吉林大学遗传学第十三章 基因突变

第十三章基因突变GenicMutationClassificationofMutationsSpontaneous自发VersusInduced诱发MutationsGametic配子VersusSomatic体细胞MutationsOtherCategoriesofMutationGameticVersusSomaticMutationsAutosomal常染色体dominant显性mutationsAutosomalrecessive隐性mutationsX-linkedrecessivemutationsOtherCategoriesofMutationmorphologicaltrait形态学特征Nutritional营养orbiochemicalvariationsregulatorymutations调节基因突变lethalmutations致死突变conditionalmutations条件突变(temperature-sensitivemutations)reversemutation回复突变MutationRateTherateisexceedinglylowforallorganisms生物studied;2.Therateisseentovaryconsiderablyindifferentorganisms;3.Evenwithinthesamespecies,thespontaneousmutationratevariesfromgenetogene.SpontaneousMutationRate10–8virus,bacteria,Neurospora脉孢菌10–6–10–5maize玉米,Drosophila果蝇10–5–10–4MouseInterpretationofLuria-DelbruckfluctuationexperimentandreplicaplatingBacterialresistancearisesfrommutationsthatexistbeforeexposuretoagentThebacteriocidebecomesaselectiveagentkillingthenonresistantcells,allowingonlythepreexistingresistantcellstosurvive.MutationsdonotariseinparticulargenesasadirectresponsetoenvironmentMutationsoccurrandomlyatanytimeReplicaplating平板影印试验verifiespreexistingmutationsFig.7.5bAuxotroph(营养缺陷型):NeedssupplementtogrowonminimalmediaPrototroph(原养型):Wild-typethatneedsnosupplement;cansynthesizeallrequiredgrowthfactorsMutagenesisandIsolationofmutantsConidia无性孢子Ascospore囊孢子Ascus子囊AmesTestforMutagenicity测试用菌种:鼠伤寒沙门氏菌(Salmonellatyphimurium)组氨酸和生物素缺陷的突变株(His-,bio-,

uvrB,rfa)His-(组氨酸缺陷突变型)Rfa(细菌荚膜脂多糖屏障缺陷突变)uvrB(DNA切除修复系统缺陷突变)Apr(抗氨苄青霉素因子)S-9溶液(诱导大鼠肝脏酶系活性)TheAmestestforcarcinogensusinghis-mutantsofSalmonellatyphimuriumWhyareenzymesadded?检测突变在分子水平上的机制(1)检测诱发碱基置换诱变剂的菌株:TA1535,TA100；(2)检测诱发移码突变诱变剂的菌株:TA1537,TA1538,TA98。airandwaterpollutionfoodpreservation防腐剂andadditives添加剂artificialsweeteners人造甜味剂herbicides(除草剂)pesticides（杀虫剂）pharmaceuticalproducts医药品四、DNA分子水平上突变的分类1、碱基替换：嘌呤替换嘌呤或嘧啶替换嘧啶（转换）；嘌呤与嘧啶互换（颠换）2、缺失3、插入4、倒位5、易位碱基的变化酮式烯醇式氨基式亚氨基式氨基式亚氨基式酮式烯醇式亚氨基式氨基式酮式烯醇式酮式5-溴尿嘧啶烯醇式5-溴尿嘧啶次黄嘌呤胞嘧啶经氧化脱氨后形成尿嘧啶和腺嘌呤配对黄嘌呤EMS(甲基磺酸乙酯)6、DNA插入剂原黄素（proflavin）

吖啶橙（acridineorange）溴化3,8-二氨基-5-乙基-6-苯基菲啶鎓（etnidiumbramide）插入模板链（增加），插入新生成链（减少）——移码突变7、点突变的类型无义突变错义突变移码突变同义突变（沉默突变）无义突变错义突变移码突变同义突变五、突变的物理因素紫外线照射诱发形成胸腺嘧啶二聚体X－射线致突变率伦琴CounteractingDNADamage:RepairSystem1、直接修复——光复活反应PhotoreactivationRepair:photoreactivationenzyme(PRE)ReversalofUVDamageinProkaryotesthyminedimer(TT)TT光裂合酶TTdimersformundertheinfluenceofUltravioletradiation紫外线照射.TTdimersmayberepairedbytwomechanisms.InPhotoreactivationrepair,thePREenzymeunderbluelightspontaneouslybreaksthedimer,restoringthenormalbasepairing.2、切除修复——一般切除修复和特殊切除修复InExcisionRepair,theuvrsystemexcisesthedimer,andthegapisfilledinbytheproof-readingactivityofDNAPolI.着色性干皮病——切除修复酶缺陷UvrABC修复系统：UvrAUvrBUvrC特殊切除修复DNA糖基化酶：不能切断磷酸二酯键，能切断N-糖苷键损伤切断糖基酶修复途径AP核酸内切酶活性3、复制后修复七、回复突变

正向突变野生型突变型

回复突变抑制突变：通过其他位点的突变减弱突变作用UAG：琥珀型密码子UGA：蛋白石（乳石）型密码子UAA：赭石型密码子基因无义抑制突变NonsensesuppressortRNAs——无义抑制tRNAs囊性纤维化-CFTR一种常见的隐性遗传疾病，主要临床症状是因为长期反复的肺部感染所导致的呼吸困难，导致逐渐的行动困难以及提早死亡。在欧美白人中最常见，25人中有1人为携带者，其他人种则极少见。发病率：欧美白人1/3300,亚裔1/32000，非裔1/15000。囊性纤维化是因为囊性纤维化跨膜转导调节因子（CFTR）的突变所造成的（Del508F），这个基因负责制造汗液、消化液以及各种黏液。非小细胞肺癌-EGFR易瑞沙Gefitinib特罗凯ErlotinibEGFR（epidermal

growth

factor

receptor）：表皮生长因子受体

Exon18：

G719S/A/CExon19:DelE746-A750Exon21:L858RK-Ras:Exon2的12号和13号密码子及Exon3的61号密码子mutation耐药突变Exon20:T790M乳腺癌/卵巢癌-BRCABRCA1/2:breastcancer1/2BRCA1突变携带者在一生中的乳腺癌发病风险高达70%，卵巢癌发病风险达40%；BRCA2突变携带者，相应发病