《医学遗传学》第四章 人类染色体与染色体病课件

第四章人类染色体和染色体病《医学遗传学》第四章人类染色体与染色体病PainterTS.Studiesinmammalianspermatogenesis.II.Thespermatogenesisofman.JExpZool.1923;37:291-336DarkAges《医学遗传学》第四章人类染色体与染色体病HsuTC.Mammalianchromosomesinvitro.I.Thekaryotypeofman.JHered.1952;43:167-172TjioJH,LevanA.Thechromosomenumberofman.AmJObstetGynecol.1956;130:723-724HypotonicPeriodDarkAges《医学遗传学》第四章人类染色体与染色体病TrisomyPeriodLejeuneJ,etal.Etudedeschromosomessomatiquesdeneufenfantsmongoliens.G.R.Acad.Sciences.1959;248:1721-1722FordCE,etal.Asexchromosomalanomalyinacaseofgonadaldysgenesis(Turner'ssyndrome).Lancet.1959;1:711-713JacobPA,etal.AcaseofhumanintersexualityhavingapossibleXXYsexdeterminingmechanism.Nature.1959;183:302-303.HypotonicPeriodDarkAges《医学遗传学》第四章人类染色体与染色体病BandingEraCasperssonT,etal.Differentialbandingofalkylatingfluorochromesinhumanchromosomes.ExpCellRes.1970;60:315-319HypotonicPeriodDarkAgesTrisomyPeriod《医学遗传学》第四章人类染色体与染色体病MolecularEraPardueML,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.HypotonicPeriodDarkAgesBandingEraTrisomyPeriod《医学遗传学》第四章人类染色体与染色体病DenverSystemThekaryotypeisaphotographofallofthechromosomesofanindividualcell;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。《医学遗传学》第四章人类染色体与染色体病Chromosomecanbedistinguishedbythe

relativesizesand

thepositionofthecentromere.Metacentric(1,3,16,19,20)Submetacentric(2,4-12,17,18,X)Acrocentric(13,14,15,21,22,Y)DenverSystem《医学遗传学》第四章人类染色体与染色体病Karyotypeanalysis:

arrangingthechromosomesofacellintoakaryotype,thenanalysisandcomparewith

Denversystem.DenverSystemThekaryotypeisaphotographofallofthechromosomesofanindividualcell;thetermcoversthenumber,relativesizesandstructureofthechromosomes.《医学遗传学》第四章人类染色体与染色体病DenverSystem《医学遗传学》第四章人类染色体与染色体病BandingPatternBand（带）:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.Bandingpattern（带型）：treatedwithchemicaldyes,24typesofchromosomesappearitsuniquestriationsindividually.《医学遗传学》第四章人类染色体与染色体病Q-banding：QMBandingPatternBand:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病Q-banding：QMG-banding：pancreatin＋GiemsaBandingPatternBand:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病R-banding：treatedspecimen＋GiemsaorAcridineOrangeBandingPatternQ-banding：QMG-banding：pancreatin＋GiemsaBand:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病C-banding：Ychromosome,centromere,secondaryconstrictionBandingPatternR-banding：treatedspecimen＋GiemsaorAcridineOrangeQ-banding：QMG-banding：pancreatin＋GiemsaBand:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病T-banding：endingofchromosomeBandingPatternC-banding：Ychromosome,centromere,secondaryconstrictionR-banding：treatedspecimen＋GiemsaorAcridineOrangeQ-banding：QMG-banding：pancreatin＋GiemsaBand:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病N-banding：AgNO3＋Giemsa,NORT-banding：endingofchromosomeBandingPatternC-banding：Ychromosome,centromere,secondaryconstrictionR-banding：treatedspecimen＋GiemsaorAcridineOrange

Q-banding：QMG-banding：pancreatin＋GiemsaBand:

treatedwithchemicaldyes,thechromosomewillappearasaseriesofalternatedarkandlightstriations.《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病LandmarkXpXqRegionBand112212345678Xq28BandingPattern《医学遗传学》第四章人类染色体与染色体病Development1.Highresolutionbandingchromosome(HRBC)《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病FISH(fluorescenceinsituhybridization)3.MolecularcytogeneticsDevelopment2.Microcytogenetics1.Highresolutionbandingchromosome(HRBC)《医学遗传学》第四章人类染色体与染色体病FISH《医学遗传学》第四章人类染色体与染色体病FISH《医学遗传学》第四章人类染色体与染色体病FISH《医学遗传学》第四章人类染色体与染色体病X染色体Y染色体13号染色体18号染色体21号染色体FISH《医学遗传学》第四章人类染色体与染色体病

FISH(fluorescenceinsituhybridization)

DNAfiber-FISH3.MolecularcytogeneticsDevelopment2.Microcytogenetics1.Highresolutionbandingchromosome(HRBC)《医学遗传学》第四章人类染色体与染色体病DNAfiber-FISH3cosmidfromMHClocus35～40Kb/cosmid《医学遗传学》第四章人类染色体与染色体病FISH(fluorescenceinsituhybridization)DNAfiber-FISH

