1、Chapter 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DNA变
2、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Mutations 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9.1 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 mutation is applied
3、 to heritable alterations that affect the function of a gene.DNA序列中可遗传序列中可遗传的改变称为的改变称为突变突变。大。大多数时候突变一词用多数时候突变一词用来指影响到基因功能来指影响到基因功能的的可遗传改变可遗传改变。Mutation can be favorable突变可以是有利的突变可以是有利的MUTAtiOn9.2 Point Mutations /点突变点突变Mutations affecting only one base pair are called point mutations.Usually,point m
4、utations 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点突变。通常，。通常，点突变涉及到一个碱
5、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。Transition vs.TransversionTCGATGGTTransition 转换转换Transversion 颠换颠换9.2.1 Mismatched Base /错配的碱基错配的碱基dMismatched base Point mutation 9.2.2 Spo
6、ntaneous 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1.Deamination /脱氨基脱氨基CUReplicationG C A TUU2.Depurination /脱嘌呤脱嘌呤AAATTTCCGGAAATTTCCGDepurinate(5000 nt)Repair(most)Depurination /脱嘌呤脱嘌呤Depurination Mutation“How can I continue my work?”DNA polAAATCG G
7、C C A A T T C C G G T-AT-A3.Tautomerization /互变异构化互变异构化Tautomeric forms of the DNA bases9.2.3 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 /紫外辐射紫外辐射1.Base Analogues /碱基类似物碱基类似物BU*MutationA:TA:BUTautome-rizationA:BU*Re
8、plicationG:BU*ReplicationA T G C2.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 DNA bases.When aklylation changes base pairing properties,it will most likely lead to
9、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的碱的碱基上。如果烷化作用基上。如果烷化作用改变了碱基的配对性改变了碱基的配对性质，它就很可能会导质，它就很可能会导致点突变。致点突变。EMS:ethylmethane sulfonate乙基甲磺酸乙基甲磺酸G:CmG:CEMSReplicationmG:TG C A T3.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Cance
10、r癌症癌症Adenine Hypoxanthine腺嘌呤腺嘌呤 次黄嘌呤次黄嘌呤A:TH:THNO2ReplicationH:CA T G CCytosine Uracil胞嘧啶胞嘧啶 尿嘧啶尿嘧啶C:GU:GHNO2ReplicationU:AC G T A4.Ultraviolet Radiation /紫外辐射紫外辐射Pyrimidine dimer /嘧啶二聚体嘧啶二聚体Cross-linking /交联交联 caused by mustard library.wustl.edu/./onlinedisplay/1910s.html 9.3 Insertions and Deletio
11、ns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9.3.1 Strand Slippage /链滑动链滑动MSI:microsatellite instability微卫星不稳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9.3.2 Transpo
12、sons /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 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元件引起。元件引起。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。9.3.3 Intercalating Ag
13、ents /嵌入剂嵌入剂A base pairIntercalation Mutation9.4 Large-Scale DNA changes大规模大规模DNA变化变化Translocation /易位易位Inversion /倒位倒位Single-strand break/单链断裂单链断裂Peroxides,Fe2+,Cu2+Ionizing radiationFree radicalsDouble-strand break/双链断裂双链断裂Other breaksRepair of Double strand breakmicrobiology.ucdavis.edu/heyerlab/
14、Rooster.htm Extreme sensitivity to X-ray Moderate sensitivity to UV Hyper-sensitive tomethylmethane sulfonate Phenotypes caused by a RAD54 deletion 9.5 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
15、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9.5.1 Consequences of Point Mutations /点突变的后果点突变的后果1.Silent 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1.Silent mutation /沉默突变沉默突变2.Missense mutation /错义突变错义突变Leaky mutation /渗漏突变渗漏突变Normal redblood cellsSickle ce
16、lls3.Nonsense mutation /无义突变无义突变9.5.2 Consequences of Insertions and Deletions插入和缺失的后果插入和缺失的后果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
17、子和终止密码子为开始和结束的标志。“The cat ate its rat.”“The cat ate its rat.”“Txh eca tat eit sra t.”hpcsc.appstate.edu/index.php?module= Frameshift mutation /移码突变移码突变9.5.3 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 Chronic Myelogenous Leukem
18、ia慢性骨髓性白血病慢性骨髓性白血病 What causes excess WBCs?Burkitts lymphoma /非洲淋巴瘤非洲淋巴瘤 www.gfmer.ch/./Maroua_case_presentation.htm What causes Burkitts lymphoma?Function of gene c- Apoptosisbegins1234CelldividesCelldiesGene bci-2Gene c-MycChromosomeNow showingOverview of Eukaryotic Gene ExpressionFile:biophoto7 G
19、enetics:A Conceptual Approach Overview of eukaryotic gene expression(15)9.5.4 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Mutation Hot Spots/突变热点突变热点9.6 Mutation Repair /突变修复突变修复Mutation Repair /突变修复突变修复9.6.1 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
20、 G.光复活主要是原核生物中的一种修复方式。光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）9.6.2 Mismatch Repair/错配修复错配修复MMR:Mismatch Repair(1/2)MMR:Mismatch Repair(2/2)11.6.3 Nucleotide Excision Repair核苷酸切除修复核苷酸切除修复NER:Nucleotide Excision Repair(1/2)NER:Nucleotide Excision Repair(2/2)MMR vs.NERMMR Mismatch NER Damaged bases9.6.
21、4 Base Excision Repair碱基切除修复碱基切除修复Damage to C(e.g.deamination)BER:Base Excision Repair(1/2)BER:Base Excision Repair(2/2)9.6.5 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 NHEJ:non-homologous end joining(1/3)NHEJ:non-homologous end joining(2/3)NHEJ:n
22、on-homologous end joining(3/3)Homologous recombination同同 源源 重重 组组 9.7 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9.7.1 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www.skina.org/./imagepages
23、/image161.htmXeroderma 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 from XP are extremely sensitive to sunlight.www.skina.org/./imagepages/image161.htmwww.eprints-scd-ulp.u-strasbg.fr:8080/archive/000.9.7.2 The Ames Test /埃姆斯测验法埃姆斯测验法The Ames Test for bacteriaThe Ames Test for mammalsChemical ANoxioussubstancesLiverNontoxicsubstancesChemical AThe Ames Test for mammals
