《医学遗传学》第四章 人类染色体与染色体病.ppt

第四章人类染色体和染色体病,PainterTS.Studiesinmammalianspermatogenesis.II.Thespermatogenesisofman.JExpZool.1923;37:291-336,DarkAges,HsuTC.Mammalianchromosomesinvitro.I.Thekaryotypeofman.JHered.1952;43:167-172TjioJH,LevanA.Thechromosomenumberofman.AmJObstetGynecol.1956;130:723-724,HypotonicPeriod,DarkAges,TrisomyPeriod,LejeuneJ,etal.Etudedeschromosomessomatiquesdeneufenfantsmongoliens.G.R.Acad.Sciences.1959;248:1721-1722FordCE,etal.Asexchromosomalanomalyinacaseofgonadaldysgenesis(Turnerssyndrome).Lancet.1959;1:711-713JacobPA,etal.AcaseofhumanintersexualityhavingapossibleXXYsexdeterminingmechanism.Nature.1959;183:302-303.,HypotonicPeriod,DarkAges,BandingEra,CasperssonT,etal.Differentialbandingofalkylatingfluorochromesinhumanchromosomes.ExpCellRes.1970;60:315-319,HypotonicPeriod,DarkAges,TrisomyPeriod,MolecularEra,PardueML,etal.MolecularhybridizationofradioactiveDNAtotheDNAofcytologicalpreparations.Proc.Natl.Acad.Sci.USA.1969;64:600-604PinkelD,etal.Cytogeneticanalysisusingquantitative,high-sensitivity,fluorescencehybridization.Proc.Natl.Acad.Sci.USA.1986;83:2934-2938.,HypotonicPeriod,DarkAges,BandingEra,TrisomyPeriod,DenverSystem,Thekaryotypeisaphotographofallofthechromosomesofanindividualcell;thetermcoversthenumber,relativesizesandstructureofthechromosomes.,核型：一个体细胞中的全部染色体，按其大小、形态特征顺序排列所构成的图像。,Chromosomecanbedistinguishedbytherelativesizesandthepositionofthecentromere.,Metacentric(1,3,16,19,20),Submetacentric(2,4-12,17,18,X),Acrocentric(13,14,15,21,22,Y),DenverSystem,Karyotypeanalysis:arrangingthechromosomesofacellintoakaryotype,thenanalysisandcomparewithDenversystem.,DenverSystem,Thekaryotypeisaphotographofallofthechromosomesofanindividualcell;thetermcoversthenumber,relativesizesandstructureofthechromosomes.,DenverSystem,BandingPattern,Band（带）:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,Bandingpattern（带型）：treatedwithchemicaldyes,24typesofchromosomesappearitsuniquestriationsindividually.,Q-banding：QM,BandingPattern,Band:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,Q-banding：QM,G-banding：pancreatinGiemsa,BandingPattern,Band:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,R-banding：treatedspecimenGiemsaorAcridineOrange,BandingPattern,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,C-banding：Ychromosome,centromere,secondaryconstriction,BandingPattern,R-banding：treatedspecimenGiemsaorAcridineOrange,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,T-banding：endingofchromosome,BandingPattern,C-banding：Ychromosome,centromere,secondaryconstriction,R-banding：treatedspecimenGiemsaorAcridineOrange,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,N-banding：AgNO3Giemsa,NOR,T-banding：endingofchromosome,BandingPattern,C-banding：Ychromosome,centromere,secondaryconstriction,R-banding：treatedspecimenGiemsaorAcridineOrange,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.,Landmark,Xp,Xq,Region,Band,1,1,2,2,12345678,Xq28,BandingPattern,Development,1.Highresolutionbandingchromosome(HRBC),FISH(fluorescenceinsituhybridization),3.Molecularcytogenetics,Development,2.Microcytogenetics,1.Highresolutionbandingchromosome(HRBC),FISH,FISH,FISH,FISH,FISH(fluorescenceinsituhybridization),DNAfiber