醫(yī)學(xué)遺傳學(xué)課件

遺傳一、緒論Epigenetics表觀遺傳學(xué)DNA序列未改變而基因表達(dá)被影響。RegulationofgeneexpressionwithoutchangesinDNAsequencesGeneticdisorders遺傳病由遺傳因素(基因或染色體)造成的疾病。Thediseasesarecausedbygeneticfactor,(genesorchromosomes)Single-geneDisorders單基因病由單個基因突變導(dǎo)致的疾病。Single-gene(ormonogenic)disordersresultfromthemutationofgene.Chromosomaldisorders染色體病由染色體異常引起的疾病。DiseasescausedbychromosomalabnormalitiesSomaticCellGeneticDisorders體細(xì)胞遺傳病體細(xì)胞中的遺傳物質(zhì)改變的結(jié)果，如腫瘤和先天性畸形。Resultfromthealteredgeneticmaterialsinsomaticcells.Tumor&congenitalmalformationsynapsis聯(lián)會偶線期同源染色體緊密配對。homologouschromosomespaircloselyalongtheirentirelengthatzygoteneKaryotype核型一個體細(xì)胞中所有染色體，按照大小、形態(tài)特征順序排列所構(gòu)成的圖像。Thekaryotypeisaphotographofallofthechromosomesofanindividualcell;thetermcoversthenumber;relativesizesandstructureofthechromosomes.Gene基因遺傳的結(jié)構(gòu)單位，合成功能產(chǎn)物所必需的的DNA或RNA序列。Astructuralunitofinheritance.AsequenceofDNA(orRNA)thatisrequiredforproductionofafunctionalproduct.Splitgene斷裂基因在大多數(shù)真核細(xì)胞的基因組中，基因既包括編碼區(qū)(外顯子)、其中又插入了非編碼區(qū)(內(nèi)含子)。艮［I基因是不連續(xù)的。Inmosteukaryoticgenome,genescontainingcodingregions(exons)thatareinterruptedbynoncodingregions(introns).GeneFamily基因家族許多基因?qū)儆诨蚣易?，它們有著密切相關(guān)的DNA序列并且編碼相關(guān)的氨基酸序列的多肽。Manygenebelongtogenefamilies,whichsharecloselyrelatedDNAsequencesandencodepolypeptideswithcloselyrelatedaminoacidsequences.Pseudogene假基因與已知基因十分相像但沒有功能的DNA序列稱為假基因。DNAsequencesthatcloselyresembleknowngenesbutarenonfunctionalarecalledpseudogene.二、細(xì)胞遺傳學(xué)Post-translationalmodifications轉(zhuǎn)錄后修飾肽鏈從核蛋白體釋放后，經(jīng)過細(xì)胞內(nèi)各種修飾處理成為有活性的成熟蛋白質(zhì)的過程.RepetitiveDNAFamilies多拷貝基因家族在基因組中出現(xiàn)次數(shù)多，達(dá)到成百上千次的拷貝數(shù)多的基因，可維持染色體結(jié)構(gòu)。Hundredstomillionsoftimesinthegenome,MaintainchromosomestructureTrisomy三體性三體細(xì)胞中含有一條多余的染色體，意即細(xì)胞中某一染色體含3個拷貝、而其余染色體含兩個拷貝。atrisomiccellinvolvesasingleextrachromosome;thatis,thecellhasthreecopiesofaparticularchromosomesandtwocopiesofotherchromosomes.Atrisomiccellis2n+lMonosomy單體性單體細(xì)胞是丟失了一條染色體的細(xì)胞。amonosomiccellinvolvesalossofasinglechromosome;thatis,thecellis2n-l.Definition缺失一種染色體部分丟失的染色體突變。isachromosomalmutationinwhichpartofachromosomeismissingDuplication重復(fù)染色體中某一片斷出現(xiàn)兩次所導(dǎo)致的染色體異常。isachromosomalmutationthatresultsinthedoublingofasegmentofachromosome.RingChromosomes環(huán)狀染色體長短臂同時發(fā)生斷裂，殘留的兩個斷短重接形成環(huán)狀染色體。deletionssometimesoccuratbothtipsofachromosome.Theremainingchromosomeendscanthenfuse,formingaringchromosome.Isochromosomes等臂染色體染色體一條臂丟失，另一條臂重復(fù)出現(xiàn)并形成鏡像對稱的連接。isachromosomeinwhichonearmismissingandtheotherduplicatedinamirror-imagefashion.DicentricChromosomes雙著絲粒染色體兩條染色體不含著絲粒部分丟失，兩個含有著絲粒的斷端相接。adicentricisararetypeofabnormalchromosomeinwhichtwochromosomesegments(fromdifferentchromosomesorfromthetwochromatidsofasingleone),eachwithacentromere,fuseendtoend,withlossoftheiracentricfragments.Inversions倒位染色體發(fā)生兩次斷裂，兩斷點間片段旋轉(zhuǎn)180°后重接。occurswhenasinglechromosomeundergoestwobreaksandisreconstitutedwiththesegmentbetweenthebreaksinverted.Translocations易位兩個染色體間的片段交換，通常是非姐妹染色單體間。involvestheexchangeofchromosomesegmentsbetweentwo,usuallynonhomologouschromosomesReciprocalTranslocations相互易位非同源染色體發(fā)生斷裂，斷端相互交換。