数学课件-Chapter-9.ppt

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1、1/81Chapter 9 /第第9章章Chapter 9 Mutations and Mutation Repair9.1 DNA Damage and Mutations9.2 Point Mutations9.3 Insertions and Deletions9.4 Large-Scale DNA changes9.5 Consequences of DNA Mutations9.6 Mutation Repair9.7 Experiments第第9章章 突变与突变与 突变修复突变修复9.1 DNA损伤与突变损伤与突变9.2 点突变点突变9.3 插入和缺失插入和缺失9.4 大规模大规模

2、DNA变化变化9.5 DNA突变的后果突变的后果9.6 突变修复突变修复9.7 实验研究实验研究2/81Mutations and Mutation Repair突变与突变修复突变与突变修复Chemicals化学物质化学物质Radiation辐射辐射Transposons转座子转座子Replicationerrors复制错误复制错误3/819.1 DNA Damage and MutationsDNA损伤与突变损伤与突变A heritable change in DNA sequence is called a mutation.Most frequently,the word mutatio

3、n is applied to heritable alterations that affect the function of a gene.DNA序列中可遗传的序列中可遗传的改变称为改变称为突变突变。大多。大多数时候突变一词用来数时候突变一词用来指影响到基因功能的指影响到基因功能的可遗传改变可遗传改变。4/81Mutation can be favorable突变可以是有利的突变可以是有利的MUTAtiOn5/819.2 Point Mutations /点突变点突变Mutations affecting only one base pair are called point mutat

4、ions.Usually,point mutations involve substitution of one base with another base.If a pyrimidine is replaced with aother pyrimidine,or a purine by another purine it is called a transition.If a purine is replaced by a pyrimidine or vice-versa,it is called a transversion.只影响到一个碱基对的只影响到一个碱基对的突变叫做突变叫做点突变

5、点突变。通常，。通常，点突变涉及到一个碱基点突变涉及到一个碱基被另一个碱基替换。如被另一个碱基替换。如果一个嘧啶被另一个嘧果一个嘧啶被另一个嘧啶、或一个嘌呤被另一啶、或一个嘌呤被另一个嘌呤取代，这样的点个嘌呤取代，这样的点突变称为突变称为转换转换。如果一。如果一个嘌呤被一个嘧啶取代个嘌呤被一个嘧啶取代或反之，这样的点突变或反之，这样的点突变称为称为颠换颠换。6/81Transition vs.TransversionTCGATGGTTransition 转换转换Transversion 颠换颠换7/819.2.1 Mismatched Base /错配的碱基错配的碱基d8/81Mismatch

6、ed base Point mutation 9/819.2.2 Spontaneous Mutation /自发突变自发突变1.Deamination /脱氨基脱氨基2.Depurination /脱嘌呤脱嘌呤3.Tautomerization /互变异构化互变异构化10/811.Deamination /脱氨基脱氨基CUReplicationG C A TUU11/812.Depurination /脱嘌呤脱嘌呤AAATTTCCGGAAATTTCCGDepurinate(5000 nt)Repair(most)12/81Depurination /脱嘌呤脱嘌呤13/81Depurinati

7、on Mutation“How can I continue my work?”DNA polAAATCG G C C A A T T C C G G T-AT-A14/813.Tautomerization /互变异构互变异构化化15/81Tautomeric forms of the DNA bases16/819.2.3 Induced Mutations /诱发突变诱发突变1.Base Analogues /碱基类似物碱基类似物2.Alkylating Agents /烷化剂烷化剂3.Nitrous Acid /亚硝酸亚硝酸4.Ultraviolet Radiation /紫外辐射紫外

8、辐射17/811.Base Analogues /碱基类似物碱基类似物18/81BU*MutationA:TA:BUTautome-rizationA:BU*ReplicationG:BU*ReplicationA T G C19/812.Alkylating Agents /烷化剂烷化剂Another class of molecules with the ability to cause point mutations is alkylating agent.These compounds can add alkyl groups to other molecules,including