ChromosomePainting3.MolecularcytogeneticsDevelopment2.Microcytogenetics1.Highresolutionbandingchromosome(HRBC)《医学遗传学》第四章人类染色体与染色体病ChromosomePainting《医学遗传学》第四章人类染色体与染色体病ChromosomePainting《医学遗传学》第四章人类染色体与染色体病ChromosomePainting《医学遗传学》第四章人类染色体与染色体病FISH(fluorescenceinsituhybridization)DNAfiber-FISH

ChromosomePainting

CGH(comparativegenomichybridization)3.MolecularcytogeneticsDevelopment2.Microcytogenetics1.Highresolutionbandingchromosome(HRBC)《医学遗传学》第四章人类染色体与染色体病CGH《医学遗传学》第四章人类染色体与染色体病CGH《医学遗传学》第四章人类染色体与染色体病CGH《医学遗传学》第四章人类染色体与染色体病AdvantagesWholegenomein1experimentNoneedtoculturetumorcellsSensitivedetectionofgeneamplificationDisadvantagesLimitedresolution(~10Mbdel/dup)LaboriousOnlygainsandlosses/nobalancedrearrangementsNoinformationonthenatureoftheaberrationsRetrospectiveanalysisCGH《医学遗传学》第四章人类染色体与染色体病HeteromorphismBandingpatternpolymorphismChromosomeheteromorphismsarenormalvariationsintheappearanceofchromosomes.BeinheritedinaMendelianfashionConstitutiveheterochromatinNotchromosomalabnormalityinclinical《医学遗传学》第四章人类染色体与染色体病HeteromorphismBandingpatternpolymorphismChromosomallengthSatelliteSecondaryconstrictionPolymorphismofQ,G,Cbanding《医学遗传学》第四章人类染色体与染色体病ChromosomalAberrationNumericalAbnormalityStructuralAberration《医学遗传学》第四章人类染色体与染色体病NumericalAbnormality单倍体:22+X,22+Y二倍体:44+XX,44+XY《医学遗传学》第四章人类染色体与染色体病NumericalAbnormalityVariationinchromosomenumbercantake2forms:整倍体:

thatwhichinvolveswholesets(genomes)ofchromosomes非整倍体:

thechromosomenumberisnotanexactmultipleofthehaploid（单倍体）number《医学遗传学》第四章人类染色体与染色体病整倍体三倍体:thecellwhichhas3sets(genomes)ofchromosomes——3n＝69NumericalAbnormality《医学遗传学》第四章人类染色体与染色体病NumericalAbnormality整倍体三倍体:thecellwhichhas3sets(genomes)ofchromosomes——3n＝69Tripolarspindle《医学遗传学》第四章人类染色体与染色体病

双雄受精:

fertilizationof1oocyteby2spermatozoa

双雌受精:

non-expulsionofthe2ndpolarbodyNumericalAbnormality整倍体三倍体:thecellwhichhas3sets(genomes)ofchromosomes——3n＝69《医学遗传学》第四章人类染色体与染色体病整倍体——多倍体四倍体:thecellwhichhas4sets(genomes)ofchromosomes——4n＝92核内复制NumericalAbnormality《医学遗传学》第四章人类染色体与染色体病核内复制双分染色体《医学遗传学》第四章人类染色体与染色体病

Diplochromosome整倍体——多倍体四倍体:thecellwhichhas4sets(genomes)ofchromosomes——4n＝92核内复制NumericalAbnormality核内有丝分裂《医学遗传学》第四章人类染色体与染色体病BefoundmorecommonlythanEuploid(整倍体)亚二倍体:lessthanthenormal2nnumberofchromosomesNumericalAbnormality非整倍体超二倍体:morethanthenormal2nnumberofchromosomes《医学遗传学》第四章人类染色体与染色体病单体型:isthepresenceofonlyonecopyofanychromosomeLossofautosomesisnottoleratedTurnersyndrome:45,XNumericalAbnormality非整倍体亚二倍体《医学遗传学》第四章人类染色体与染色体病BefoundmorecommonlythanMonosomyTrisomy

ofsexchromosomeismorecommonlyNumericalAbnormality非整倍体超二倍体三体型:isthepresenceofonlythreecopyofanychromosome《医学遗传学》第四章人类染色体与染色体病Meiotic(减数分裂)non-disjunctionMitotic(有丝分裂)non-disjunctionChromosomenon-disjunctionNumericalAbnormalityMechanismofAneuploid(非整倍体)《医学遗传学》第四章人类染色体与染色体病Meiosisinanimals.《医学遗传学》第四章人类染色体与染色体病MeioticNon-DisjunctionMeioticnon-disjunctionarisesfromfailureofpairedhomologouschromosomesorsisterchromatidtodisjoinatmeioticanaphase.《医学遗传学》第四章人类染色体与染色体病MeioticNon-Disjunction2NNN＋1N－12N＋12N＋12N－12N－1N＋1N＋1N－1N－12N2N2N＋12N－12NNNNNN－1N＋1《医学遗传学》第四章人类染色体与染色体病Primarynon-disjunctionPrimarynon-disjunction