-FISH,3.Molecularcytogenetics,Development,2.Microcytogenetics,1.Highresolutionbandingchromosome(HRBC),DNAfiber-FISH,3cosmidfromMHClocus3540Kb/cosmid,FISH(fluorescenceinsituhybridization),DNAfiber-FISH,ChromosomePainting,3.Molecularcytogenetics,Development,2.Microcytogenetics,1.Highresolutionbandingchromosome(HRBC),ChromosomePainting,ChromosomePainting,ChromosomePainting,FISH(fluorescenceinsituhybridization),DNAfiber-FISH,ChromosomePainting,CGH(comparativegenomichybridization),3.Molecularcytogenetics,Development,2.Microcytogenetics,1.Highresolutionbandingchromosome(HRBC),CGH,CGH,CGH,Advantages,Wholegenomein1experiment,Noneedtoculturetumorcells,Sensitivedetectionofgeneamplification,Disadvantages,Limitedresolution(10Mbdel/dup),Laborious,Onlygainsandlosses/nobalancedrearrangements,Noinformationonthenatureoftheaberrations,Retrospectiveanalysis,CGH,Heteromorphism,Bandingpatternpolymorphism,Chromosomeheteromorphismsarenormalvariationsintheappearanceofchromosomes.,BeinheritedinaMendelianfashion,ConstitutiveheterochromatinNotchromosomalabnormalityinclinical,Heteromorphism,Bandingpatternpolymorphism,ChromosomallengthSatelliteSecondaryconstrictionPolymorphismofQ,G,Cbanding,ChromosomalAberration,NumericalAbnormality,StructuralAberration,NumericalAbnormality,单倍体:22+X,22+Y,二倍体:44+XX,44+XY,NumericalAbnormality,Variationinchromosomenumbercantake2forms:,整倍体:thatwhichinvolveswholesets(genomes)ofchromosomes,非整倍体:thechromosomenumberisnotanexactmultipleofthehaploid（单倍体）number,整倍体,三倍体:thecellwhichhas3sets(genomes)ofchromosomes3n69,NumericalAbnormality,NumericalAbnormality,整倍体,三倍体:thecellwhichhas3sets(genomes)ofchromosomes3n69,Tripolarspindle,双雄受精:fertilizationof1oocyteby2spermatozoa,双雌受精:non-expulsionofthe2ndpolarbody,NumericalAbnormality,整倍体,三倍体:thecellwhichhas3sets(genomes)ofchromosomes3n69,整倍体多倍体,四倍体:thecellwhichhas4sets(genomes)ofchromosomes4n92,核内复制,NumericalAbnormality,核内复制,双分染色体,Diplochromosome,整倍体多倍体,四倍体:thecellwhichhas4sets(genomes)ofchromosomes4n92,核内复制,NumericalAbnormality,核内有丝分裂,BefoundmorecommonlythanEuploid(整倍体),亚二倍体:lessthanthenormal2nnumberofchromosomes,NumericalAbnormality,非整倍体,超二倍体:morethanthenormal2nnumberofchromosomes,单体型:isthepresenceofonlyonecopyofanychromosome,Lossofautosomesisnottolerated,Turnersyndrome:45,X,NumericalAbnormality,非整倍体,亚二倍体,BefoundmorecommonlythanMonosomy,Trisomyofsexchromosomeismorecommonly,NumericalAbnormality,非整倍体,超二倍体,三体型:isthepresenceofonlythreecopyofanychromosome,Meiotic(减数分裂)non-disjunction,Mitotic(有丝分裂)non-disjunction,Chromosomenon-disjunction,NumericalAbnormality,MechanismofAneuploid(非整倍体),Meiosisinanimals.,MeioticNon-Disjunction,Meioticnon-disjunctionarisesfromfailureofpairedhomologouschromosomesorsisterchromatidtodisjoinatmeioticanaphase.,MeioticNon-Disjunction,Primarynon-disjunction,Primarynon-disjunctionisthefailureofchromosomesorsisterchromatidtoseparateinmeiosis.Thegametethushastwocopiesofachromosome.Fertilizationaddsanothercopytogiveatotalof3copies.,Secondarynon-disjunction,Trisomyoffspringarisefromsegregationatmeiosisofanalready-trisomyparent.,MeioticNon-Disjunction,MeioticNon-Disjunction,Meioticnon-disjunction,Mitoticnon-disjunction,Chromosomenon-disjunction,NumericalAbnormality,MechanismofAneuploid,Mitosisinanimalcells.,MitoticNon-Disjunction,Mitoticnon-disjunctionarisesfromfailureofsisterchromatidstodisjoinatmitoticanaphase.,47/45Mosaic,46/47/45Mosaic,Meioticnon-disjunction,Mitoticnon-disjunction,Chromosomenon-disjunction,Chromosomeloss,NumericalAbnormality,MechanismofAneuploid,Thecausalitywhereachromosomeismissingfromthenewcellcreatedviacelldivision.,Anaphaselag(染色体分裂后期延滞)maybeduetodelayedmovementofachromosomeatanaphase.,ChromosomeLoss,TheBreakageandtheRejoinafterbreakagearethebasisofchromosomalstructuralaberration.,Chromosomalrearrangement,Rearrangementchromosome,StructuralAberration,TerminalDeletion,StructuralAberration,InterstitialDeletion,StructuralAberration,4q13,ParacentricInversion,StructuralAberration,4q13,PericentricInversion,StructuralAberration,4p14,StructuralAberration,PericentricInversion,StructuralAberration,PericentricInversion,Inversionloop,StructuralAberration,PericentricInversion,StructuralAberration,PericentricInversion,Inversionloop,StructuralAberration,PericentricInversion,RingChromosome,StructuralAberration,RingChromosome,StructuralAberration,RingChromosome,StructuralAberration,RingChromosome,StructuralAberration,ReciprocalTranslocation,StructuralAberration,StructuralAberration,ReciprocalTranslocation,StructuralAberration,ReciprocalTranslocation,StructuralAberration,ReciprocalTranslocation,RobertsonianTranslocation,StructuralAberration,StructuralAberration,RobertsonianTranslocation,WholeArmTranslocation,StructuralAberration,ComplexTranslocation,StructuralAberration,Isochromosome,StructuralAberration,Isochromosome,StructuralAberration,DicentricChromosome,StructuralAberration,DirectInsertion,StructuralAberration,InverseInsertion,StructuralAberration,ChromosomeDiseaseinClinical,Clinicalfeature,Thegeneralfeaturesinautosomeabnormalitiesareatriadofgrowthretardation,mentalretardation,andspecificsomaticabnormalities.,Changeofsexchromosomealsohavetheabnormalitiesandmalformationsofinternalorexternalgenitalorgans.,DownSyndrome(trisomy21syndrome),ChromosomeDiseaseinClinical,Characteristics,GrowthretardationVaryingdegreesofmentalretardationFlattenedfaceUpwardslantingoftheeyeswithepicanthalfolds(内眦赘皮),1in600800newborns,ChromosomeDiseaseinClinical,DownSyndrome(trisomy21syndrome),1.Trisomy95%,47,XX(XY),21,Causedbynon-disjunctionofchromosome21,correlatedwithageofmother.,ChromosomeDiseaseinClinical,DownSyndrome(trisomy21syndrome),Karyotypeofaffected：46,XX(XY),14,t(14q21q),2.Mosaic2%4%,46/47,3.Unbalancetranslocation,Karyotypeofbalancecarrier：,45,XX(XY),14,21,t(14q21q),ChromosomeDiseaseinClinical,1.Trisomy92.5%,47,XX(XY),21,DownSyndrome(trisomy21syndrome),1in35008000newborns,EdwardsSyndrome(trisomy18syndrome),Characteristics,GrowthretardationMentalretardationCongenitalheartdiseaseRocker-bottomfeetfixedflexiondeformityofthefingers,ChromosomeDiseaseinClinical,ChromosomeDiseaseinClinical,1in35008000newborns,EdwardsSyndrome(trisomy18syndrome),1in25000newborns,PatauSyndrome(trisomy13syndrome),Characteristics,VaryingdegreesofmentalretardationCleftlip&CleftpalatePolydactyly(postaxial)Equinovarus,ChromosomeDiseaseinClinical,1in50000newborns,5p-Syndrome(CatCrysyndrome),Characteristics,Round,moon-sha