(医学遗传学)02基因突变

微测验No.1

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“消息发布”栏目微测验输入密码并开始测验,5min后关闭密码:237803基因突变

GeneMutationGeneMutation

Mutationsareheritablechangesingeneticmaterial.

ChangeingenescausedbychangeinstructureoftheDNA.Base(s)inDNAis(are)changedtoother(s),orabase(s)is(are)addedorremoved.Rearrangementsofthechromosomesoccurandarealsoconsidered.多向性重复性随机性稀有性可逆性forwardmutation,reversemutation有害性1.MutagensorMutagenicAgents

Mutationscanoccurataspontaneousrate(spontaneousmutation),orafargreaterratewhenthereisexposuretomutagenicagents(inducedmutation).

Thesearesubstances,conditionsandformsthatsignificantlyincreasethefrequencyofmutations.Mutagens

Exposuretotoohighalevelofmutagenscanthreatenthesurvivalofaspecies;e.g.,frogspeciesinthestatesofWashingtonandOregonarefacingextinction.Thisappearstobecausedbyreducedatmosphericozone,andtheresultingincreasedlevelofultravioletradiation.AformsofenergyExamplesofaformsofenergyareultravioletlight,x-rays,cosmicenergy,gammaradiation,alphaparticles,betaparticlesandneutrons.Ultraviolet(UV)lightUVlighthasshorterwavelengthsthanvisiblelight.Thoughthesewavesareinvisibletothehumaneye,someinsects,likebumblebees,canseethem!Scientistshavedividedtheultravioletpartofthespectrumintothreeregions:thenearultraviolet,thefarultraviolet,andtheextremeultraviolet.Thethreeregionsaredistinguishedbyhowenergetictheultravioletradiationis,andbythe"wavelength"oftheultravioletlight,whichisrelatedtoenergy.UVAUVBUVC

Thenearultraviolet,abbreviatedNUV,isthelightclosesttoopticalorvisiblelight.Theextremeultraviolet,abbreviatedEUV,istheultravioletlightclosesttoX-rays,andisthemostenergeticofthethreetypes.Thefarultraviolet,abbreviatedFUV,liesbetweenthenearandextremeultravioletregions.

UltravioletRadiationcausespyrimidine

dimers(嘧啶二聚体).ThesecanblockDNAreplication.Also,dimersinterferewithbasepairingbetweenthetwoDNApolymeres.U.V.lightalsogeneratesfree-radicals,whichcreateotherkindsofgeneticdamage.Radiation（GammaandX-Rays）ThesecanactdirectlyonDNA;also，damageiscausedindirectlywhenmoleculesaroundtheDNAsuchaswater,areionized,creatingfree-radicals,substanceswithunpairedelectrons.BChemicalAgentsExamplesofsubstancesthataremutagensare：nitrousacid（亚硝酸）

hydroxylamine（羟胺）

Alkylatingagents(烷化基)5-bromouracil（5-溴尿嘧啶，5-BU）benzo(a)pyreneacridinedyes（吖啶）

Hydroxylatingagents(hydroxylamine，HA)（羟胺）

Nitrousacidisadeaminatingagent.（亚硝酸）

图中A被其脱去氨基后可变成次黄嘌呤（H），H不能再与T配对，而变为与C配对，经DNA复制后，可形成T-A→C-G的转换。Alkylatingagents

(烷化基)

Alkylatingagentsarechemicalsthatdonatealklygroupstoothermolecules.Ethylmethanesulfonate(EMS,甲烷磺酸乙酯)methylaldehyde（甲醛）Caryolysine（氮芥）

G－C------T-ABaseanalogs

BaseanalogsaresimilartotheactualcorrectbaseandsogetincorporatedintotheDNAaswoulditsnaturalcounterpart.Theproblemisthat,iftheyaremorepronetotautomericshiftsthanthenaturalbase,thefrequencyformutationgoesup,substantially.Thecompound5-bromouracilisanexampleofananalogtothymine.Itundergoesatautomericshifttobasepairwithguanineinsteadofadenine,causingatransition.5-BU引起的DNA碱基对的改变5-BU与腺嘌呤（A）和鸟嘌呤（G）均可配对。如果5-BU取代T以后一直保持与A配对，所产生的影响并不大；若与G配对，经一次复制后，就可以使原来的A-T对变换成G-C对。N-二甲基亚硝胺Viruses、Eumycete、Bacteria

