrecombinationinyeast(1/2)Mechanismofrecombinationinyeast(2/2)HollidayjunctionsBranchmigrationofHollidayjunctions

Holliday交叉的分支遷移ResolutionoftheHollidayjunction

Holliday交叉的拆分ResolutionoftheHollidayjunction

tocreateacrossover

產(chǎn)生交換的Holliday交叉拆分ResolutionofHollidayjunctions

fornon-crossover

不產(chǎn)生交換的Holliday交叉拆分ResolutionoftheHollidayjunction

tocreateacrossover

產(chǎn)生交換的Holliday交叉拆分10.1.2MechanismforDouble-StrandedBreakRepair/雙鏈斷裂修復(fù)機(jī)理ResolutionofHollidayjunctions

fornon-crossover

不產(chǎn)生交換的Holliday交叉拆分Brca1/Brca2deletionandbreastcancerBrca1/Brca2缺失與乳腺癌/cancer/breast.htm

TherolesofBRCA1andBRCA2inDNArepairBRCA1和BRCA2在DNA修復(fù)中的作用www-ermm.cbcu.cam.ac.uk/01003118h.htm

Nowshowing

Meselson-RaddingHeteroduplexModelFile:biophoto7\IntroductiontoGeneticAnalysis\Meselson-RaddingheteroduplexModel10.1.3TheRecBCDPathway(1/3)TheRecBCDPathway(2/3)TheRecBCDPathway(3/3)10.1.4GeneConversion/基因轉(zhuǎn)換GTATGCATHomologous,Notidentical.3’5’3’5’3’5’3’5’GeneConversion/基因轉(zhuǎn)換GeneConversion/基因轉(zhuǎn)換Neurosporacrassa

粗糙脈孢菌++mmMeiosisI減數(shù)分裂IMeiosisII減數(shù)分裂IIMitosis有絲分裂++mm++mmmmmm++++4:4Neurosporacrassa

粗糙脈孢菌/Initiatives/Models/

4:45:36:2Nowshowing

GeneConversionFile:biophoto7

IntroductiontoGeneticAnalysis

GeneticConsequencesofMeselson-RaddingModel10.2Non-homologousRecombination

非同源重組10.2.1Transposons

轉(zhuǎn)座子10.2.2Retrotransposons

反轉(zhuǎn)錄轉(zhuǎn)座子10.2.3Bacteriophageλintegration

λ噬菌體的整合10.2.1Transposons

/轉(zhuǎn)座子Transposition/轉(zhuǎn)座Generationofdirectrepeats

同向重復(fù)序列的產(chǎn)生Nowshowing

ReplicativetranspositionFile:biophoto7\

IntroductiontoGeneticAnalysis\Replicativetransposition.(5’)10.2.2Retrotransposons

反轉(zhuǎn)錄轉(zhuǎn)座子LTR-Retrotransposons

LTR反轉(zhuǎn)錄轉(zhuǎn)座子Non-LTRRetrotransposons

非LTR反轉(zhuǎn)錄轉(zhuǎn)座子LTR-Retrotransposons

LTR反轉(zhuǎn)錄轉(zhuǎn)座子Non-LTRretrotransposons

非LTR反轉(zhuǎn)錄轉(zhuǎn)座子Weaver’sMolecularBiology,3rdEdition,Figure23.3110.2.3Bacteriophageλintegration