thistypeofrearrangementresultsfrombreakageofnonhomologouschromosomes,withreciprocalexchangeofthebroken-offsegments.RobertsonianTranslocations羅伯遜易位又稱著絲粒融合。在著絲粒部位或著絲粒附近部位發(fā)生斷裂后，兩者的長臂在兩條近端著絲粒染色體著絲粒處結(jié)合在一起，形成一條由長臂構(gòu)成的衍生染色體，兩個短臂則構(gòu)成一個小染色體，小染色體往往在第二次細(xì)胞分裂時丟失，這可能是由于缺乏著絲?；蚱渫耆僧惾旧|(zhì)構(gòu)成所致。thistypeofrearrangementinvolvestwoacrocentricchromosomesthatfusenearthecentromereregionwithlossoftheshortarmsInsertions插入兩條非同源染色體同時斷裂、其中一條插入到另一條的非末端部位。aninsertionisanonreciprocaltypeoftranslocationthatoccurswhenasegmentremovedfromonechromosomeisinsertedintoadifferentchromosome,eitherinitsusualorientationorinverted.Mosaicism嵌合體一個個體有兩個或以上的不同的染色體組。twoormoredifferentchromosomecomplementsarepresentinanindividual,thissituationiscalledmosaicism三、臨床細(xì)胞遺傳學(xué)Trisomy21Syndrome21三體綜合征完全或部分21號染色體三體，俗稱唐氏綜合征。Asyndromeresultsfromcompleteorpartialtrisomy21chromosome,knownasDownsyndrome四、單基因病Pedigree系譜用標(biāo)準(zhǔn)符號代表個體性狀，根據(jù)親緣關(guān)系繪成圖譜。Agraphicalrepresentationofafamilytree,usingstandardsymbolsfordocumentingbiologicalrelationshipsinfamiliesandthepresenceoftraitsorband,orindexcase先證者、索引病例在遺傳病家族中第一例引起注意的成員。Thememberthroughwhomafamilywithageneticdisorderisfirstbroughttoattentiongenelocus基因座基因在染色體上的特定位點。allele等位基因同源染色體上相同位點的一對基因。phenotype表型特定性狀所表現(xiàn)出的類型。GeneticImprinting遺傳印記一個個體同源染色體因分別來自其父方或母方而表現(xiàn)出功能上的差異，當(dāng)它們其一發(fā)生改變時，所形成的表現(xiàn)型也有所不同，即不同性別雙親遺傳給后代的情況不同。Carrier攜帶者AaCriss-crossinheritance交叉遺傳expressivity表現(xiàn)度基因在個體中的表現(xiàn)程度，或者說具有同一基因型的不同個體或同一個體的不同部位，由于各自遺傳背景不同，所表現(xiàn)的程度可能有顯著差異。pleiotropy多效性一個基因可以決定或影響多個性狀，一個基因的改變直接影響其它生化過程的正常進(jìn)行，從而引起其它性狀的改變。遺傳異質(zhì)性一個性狀可以由多個不同的基因控制sex-conditionedinheritance從性遺傳位于常染色體上的基因由于性別的差異而顯示出男女性分布比例上的差異或基因表達(dá)程度上的差異sex-limitedinheritance限性遺傳常染色體上的基因，由于基因表達(dá)的性別限制，只在一種性別表達(dá)，而在另一種性別則完全不能表達(dá)anticipation早現(xiàn)一些遺傳病在連續(xù)幾代的遺傳中，發(fā)病年齡提前并且病情嚴(yán)重程度增加五、復(fù)雜遺傳病QuantitativeTrait數(shù)量性狀Susceptibility易感性由遺傳因素決定的患病風(fēng)險，僅代表個體所含有的遺傳因素。Characterizethegeneticfactorsthataffecttheprobabilityofmultifactorialdisorder.Liability易患性包含遺傳因素以及環(huán)境因素決定的患病風(fēng)險。Beameasureofallofthefactorsthataffecttheprobabilityofmultifactorialdisorder,bothgeneticandenvironmental.Threshold閾值個體易患性高達(dá)一定限度后會得病，閾值是由易患性導(dǎo)致的多基因遺傳病的發(fā)病限度。Heritability遺傳率統(tǒng)計定義：遺傳方差在表型方差中占的比例。普通定義：在復(fù)雜性疾病中遺傳因素所起的作用的大小。StatisticalDefinition:Theproportionofphenotypicvarianceattributabletoadditivegeneticvariance.CommonDefinition:Theextenttowhichgeneticindividualdifferencescontributetoindividualdifferencesinphenotypicindividualdifferences.六、分子病原理Gene基因遺傳的基本單位，編碼的功能產(chǎn)物通常為蛋白質(zhì)、罕有未翻譯RNA的DNA序列。Thebasichereditaryunit,aDNAsequencerequiredforproductionofafunctionalproduct,usuallyaprotein,butrarely,anuntranslatedRNA.Genemutation基因突變DNA序列中堿基序列的改變或DNA序列的改變，通常賦予一個有害的效應(yīng)°AchangeinbasessequenceororganizationofDNA,usuallyconferringadeleteriouseffect.Moleculardisease分子病由基因突變引起的蛋白異常造成的疾病。Thediseasesiscausedbygenemutationwhichleadtoproteinvariants.Abnormalhemoglobin.Sicklecellhemoglobin(HbS)鐮刀形紅細(xì)胞貧血癥因為一個核甘酸的替換使編碼B鏈的第六個氨基酸由谷氨酸轉(zhuǎn)變?yōu)榫Y氨酸。ItisduetoasinglenucleotidesubstitutionthatchangesthecodonofthesixthaminoacidofBglobinfromglutamicacidtovalineThalassemia地中海貧血由珠蛋白鏈合成的不平衡導(dǎo)致，基因突變使。或B珠蛋白鏈合成減少或降低其穩(wěn)定性，分別導(dǎo)致。和B地中海貧血。