Viruses

thatcanintegrateintothegenomearealsomutagenicagents

fungallycontaminatedpeanutsorpeanutbutter,andmany,manymore2.MechanismofMutationStaticmutationDynamicmutationStaticmutationMicroalterationsMacroalterations

Microalterations

involvesinglebasepair.PointmutationbasesubstitutionTransitions（转换）:Purinechangestoanalternatepurine;pyrimidinechangestoanalternatepyrimidine.Transversions(颠换):Apositionwithapyrimidinechangestohaveapurine;or,purinetopyrimidineTransitionsoccurmorecommonlythantransversionseventhoughmoretheoreticalcombinationsoftransversionsarepossible.

Forexample,theonlypossibletransitionforthebaseAistochangetothebaseG.TwotransversionsarepossibleforthebaseA:CandT.

FrameshiftmutationFrameshiftmutationsaretheresultofasinglebase,ormore,insertionordeletion.

Macroalterationsarelargechanges,suchasduplications,deletions,inversionsorrearrangementsofalargenumberofbases.DynamicmutationTheterm‘dynamicmutation’wasintroducedtodistinguishtheuniquepropertiesofexpanding,unstableDNArepeatsequencesfromotherformsofmutation.Trinucleotide

repreatexpansionThepastdecadehasseendynamicmutationsuncoveredasthemolecularbasisforagrowingnumberofhumangeneticdiseasesandforallofthecharacterized‘rare’chromosomalfragilesites.串联重复的三核苷酸序列随着世代传递而拷贝数逐代累加的突变方式。

疾病遗传方式染色体定位重复定位重复类型正常范围异常范围父母来源蛋白突变效应HDAD4p16.3编码区CAG6-3536-121父>母huntingin囊泡转运，细胞骨架DRPLAAD12p13.31编码区CAG7-2549-88父>母Atrophin-1神经元毒性SBMAXXq11-q12编码区CAG11-3440-72父>母雄激素受体运动神经元毒性SCA1AD6p23编码区CAG6-3941-81父>母ataxin-1降解成分在核内聚集SCA2AD12q24.1编码区CAG15-2935-59父=母ataxin-2不明MJDAD14q24.3-q31编码区CAG16-3668-82父=母ataxin-3不明SCA6AD19p13编码区CAG4-1721-30父>母钙通道不明SCA7AD3p21.1-p12编码区CAG7-3538-200父>母ataxin-7不明PMED19p13.1-p12编码区CAC56-7OMD14q11.2-q13编码区GCG67-13CCD6p21编码区GCGGCTGCA1727syn编码区GCGGCTGCA1522-25Microalterationssamesensemutation

3.Resultofmutationmissensemutation

Whenasinglebasepaircausesthesubstitutionofoneaminoacidforanother,itiscalledamissensemutation.Non-sensemutationTerminatorcodonmutation错义突变引发疾病——镰刀状红细胞贫血nonsensemutation

Whenasinglebasepairchange,deletionorinsertionresultinthegenerationofaprematuretranslationterminationbecauseofthegenerationofanewstopcodon,thisiscalledanonsensemutation.terminatorcodonmutationMicroalterations/MacroalterationsFrameshiftmutationsTheresultcanbethegenerationofanentirelydifferentproteinfromthepointwithinthecodingregionwhereitoccurs.Becausetheymayinvolvemanybasesorjustone,frameshiftsaresometimesmacroalterationsandsometimesmicroalterations.Trinucleotide

repreatexpansiondiseases,TREDs例如：脆性X综合症

Xq27.3内（CGG）n重复数：60-200，正常：6-60脆性X综合症患者：智能低下，皮肤松弛，关节过度伸展，长脸。例如：Huntington舞蹈病4p16.3CAG36～121正常6～354.RepairofMutationTherearemanydifferentrepairssystemsusedbyorganisms.photoreactivationrepair

Base-excisionrepairRecombinationrepair

photoreactivationrepair

photoreactivationrepairofpyrimidine

dimersisthesimplestsystemtounderstand,andisquiteinteresting.An

enzyme,photolyase,sitsontopofthedimer,thenusingawavelengthoflightlongerthanU.V.asasourceofenergy,itbreak