λ噬菌體的整合LysisLysogenyPhageintegrationandexcisionattP:attachmentsitesofphageattB:attachmentsitesofbacteriumNucleicacids:theinformationcarrierInformationformakingproteinsisstoredinnucleicacids.ProteinsNucleicacids(mainlyDNA)Chapter2Nucleicacids2.1PropertiesofaGeneticMaterial2.2NucleicAcidsandDNAstructure2.3DNAastheGeneticMaterial2.4DNAintheCell2.5RNA(RibonucleicAcid)2.6Experiments2.1遺傳物質(zhì)的性質(zhì)2.2核酸與DNA結(jié)構(gòu)2.3DNA作為遺傳物質(zhì)2.4細(xì)胞中的DNA2.5RNA（核糖核酸）2.6實(shí)驗(yàn)研究VocabularyofDay3(1/4)nucleicacidgeneticmaterialinheritnucleotidenitrogenousbasetriphosphatebasephosphateribosedeoxyribose核酸遺傳物質(zhì)遺傳，繼承核苷酸含氮堿基三磷酸（基團(tuán)）堿基磷酸根核糖脫氧核糖VocabularyofDay3(2/4)hydroxylgrouppurineadenineguaninepyrimidinecytosinethymineuracilribonucleotidedeoxyribonucleotide羥基嘌呤腺嘌呤鳥(niǎo)嘌呤嘧啶胞嘧啶胸腺嘧啶尿嘧啶核糖核苷酸脫氧核糖核苷酸VocabularyofDay3(3/4)ribonucleicaciddeoxyribonucleicacidphosphodiesterbondthreeprimeendfiveprimeendsugar-phosphatebackbonesingle-strandedDNAdoublestrandedDNAdoublehelixcomplementary核糖核酸（RNA）脫氧核糖核酸（DNA）磷酸二酯鍵3’末端5’末端糖-磷酸骨架單鏈DNA雙鏈DNA雙螺旋互補(bǔ)的VocabularyofDay3(4/4)anti-parallelbase-stackingmajorgrooveminorgroovenanometerdenaturedenaturationabsorbanceabsorbadsorb反向平行的堿基堆積（DNA）大溝（DNA）小溝納米變性（動(dòng)詞）變性（名詞）吸收（名詞）吸收（動(dòng)詞）吸附2.1PropertiesofaGeneticMaterialItmustbeabletoholdinformationforhowtomakeproteins.Itmustbestable.Itmusthavesomecapacityforchange.Itmustbeabletobecopied.它必須能夠保持如何生產(chǎn)蛋白質(zhì)的信息。它必須是穩(wěn)定的。它必須具有容忍變化的能力。它必須能夠被復(fù)制。Itmustbeabletoholdinformationforhowtomakeproteins

1．它必須能夠保持如何生產(chǎn)蛋白質(zhì)的信息Itmustbestable/2．它必須是穩(wěn)定的Lizard:1,000,000B.C.Lizard:2008A.D.Nochange!Itmustbestable/它必須是穩(wěn)定的Age:15Age:45Age:75Nochange!Nochange!3.Itmusthavesomecapacityforchange

3．它必須具有容忍變化的能力Itmusthavesomecapacityforchange

它必須具有容忍變化的能力MUTAtiOnItmustbeabletobecopied

4．它必須能夠被復(fù)制2.2NucleicAcidsandDNAstructure

2.2核酸與DNA結(jié)構(gòu)2.2.1Nucleotides /2.2.1核苷酸Nucleotidesarecomposedofthreeparts:1)anitrogenousbase,2)asugar,and3)atriphosphate.N-glycosidicbond1)Nitrogenousbase

/含氮堿基2)Sugar/糖Nooxygenhere!Ribonucleotidesanddeoxyribonucleotides

核糖核苷酸與脫氧核糖核苷酸3)Triphosphate

/三磷酸2.2.2GeneralStructureofNucleicAcids

2.2.2核酸的一般結(jié)構(gòu)deoxyribonucleicacid(DNA)ribonucleicacid(RNA)Phosphodiesterbond

/磷酸二酯鍵Threeprimeend

andfiveprimeend

三一撇末端與

五一撇末端Sugar-phosphatebackbone/糖-磷酸骨架NegativechargesNucleosome

/核小體Chapter72.2.3StructureofDNA/2.2.3DNA的結(jié)構(gòu)Double-strandedDNAHydrogenbondsBasepair/堿基對(duì)ComplementarybasepairsAntiparallelDNAstrands

反向平行的DNA鏈TheDNAdoubleHelix/DNA雙螺旋MinorgrooveMajorgroove2nanometers1turn=10bases=3.4nanometersBasestackingDenaturationofDNA/DNA變性LightabsorbancebyDNADNA對(duì)光的吸收λ=260nmλ=260nmssDNAdsDNANowshowing

Macromolecules–NucleicAcidsFile:biophoto7\Life\Macromoleculs–NucleicAcids(3’)Summary/小結(jié)

Chapter2Nucleicacids2.1PropertiesofaGe