AnImbalanceofGlobin-Chainsynthesis.Themutationsreducethesynthesisorstabilityofeitherthea-or3-globinchain,tocausea-orB?thalassemia,respectively.Hereditaryenzymopathy(Enzymopathy)遺傳性酶變由于基因突變引起的先天性酶代謝紊亂，常染色體隱性遺傳。Theinbornerrorsofmetabolismiscausedbygenemutationwhichleadtoenzymeproteinvariants,AROPhenylketonuria(PKU)苯丙酮尿癥苯丙氨酸羥化酶基因異常。臨床癥狀：弱智、尿臭、白化。AnimportantcauseofmentalretardationzPKUiscausedbydefectivefunctionofthephenylalaninehydroxylase(PAH)gene.Pharmacogenetics遺傳藥理學(xué)生化遺傳學(xué)的一個特殊領(lǐng)域，研究由于遺傳變異引起的對藥物反應(yīng)的變異性。Thespecialareaofbiochemicalgeneticsthatdealswiththevariabilityinresponsetodrugsthatisduetogeneticvariation.七、基因多態(tài)性與突變Mutation突變核昔酸序列或DNA分子序列的改變。isdefinedasanychangesinthenucleotidesequenceorarrangementofDNAMissensemutations錯義突變DNA堿基序列中的單核甘酸突變可導(dǎo)致密碼子改變引起氨基酸變化。在致病突變中占50%oasinglenucleotidesubstitutioninaDNAsequencecanalterthecodeinatripletofbasesandcausethereplacementofoneaminoacidbyanotherinthegeneproduct.Accountforalmost50percentofalldisease-causingmutations(p-thalassemia)Nonsensemutations無義突變突變?yōu)榻K止子可造成轉(zhuǎn)錄過早終止。amutationthatgeneratesaterminationcondoncancauseprematurecessationoftranslation.Accountforapproximately12percentofalldisease-causingmutationsRNASplicingMutationsRNA剪接突變1、在受體或供體的突變干擾正常的RNA剪接、2、在RNA加工過程中產(chǎn)生競爭性的受體或供體結(jié)合位點。1.Mutationsateitherthedonor(exon-intron)oraccepter(intron-exon)siteinterferewithnormalRNAsplicing. 2.CreatealternativedonororacceptorsitesthatcompetewiththenormalsiteduringRNAprocessing.Accountforapproximately10percentofalldisease-causingmutationsTransition轉(zhuǎn)換嚓吟間或者嗑咤間的替換。thesubstitutionofonepurinefortheother(A?G)oronepyrimidinefortheother(T?C).Transvertion顛換喋吟與喀咤間的相互轉(zhuǎn)換。thereplacementofapurineforapyrimidine.Frameshiftmutations移碼突變當(dāng)編碼序列的堿基數(shù)量不是3的倍數(shù)時、在缺失和插入的地方閱讀框架會被改變。whenthenumberofbasesinvolvedisnotamultipleofthree,andwhenitoccursinacodingsequence,thereadingframeisalteredbeginningatthepointofthedeletionandinsertion.Smalldeletionsandinsertionsconstitutenearly%ofalldisease-causingmutationsDynamicMutations動態(tài)突變涉及三核甘酸重復(fù)序列擴(kuò)增的突變，不能以孟德爾遺傳規(guī)律作解釋。mutationsindisordersinvolvingamplificationoftrinucleotiderepeatsequences.NonmendelianinheritanceGeneticpolymorphism遺傳多態(tài)性若某種變異體相對常見，在總?cè)丝诘乃腥旧w的發(fā)生率超1%,稱為遺傳多態(tài)性。Theallelesarefoundinmorethan1%ofchromosomesinthegeneralpopulation.Rarevariants:<1%ofchromosomesofthegeneralpopulationRFLP(RestrictionFragmentLengthPolymorphisms)限制性酶切多態(tài)性用某種限制性內(nèi)切酶酶切基因組DNA,得到的長度不同的DNA片段DNA-basedvariationsatrestrictionsitesGenemapping基因定位用不同方法將一個基因定位至特定染色體的特定帶上分析其與其他基因的關(guān)系、Assigningagenetoaparticularbandofparticularchromosomeanditsrelationshiptoothergeneswithdifferentmethods.GeneticLinkageAnalysis基因鏈鎖分析應(yīng)用系譜分析確定被定位的基因與另一已知位置的基因是否有連鎖關(guān)系。Amethodofmappinggenesthatusesfamilypedigreesanalysistodeterminewhethertwogenesshowlinkagewhenpassedonfromonegenerationtothenext.Linkage連鎖減數(shù)分裂時，同一染色體上的基因作為一個整體傳遞的緊密程度。Thetendencyforallelesclosetogetheronthesamechromosometobetransmittedtogether;asaintactunit,throughmeiosisRecombination重組值基因定位時，兩個基因間遺傳圖距的量度，即基因間的遺傳距離。FrequencyofrecombinationasameasureofhowfaraparttwolociareHaplotype單體型一條染色體上兩個或兩個以上的多態(tài)性位點狀態(tài)(等位基因)的組合叫作染色體單體型。thelinkedphaseoftwoormoregeneticpolymorphisms(alleles)onthesamechromosome.Geneticmaps(linkagemaps)遺傳圖(連鎖圖)是指基因或DNA標(biāo)記在染色體上的相對位置與遺傳距離。以cM為單位。