9、DNA bases.When aklylation changes base pairing properties,it will most likely lead to point mutations.能够引起点突变的另能够引起点突变的另一类分子是一类分子是烷化剂烷化剂。这些化合物能够将这些化合物能够将烷烷基基加到其它分子上，加到其它分子上，包括加到包括加到DNA的碱基的碱基上。如果烷化作用改上。如果烷化作用改变了碱基的配对性质，变了碱基的配对性质，它就很可能会导致点它就很可能会导致点突变。突变。20/81EMS:ethylmethane sulfonate乙基甲磺酸乙基甲磺酸G:CmG:C

10、EMSReplicationmG:TG C A T21/813.Nitrous Acid /亚硝酸亚硝酸Pickled food腌制食品腌制食品 Nitrous acid亚硝酸亚硝酸Cancer癌症癌症22/81Adenine Hypoxanthine腺嘌呤腺嘌呤 次黄嘌呤次黄嘌呤A:TH:THNO2ReplicationH:CA T G C23/81Cytosine Uracil胞嘧啶胞嘧啶 尿嘧啶尿嘧啶C:GU:GHNO2ReplicationU:AC G T A24/814.Ultraviolet Radiation /紫外辐射紫外辐射25/81Pyrimidine dimer /嘧啶二

11、聚体嘧啶二聚体26/81Cross-linking /交联交联 caused by mustard library.wustl.edu/./onlinedisplay/1910s.html 28/819.3 Insertions and Deletions插入和缺失插入和缺失9.3.1 Strand Slippage /链滑动链滑动9.3.2 Transposons /转座子转座子9.3.3 Intercalating Agents /嵌入剂嵌入剂29/819.3.1 Strand Slippage /链滑动链滑动30/81MSI:microsatellite instability微卫星不稳

12、定性微卫星不稳定性www.med.upenn.edu/./MDGF/technology.shtml?MDGF Hereditary Non-PolyposisColorectal Cancer,HNPCC遗传性非息肉型结肠癌遗传性非息肉型结肠癌31/819.3.2 Transposons /转座子转座子Insertions and deletions may also be caused by DNA elements called transposons.When a transposon relocates to another area of the genome it causes

13、an insertion.插入和缺失也可能由插入和缺失也可能由称为称为转座子转座子的的DNA元元件引起。件引起。当转座子再次定位到当转座子再次定位到基因组的另一个区域基因组的另一个区域时，它就会引起一个时，它就会引起一个插入突变插入突变。32/819.3.3 Intercalating Agents /嵌入剂嵌入剂A base pair33/81Intercalation Mutation34/819.4 Large-Scale DNA changes大规模大规模DNA变化变化Translocation /易位易位35/81Inversion /倒位倒位36/81Single-strand b

14、reak/单链断裂单链断裂Peroxides,Fe2+,Cu2+Ionizing radiationFree radicals37/81Double-strand break/双链断裂双链断裂Other breaks38/81Repair of Double strand breakmicrobiology.ucdavis.edu/heyerlab/Rooster.htm Extreme sensitivity to X-ray Moderate sensitivity to UV Hyper-sensitive tomethylmethane sulfonate Phenotypes cau

15、sed by a RAD54 deletion 39/819.5 Consequences of DNA MutationsDNA突变的后果突变的后果11.5.1 Consequences of Point Mutations 点突变的后果点突变的后果11.5.2 Consequences of Insertions and Deletions 插入和缺失的后果插入和缺失的后果11.5.3 Consequences of Translocations 易位的后果易位的后果40/819.5.1 Consequences of Point Mutations /点突变的后果点突变的后果1.Sile

16、nt mutation 沉默突变沉默突变2.Missense mutation 错义突变错义突变3.Nonsense mutation 无义突变无义突变41/811.Silent mutation /沉默突变沉默突变42/812.Missense mutation /错义突变错义突变43/81Leaky mutation /渗漏突变渗漏突变Normal redblood cellsSickle cells44/813.Nonsense mutation /无义突变无义突变45/819.5.2 Consequences of Insertions and Deletions插入和缺失的后果插入和

17、缺失的后果Reading frame:The organization of bases in a coding region into groups of three,marked at the beginning and end by start and stop codons.读码框读码框：编码区中碱基以三个一组形成的结构，以：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。起始密码子和终止密码子为开始和结束的标志。46/81“The cat ate its rat.”“The cat ate its rat.”“Txh eca tat eit sra t.