ThemapsoftherelativepositionandgeneticdistanceonthechromosomeofAllelesorgeneticmarkers.Physicalmaps物理圖以DNA堿基對數(shù)目為距離單位標(biāo)明遺傳標(biāo)記在DNA分子或染色體上所處位置的圖譜。Themapsofthepositionofageneticmarkeronaparticularbandofparticularchromosomeanditsrelationshiptoothergenesintermsofnumbersofbasepairs.八、群體遺傳學(xué)PopulationGenetics群體遺傳學(xué)以群體為單位，研究群體內(nèi)的遺傳結(jié)構(gòu)及其變化規(guī)律的遺傳學(xué)分支學(xué)科。PopulationgeneticsisthestudyofthedistributionofgenesinpopulationsandofhowthefrequenciesofgenesandgenotypesaremaintainedorchangedoMendelianPopulation孟德爾群體能相互交配和繁殖的個體群，他們共享一個基因庫。AReproductivecommunityofindividualswhichshareinacommongenepool.GenePool基因庫一個群體中所有等位基因的總和。acollectionofalltheallelesataparticularlocusfortheentirepopulation.GeneFrequency?Allelefrequency基因頻率一個群體中，某類等位基因的數(shù)量占該基因座上全部等位基因的比率。theproportionofallallelesatonegenelocusthatareofonespecifictypeinapopulation.Genotype基因型個體在某一基因座上的等位基因構(gòu)成。thegeneticconstitutionorcompositionofanindividual(atalocus).GenotypeFrequency基因型頻率一個群體中某一基因型的個體占群體中全部個體的比率。therelativefrequencyofanparticulargenotypeina(Mendelian)population.Fitness適合度某個基因型個體存活及把其基因傳遞給后代的相對能力。Thepotentialforindividualsofagivengenotypetosurviveandreproduceinthefaceofnaturalselection/=1(thefitnessofnormalallele)f=0(ageneticlethal)SelectionCoefficient(s)選擇系數(shù)一種度量基因選擇性的度量方法。Ameasureoftheloseoffitnessandisdefinedas1-fs=l-Heterozygoteadvantage雜合子優(yōu)勢在某些遺傳病中，存在雜合子優(yōu)勢，也叫雜合子的正選擇作用，即雜合子比突變等位基因的純合子，甚至是正常等位基因的純合子的適合度都要高。positiveselectionforheteroz-ygoteGeneticdrift遺傳漂變由于抽樣誤差導(dǎo)致的基因頻率的隨機波動。遺傳漂變在任何群體中都存在，但在小群體其效應(yīng)最明顯。小群體中，由于所生的子女較少，可導(dǎo)致等位基因頻率產(chǎn)生相當(dāng)大的隨機波動。insmallpopulation,allelefrequenciescanfluctuatefromgenerartiontogenerationbychance.FounderEffect“建立者”效應(yīng)當(dāng)從一個大群體中隨機選取少數(shù)動物(始祖)以建立一個獨立群體時，始祖只包括了親本群體部分遺傳多樣性。結(jié)果因為進(jìn)化壓力不同，導(dǎo)致親本群和新產(chǎn)生群體基因庫的進(jìn)化途徑不同。Asmallsubpopulationbreaksofffromalargerpopulationtoforma“dosed“population.Thegenefrequenciesinthesmallpopulationmaybedifferentfromthoseoftheorignialpopulation.Ifoneoftheorignialfoundersofthenewgroupjusthappenstocarryarelativerareallele,thatallelewillhaveafarhigherfrequencythanithadinthelargeroriginalgroup,continuedrelativelyhighfrequencyduetopopulationbeing“dosed”Geneflow基因流動由于遷移而造成同一物種不同群體的基因交換，通常會導(dǎo)致受體群基因庫許多等位基因座上基因頻率發(fā)生緩慢變化。Migrationofpopulationintonewregionsandintermarriagewithindigenouspopulationscanresultinachangeinallelefrequenciesinbothpopulations.九、分子遺傳工具ThePolymeraseChainReaction聚合酶鏈?zhǔn)椒磻?yīng)應(yīng)用酶學(xué)方法，在目的基因兩端加引物擴(kuò)增DNA片段，具有敏感性和特異性。EnzymaticamplificationofafragmentofDNAlocatedbetweenapairofprimers,sensitivenessandspecificityNucleicacidhybridization核酸分子雜交通過不同的手段使雙鏈DNA解旋，解旋后可與同源互補序列雜交并在一定條件下復(fù)性。DoublecomplementarystrandsDNAcanbedenaturedbyavarietytreatmentsandcanhybridizetothehomologoussequenceunderconditionsthatfavorformationofdoublestrandedDNA.Probe探針同位素標(biāo)記的DNA序列。aspecificDNAsequencelabeledwithisotopeorfluorescenceFluorescenceInSituHybridization(FISH)熒光原位雜交用切口平移法將核酸分子熒光標(biāo)記。NucleicacidProbeslabeledwithfluorescencebynicktranslation間期核酸和中期染色體原位雜交。Hybridizedwithinterphasenucleusandmetaphasechromosomeinsitu.依照堿基互補配對原則。AccordingtoBasePaircomplementaryprinciplesDNAsequencing-sangersequencing末端終止法只用一個引物（正或反），少量ddNTP熒光標(biāo)記，ddNTP只要插入就不再復(fù)制，可終止復(fù)制過程。