18、”hpcsc.appstate.edu/index.php?module= 47/81Frameshift mutation /移码突变移码突变48/819.5.3 Consequences of Translocations易易 位位 的的 后后 果果Chronic myelogenous leukemia慢性骨髓性白血病慢性骨髓性白血病 Burkitts lymphoma非洲淋巴瘤非洲淋巴瘤 49/81Chronic Myelogenous Leukemia慢性骨髓性白血病慢性骨髓性白血病 50/81What causes excess WBCs?51/81Burkitts lymphom

19、a /非洲淋巴瘤非洲淋巴瘤 www.gfmer.ch/./Maroua_case_presentation.htm 52/81What causes Burkitts lymphoma?53/81Function of gene c- Apoptosisbegins1234CelldividesCelldiesGene bci-2Gene c-MycChromosome54/81Now showingOverview of Eukaryotic Gene ExpressionFile:biophoto7 Genetics:A Conceptual Approach Overview of eu

20、karyotic gene expression(15)55/819.5.4 Mutation Hot Spots/突变热点突变热点前方前方500500米米事故事故多发多发地段地段56/81Mutation Hot Spots/突变热点突变热点57/819.6 Mutation Repair /突变修复突变修复58/81Mutation Repair /突变修复突变修复59/819.6.1 Direct Reversal /直接回复直接回复UV lightVisible lightPhotolyaseT C A T T G C CA G T A A C G G.光光复活主要是原核生物中的一种修

21、复方式。复活主要是原核生物中的一种修复方式。（遗传学遗传学教材第教材第451页）页）60/819.6.2 Mismatch Repair/错配修复错配修复61/81MMR:Mismatch Repair(1/2)62/81MMR:Mismatch Repair(2/2)63/8111.6.3 Nucleotide Excision Repair核苷酸切除修复核苷酸切除修复64/81NER:Nucleotide Excision Repair(1/2)65/81NER:Nucleotide Excision Repair(2/2)66/81MMR vs.NERMMR Mismatch NER D

22、amaged bases67/819.6.4 Base Excision Repair碱基切除修复碱基切除修复Damage to C(e.g.deamination)68/81BER:Base Excision Repair(1/2)69/81BER:Base Excision Repair(2/2)70/819.6.5 Double-Stranded Break Repair双链断裂修复双链断裂修复Extreme sensitivity to X-ray Moderate sensitivity to UV 71/81NHEJ:non-homologous end joining(1/3)7

23、2/81NHEJ:non-homologous end joining(2/3)73/81NHEJ:non-homologous end joining(3/3)74/81Homologous recombination同同 源源 重重 组组 75/819.7 Experiments /实验研究实验研究11.7.1 Nucleotide Excision Repair and Human Disease 核苷酸切除修复与人类疾病核苷酸切除修复与人类疾病11.7.2 The Ames Test 埃姆斯测验法埃姆斯测验法76/819.7.1 Nucleotide Excision Repair a

24、nd Human Disease核苷酸切除修复与人类疾病核苷酸切除修复与人类疾病www.skina.org/./imagepages/image161.htm77/81Xeroderma pigmentosum/着色性干皮病着色性干皮病In mammalian cells,excision repair involves many more enzymes.At least a dozen different genes are involved in recognizing and excising the damaged DNA segment.Individuals who suffer

25、 from XP are extremely sensitive to sunlight.www.skina.org/./imagepages/image161.htmwww.eprints-scd-ulp.u-strasbg.fr:8080/archive/000.78/819.7.2 The Ames Test /埃姆斯测验法埃姆斯测验法79/81The Ames Test for bacteria80/81The Ames Test for mammalsChemical ANoxioussubstancesLiverNontoxicsubstancesChemical A81/81The Ames Test for mammals