Preimplantationgeneticdiagnosis植入前遺傳學(xué)診斷植入前遺傳學(xué)診斷就是在體外受精中，運用分子或細(xì)胞遺傳學(xué)技術(shù)，選擇不攜帶某種遺傳病的胚胎植入到子宮中。istheuseofmolecularorcytogenetictechniquesduringinvitrofertilizationtoselectembryosfreeofaspecificgeneticconditionfortransfertotheuterus.十、發(fā)育遺傳學(xué)developmentbiology發(fā)育遺傳學(xué)基因組成對發(fā)育的指導(dǎo)作用。regulativedevelopment調(diào)節(jié)式發(fā)育胚胎某部分損害或移走后其他部分可影響機體調(diào)節(jié)進(jìn)行補償式發(fā)育最終成長為正常個體mosaicdevelopment鑲嵌式發(fā)育胚胎某部分損害后即使機體有調(diào)節(jié)信號，其他部分也不可補償?！径縋ost-TranslationProcessing肽鏈從核蛋白體釋放后，經(jīng)過細(xì)胞內(nèi)各種修飾處理成為有活性的成熟蛋白質(zhì)的過程。初級轉(zhuǎn)錄產(chǎn)物經(jīng)過折疊和結(jié)合形成特殊的三維結(jié)構(gòu)。Primarytranslationproductisfoldedandbondedintoaspecificthree-dimensionalstructure.兩條或多條多肽鏈結(jié)合形成一個成熟的蛋白質(zhì)復(fù)合體。Twoormorepolypeptidechainscombinetoformasinglematureproteincomplex.蛋白質(zhì)分裂。Cleavageoftheprotein蛋白質(zhì)產(chǎn)物的化學(xué)修飾。TheproteinproductsmayalsobemodifiedchemicallyFluorescenceInSituHybridization（FISH:熒光原位雜交）Principles:Labelingprobewithafluorescentdye熒光標(biāo)記探針Denatureoftheprobeandmetaphase>prophaseorinterphasechromosomes探針以及前中期染色體的變性Hybridization雜交Visualizingthelocationofhybridizationunderafluorescencemicroscope熒光顯微鏡肉眼觀察雜交位置Probes:threetypes三種探針gene-specificorlocus-specificprobes（單拷貝）基因座特異性探針：針對某個特殊基因repetitiveDNAprobes(satelliteDNAprobes)(重復(fù)序列)重復(fù)DNA探針：針對結(jié)構(gòu)基因，染異染色質(zhì)chromosomepaintingprobes(probesforentirechromosomesorchromosomearms)(染色體涂染)染色體探針：針對染色體臂或整條染色體Application:應(yīng)用toexaminethepresenceorabsenceofaparticularDNAsequence檢測特定DNA序列的存在或缺失todiagnosetheexistenceofanabnormalchromosomenumberinclinicalmaterial臨床診斷染色體數(shù)目異常todetectchromosomerearrangementswithcombinationsofFISHprobes通過FISH探針檢測染色體重排ChromosomeAbnormalities染色體異常AbnormalitiesofChromosomeNumber染色體數(shù)目異常EuploidVariation整倍體畸變：以染色體組為單位發(fā)生的染色體成倍的增減AneuploidVariation非整倍體畸變：細(xì)胞內(nèi)染色體數(shù)目增加或減少一條或幾條AbnormalitiesofChromosomeStructure染色體結(jié)構(gòu)異常Mechanism:chromosomebreakage、reconstitutioninanabnormalcombination機制：斷裂后發(fā)生錯誤重接Incidence:1in375newbornsTypesofstructurerearrangements結(jié)構(gòu)重排類型Balanced平衡畸變Unbalanced不平衡畸變UnbalancedRearrangements（非平衡重排）Deletion（delz缺失）Definition:isachromosomalmutationinwhichpartofachromosomeismissing一種染色體部分丟失的染色體突變。Types:terminal（末端缺失），interstitial（中間缺失）Reasons:Deletionsmayoriginatesimplybychromosomebreakageandlossoftheacentricsegment.斷裂后不含著絲粒部分丟失。Unequalcrossingoverbetweenmisalignedhomologouschromosomesorsisterchromatids.不均等交換Deletionscanalsobegeneratedbyabnormalsegregationfromabalancedtranslocationorinversion平衡畸變（異位/倒位者產(chǎn)生的配子）Duplication（dup,重復(fù)）Definition:isachromosomalmutationthatresultsinthedoublingofasegmentofachromosome.染色體中某一片斷出現(xiàn)兩次所導(dǎo)致的染色體異常。Reasons:Canoriginatebyunequalcrossingover不均等交換Byabnormalsegregationfrommeiosisinacarrierofatranslocationorinversion.異位、倒位者產(chǎn)生的配子RingChromosomes(r，環(huán)狀a)RingChromosome(r)Definition:deletionssometimesoccuratbothtipsofachromosome.Theremainingchromosomeendscanthenfuse,formingaringchromosome.長短臂同時發(fā)生斷裂，殘留的兩個斷短重接形成環(huán)狀染色體。Isochromosomes(I,等臂)Definition:isachromosomeinwhichonearmismissingandtheotherduplicatedinamirror-imagefashion.染色體一條臂丟失，另一條臂重復(fù)出現(xiàn)并形成鏡像對稱的連接。Mechanisms:MisdivisionthroughthecentromereinmeiosisII減II時在著絲粒處的錯誤分裂Exchangeinvolvingonearmofachromosomeanditshomolog(orsisterchromatid)attheproximaledgeofthearm,adjacenttothecentromere.姐妹染色體一條臂與另一條臂在近側(cè)邊緣、靠近著絲粒處交換。DicentricChromosomes（die,雙著絲粒））Definition:adicentricisararetypeofabnormalchromosomeinwhichtwochromosomesegments（fromdifferentchromosomesorfromthetwochromatidsofasingleone）,eachwithacentromere,fuseendtoend,withlossoftheiracentricfragments.兩條染色體不含著絲粒部分丟失，兩個含有著絲粒的斷端相接。BalancedRearrangements（平衡重排）Inversions（inv,倒位）Definition:occurswhenasinglechromosomeundergoestwobreaksandisreconstitutedwiththesegmentbetweenthebreaksinverted.染色體發(fā)生兩次斷裂，兩斷點間片段旋轉(zhuǎn)180°后重接。Types:Paracentric（notincludingcentromere）同臂內(nèi)倒位Pericentric（includingcentromere）臂間倒位Inversioncarrier:acarrierofeithertypeofinversionisatriskofproducingabnormalgametesthatmayleadtounbalancedoffspring倒位攜帶者：有產(chǎn)生異常配子的風(fēng)險，從而可產(chǎn)生異常后代。Translocations（t,易位）Definition:involvestheexchangeofchromosomesegmentsbetweentwo,usuallynonhomologouschromosomes兩個染色體間的片段交換，通常是非姐妹染色單體間。Maintypes:reciprocal（rep,相互易位），Robertsonian（rob,羅伯遜易位）ReciprocalTranslocations（rep）Definition:thistypeofrearrangementresultsfrombreakageofnonhomologouschromosomes,withreciprocalexchangeofthebroken-offsegments.非同源染色體發(fā)生斷裂，斷端相互交換。Carriersofbalancedreciprocaltranslocation:areassociatedwithahighriskofunbalancedgametesandabnormalprogeny相互易位攜帶者：極可能產(chǎn)生異常配子，不正常懷孕。RobertsonianTranslocations（rob）Definition:thistypeofrearrangementinvolvestwoacrocentricchromosomesthatfusenearthecentromereregionwithlossoftheshortarms又稱著絲粒融合。在著絲粒部位或著絲粒附近部位發(fā)生斷裂后，兩者的長臂在兩條近端著絲粒染色體著絲粒處結(jié)合在一起，形成一條由長臂構(gòu)成的衍生染色體，兩個短臂則構(gòu)成一個小染色體，小染色體往往在第二次細(xì)胞分裂時丟失，這可能是由于缺乏著絲?；蚱渫耆僧惾旧|(zhì)構(gòu)成所致。CarrierofRobertsoniantranslocation:acarrierofaRobertsoniantranslocationisphenotypicallynormal,thereisariskofunbalancedgametesandthereforeoffspring.羅伯遜易位攜帶者：表型正常，極可能產(chǎn)生異常配子。Insertions（ins,插入）Definition:aninsertionisanonreciprocaltypeoftranslocationthatoccurswhenasegmentremovedfromonechromosomeisinsertedintoadifferentchromosome,eitherinitsusualorientationorinverted.兩條非同源染色體同時斷裂、其中一條插入到另一條的非末端部位。Mosaicism（mos,嵌合體）Definition:twoormoredifferentchromosomecomplementsarepresentinanindividual,thissituationiscalledmosaicism一個個體有兩個或以上的不同的染色體組。Types:numerical（mostcommontype）,structural染色體數(shù)目不同的嵌合體、染色體結(jié)構(gòu)不同的嵌合體Reasons:mosaicismisnondisjunctioninanearlypostzygoticmitoticdivision.受精后早期分裂中的不正確分離【三】TheLyonhypothesis萊昂假說Inthesomaticcellsoffemalemammals,onlyoneXchromosomeistranscriptionallyactive.ThesecondXisheterochromaticandinactiveandappearsininterphasecellsassexchromatin,theBarrbody.女性僅有一條X染色體有轉(zhuǎn)錄活性，另一條在間期以異染色質(zhì)（巴氏小體）形式存在。Inactivationoccursearlyinembryoniclife.失活發(fā)生在胚胎早期。Inanyonefemalesomaticcell,theinactiveXmaybeeitherthepaternalorthematernalX,namelytheinactivationisrandomly.任一體細(xì)胞中失活的X可能來自父母雙方，即失活是隨機的?！舅摹縫edigreeanalysis（系譜分析）Determiningthemodeofinheritanceofgeneticdiseases.用于確定遺傳病類型及傳遞規(guī)律Identifyavirulencegenerunningthroughafamily確定致病基因在家族中的傳遞過程Determiningwhointhefamilyisatriskofbeingaffected推測再發(fā)風(fēng)險CharacteristicsofAutosomalDominantinheritanceThephenotypeusuallyappearsineverygeneration,eachaffectedpersonhavinganaffectedparent連代遺傳，患者雙親必有患者。Exceptions:(l)freshmutation自身突變(2)thedisorderisnotexpressedorisexpressedonlysubtlyinapersonwhohasinheritedtheresponsiblegene.變異不表達(dá)或表達(dá)程度低、不典型。Anychildofanaffectedparenthasa50percentriskofinheritingthetrait50%的幾率傳給后代bothmalesandfemalesareaffectedina1:1ratio男女發(fā)病機會均等ADtypesCompletedominance(完全顯性遺傳)Incompletedominance(不完全顯性遺傳)也稱半顯性，雜合子的表現(xiàn)型介于顯性純合子和隱性純合子之間Irregulardominance（不規(guī)則顯性遺傳）Aa有時表達(dá)有時不表達(dá)，需要其他基因修飾（包括環(huán)境因素）出現(xiàn)隔代遺傳Codominance（共顯性遺傳）一對等位基因之間，沒有顯性和隱性的差別，在雜合體時兩種基因的作用都完全表現(xiàn)出來Delayeddominance（延遲顯性遺傳）雜合子生命的早期，因致病基因不表達(dá)或表達(dá)但尚不足以引起明顯的臨床癥狀，只在到達(dá)一定年齡后才表現(xiàn)出疾病CharacteristicsofAutosomalRecessiveInheritance常隱特征AnautosomalRecessivephenotype,typicallyisseenonlyinthesibshipoftheproband,notinparents,offspring,orotherrelatives.散發(fā)、不連代，患者雙親可無患者bothsexesareaffectedwithequalfrequencyataratioof1:1男女發(fā)病機會均等Parentsofanaffectedchildareasymptomaticcarriersofmutantalleles,heterazygousparentshaveariskof25%ofaffectedoffspring兩個雜合子后代發(fā)病幾率為1/4Theparentsoftheaffectedpersonmayinsomecasesbeconsanguineous.Thisisespeciallylikelyifthemutantgeneisrareinthepopulation.近親婚配極易發(fā)病CharacteristicsofX-linkedDominantInheritanceX顯特征Theincidenceofthetraitismuchhigherinfemalesthaninmales（abouttwice）zbutaffectedfemalestypicallyhavemilder（variable）expressionofthephenotype.女性發(fā)病率高但病情不完全一樣AffectedmaleswithnormalmateshavenormalsonsandAffecteddaughters.男病人只能遺傳女兒BothmaleandfemaleoffspringofAffectedfemalehavea50percentriskofinheritingthephenotype.患病母親后代中男女患病幾率均等4.Thepedigreepatternisthesameasautosomaldominantinheritance.家系特點與常染色體顯性遺傳病相似CharacteristicsofX-LinkedRecessiveInheritanceX隱特征Theincidenceofthetraitismuchhigherinmalesthaninfemales.男性發(fā)病率大于女性Thegeneisordinarilynevertransmitteddirectlyfromfathertoson(male-to-male),butitistransmittedbyanaffectedmaletoallhisdaughters.父親不傳給兒子，但傳給所有女兒AcarrierFemaleforanX-chromosomalmutationhasariskof50%Foranaffectedson.女性攜帶者兒子50%患病Thegenemaybetransmittedthroughaseriesofcarrierfemales;affectedmalesinheritthemutantallelefromthemotheronly基因通過一系列女性攜帶者傳遞，兒子只從母親處得到【五】CharacteristicsofPolygenicInheritance多基因遺傳特點ThemeanoftheFlisapproximatelyintermediatebetweenthemeansofthetwoparenttype.兩個極端個體結(jié)合Fl為中間類型，介于雙親之間

2.ThemeansoftheFlandtheF2generationsaresimilar.Fl、F2均值相似TheF2generationisconsiderablymorevariablethanFlF2比Fl變異范圍更大ThereisanoverlapinmeasurementsoftheextremetypeintheF2andinthedistributionsofvaluesforthetwoparentaltype.F2的正態(tài)分布中有極端類型個體與F0重疊GeneticAnalysisofQuantitativeTraits數(shù)量性狀的遺傳分析Minorgene（微效基因）人類的一些遺傳性狀或某些遺傳病的遺傳不是取決于一對基因，而是幾對基因，每一對基因?qū)z傳性狀或遺傳病的形成作用是微小的Additiveeffect（加性效應(yīng)）若干對基因作用積累后，可以形成一個明顯的表型效應(yīng)。Susceptibility（易感性）由遺傳因素決定的患病風(fēng)險，僅代表個體所含有的遺傳因素。Liability（易患性）包含遺傳因素以及環(huán)境因素決定的患病風(fēng)險。Threshold（閾值）個體易患性高達(dá)一定限度后會得病，閾值是由易患性導(dǎo)致的多基因遺傳病的發(fā)病限度。EstimatesofTheRecurrenceRiskforPolygeneticDiseases多基因病復(fù)發(fā)風(fēng)險的估計1.Edwardformula：1.Edwardformula：f=。根號下pf:Therecurrenceriskforfirstdegreerelatives一級親屬再發(fā)風(fēng)險p:Thefrequencyofdiseaseamonggeneralpopulation群體發(fā)病率應(yīng)用條件Frequency=0.1%~1%Heritability=70%"80%Theriskincreaseswiththenumberofaffectedrelatives再發(fā)風(fēng)險隨患者數(shù)目增加而增加Theriskincreaseswiththeseverityofthemalformationordisease.再發(fā)風(fēng)險隨病情嚴(yán)重程度增加Therecurrenceriskforrelativeswilldeclinesharplyasthedegreeofrelatednessdecreases.親屬級別降低，發(fā)病風(fēng)險迅速降低Whenthesexratioofaffectedprobandsdeviatessignificantlyfromunity,offspringofaffectedprobandsofthelessfrequentlyaffectedsexareathigherrelativerisk.發(fā)病率低的性別后代再發(fā)風(fēng)險高(有時男女發(fā)病率不同、可能原因是男女閾值不同，而不是基因在性染色體上。)【六】Abnormalhemoglobin鐮刀形紅細(xì)胞貧血癥因為一個核昔酸的替換使編碼B鏈的第六個氨基酸由谷氨酸轉(zhuǎn)變?yōu)榫Y氨酸。ItisduetoasinglenucleotidesubstitutionthatchangesthecodonofthesixthaminoacidofBglobinfromglutamicacidtovaline病理學(xué)：B鏈的突變使得血紅蛋白的溶解性降低并形成纖維狀聚合物，使紅細(xì)胞的粘滯性升高變形為鐮刀狀。Pathology：Themutation(GAGGTG:Glu6val)inBglobindecreasesthesolubilityofdeoxygenatedhemoglobinandcauseittoformagelatinousnetworkof

fibrouspolymers.Thus,erythrocytesbecomefirmanddeformintosickle-shapedcells.鐮刀形細(xì)胞不易通過毛細(xì)血管及血竇，造成組織局部缺氧而壞死。Sicklecellsareunabletopassthroughsmallarteriesandcapillaries.Thesebecomecloggedandcauselocaloxygendeficiencyinthetissues.鐮刀形紅細(xì)胞貧血癥的分子基礎(chǔ)有缺陷的紅細(xì)胞被擠壓破裂，導(dǎo)致溶血性貧血和諸多后遺癥如心衰、肝損傷以及感染等結(jié)果。Defectiveerythrocytesaredestroyed(hemolysis).ChronicanemiaanditsnumeroussequelaesuchasheartfailureJiverdamage,andinfectionaretheresult.鐮刀形紅細(xì)胞貧血癥的分子基礎(chǔ)MolecularBasisofAbnormalhemoglobin1.Missensemutation:錯義突變1.Missensemutation:錯義突變HbS(P6glu-*val)2.Non-sensemutation:2.Non-sensemutation:無義突變HbMckees-Rock(B145UAU-UAA).Terminationcodonmutation:終止子突變Hbconstantspring(a142UAA-*CAA)Hbwayne(a138UCCt).Frame-shiHbwayne(a138UCCt).Codonmutation:整碼突變HbGumHiu(0.Codonmutation:整碼突變HbGumHiu(091-95t).Fusiongene:融合基因Hblepore(6B)Hbanti-lepore(06)ThemechanismofHereditaryenzymopathy.造成分子病的6種可能機理及后果ProductdeficienceAlbinismSubstrateaccumulationGlycogenstoragediseaseMiddleproductaccumulationGalactosemiaSideproductaccumulationPhenylketonuria(PKU)ProductincreaseGoutLossofnormalfeedbackinhibitionLesch-nyhansyndrome產(chǎn)物缺乏：白化病底物積累：糖原儲蓄癥中間產(chǎn)物積累：半乳糖血癥副產(chǎn)物積累：苯丙酮尿癥產(chǎn)物增加：痛風(fēng)反饋抑制受影響：自毀容貌綜合征Thalassemia地中海貧血AnImbalanceofGlobin-Chainsynthesis.Themutationsreducethesynthesisorstabilityofeitherthea-orP-globinchain,tocausea-orP-thalassemia,respectively.由珠蛋白鏈合成的不平衡導(dǎo)致，基因突變使?；駼珠蛋白鏈合成減少或降低其穩(wěn)定性，分別導(dǎo)致a和B地中海貧血。Alpha-Thalassemiasagenemutationordeletion,p-globinisinrelativeexcessa突變或缺失，B相對過剩Beta-ThalassemiasBgenemutationordeletion,。-globinisinrelativeexcessB突變或缺失，a相對過?！酒摺縇evelofintervention介入層面Mutantgene突變基因MutantmRNAMutantproteinMetabolicorotherbiochemicaldysfunction代謝或其他生化功能障礙Clinicalphenotype臨床表型Thefamily家系分析Treatmentstrategy治療策略Modificationofthesomaticgenotype修正體細(xì)胞基因型Transplantation移植Eg,bonemarrowtransplantationinB-thalassemiaB■地中海貧血的骨髓移植2)genetherapy基因療法E.g.,transferoftheyccytokinereceptorsubunitofinterleukinreceptorinSCID-X1PharmacologicalmodulationofgeneexpressionE.g.，butyratetoincreaseHbFinsicklecelldiseaseRibozymegenetransfertodegrademutantmRNA(experimentalonly)ProteinreplacementE.g.,glucocerebrosidaseadministrationinGaucherdisease.FactorVIIIinhemophiliaA.EnhancementofresidualfunctionEg,pyridoxineinclassicalhomocystinuriaDisease-specificcompensationl)DietaryEg,lowphenylalaninedietinPKU2)PharmacologicEg,sodiumbenzoateinureacycledefectsMedicalintervention醫(yī)療干預(yù)Eg,transfusionforsicklecellanemia鐮刀形紅細(xì)胞貧血癥的輸血Surgicalintervention手術(shù)干預(yù)Eg,correctionofcongenitalheartdisease先天性心臟病的矯正Geneticcounseling遺傳咨詢Eg,afterchildbornwithtrisomy21在21三體綜合征孩子出世后Carrierscreening