isthefailureofchromosomesor

sisterchromatid

toseparateinmeiosis.Thegametethushastwocopiesofachromosome.Fertilizationaddsanothercopytogiveatotalof3copies.Secondarynon-disjunctionTrisomyoffspringarisefromsegregationatmeiosisofanalready-trisomyparent.MeioticNon-Disjunction《医学遗传学》第四章人类染色体与染色体病MeioticNon-Disjunction2N+1N2N2N2N＋12N＋1NN＋1NNN＋1N＋1《医学遗传学》第四章人类染色体与染色体病Meioticnon-disjunctionMitoticnon-disjunctionChromosomenon-disjunctionNumericalAbnormalityMechanismofAneuploid《医学遗传学》第四章人类染色体与染色体病Mitosisinanimalcells.《医学遗传学》第四章人类染色体与染色体病MitoticNon-DisjunctionMitoticnon-disjunctionarisesfromfailureofsisterchromatidstodisjoinatmitoticanaphase.2N2N2N2N2N2N－12N＋12N2N－12N＋147/45Mosaic46/47/45Mosaic《医学遗传学》第四章人类染色体与染色体病Meioticnon-disjunctionMitoticnon-disjunctionChromosomenon-disjunctionChromosomelossNumericalAbnormalityMechanismofAneuploid《医学遗传学》第四章人类染色体与染色体病Thecausalitywhereachromosomeismissingfromthenewcellcreatedviacelldivision.Anaphaselag(染色体分裂后期延滞)

maybeduetodelayedmovementofachromosomeatanaphase.ChromosomeLoss《医学遗传学》第四章人类染色体与染色体病TheBreakage

andthe

Rejoin

afterbreakagearethebasisofchromosomalstructuralaberration.ChromosomalrearrangementRearrangementchromosomeStructuralAberration《医学遗传学》第四章人类染色体与染色体病TerminalDeletionStructuralAberration4q27《医学遗传学》第四章人类染色体与染色体病InterstitialDeletionStructuralAberration4q134q25《医学遗传学》第四章人类染色体与染色体病ParacentricInversionStructuralAberration4q134q24《医学遗传学》第四章人类染色体与染色体病PericentricInversionStructuralAberration4p144q21《医学遗传学》第四章人类染色体与染色体病StructuralAberrationPericentricInversion《医学遗传学》第四章人类染色体与染色体病StructuralAberrationPericentricInversion《医学遗传学》第四章人类染色体与染色体病InversionloopStructuralAberrationPericentricInversion《医学遗传学》第四章人类染色体与染色体病StructuralAberrationPericentricInversion《医学遗传学》第四章人类染色体与染色体病InversionloopStructuralAberrationPericentricInversion《医学遗传学》第四章人类染色体与染色体病RingChromosomeStructuralAberration2q312p21《医学遗传学》第四章人类染色体与染色体病RingChromosomeStructuralAberration2q312p21p21q31《医学遗传学》第四章人类染色体与染色体病RingChromosomeStructuralAberration《医学遗传学》第四章人类染色体与染色体病RingChromosomeStructuralAberration《医学遗传学》第四章人类染色体与染色体病ReciprocalTranslocationStructuralAberration4q2520q12《医学遗传学》第四章人类染色体与染色体病StructuralAberrationReciprocalTranslocation《医学遗传学》第四章人类染色体与染色体病StructuralAberrationReciprocalTranslocation《医学遗传学》第四章人类染色体与染色体病ABCDFour-wayjunctionStructuralAberrationReciprocalTranslocation《医学遗传学》第四章人类染色体与染色体病RobertsonianTranslocationStructuralAberration《医学遗传学》第四章人类染色体与染色体病StructuralAberrationRobertsonianTranslocation《医学遗传学》第四章人类染色体与染色体病WholeArmTranslocationStructuralAberration《医学遗传学》第四章人类染色体与染色体病ComplexTranslocationStructuralAberration《医学遗传学》第四章人类染色体与染色体病IsochromosomeStructuralAberration《医学遗传学》第四章人类染色体与染色体病IsochromosomeStructuralAberration《医学遗传学》第四章人类染色体与染色体病DicentricChromosomeStructuralAberration6q2211p15《医学遗传学》第四章人类染色体与染色体病DirectInsertionStructuralAberration《医学遗传学》第四章人类染色体与染色体病InverseInsertionStructuralAberration《医学遗传学》第四章人类染色体与染色体病ChromosomeDiseaseinClinicalClinicalfeatureThegeneralfeaturesinautosomeabnormalitiesareatriadof

growthretardation,mentalretardation,and

specificsomaticabnormalities.Changeof

sexchromosome

alsohavetheabnormalitiesandmalformationsofinternalorexternalgenitalorgans.《医学遗传学》第四章人类染色体与染色体病DownSyndrome(trisomy21syndrome)ChromosomeDiseaseinClinical《医学遗传学》第四章人类染色体与染色体病CharacteristicsGrowthretardationVaryingdegreesofmentalretardationFlattenedfaceUpwardslantingoftheeyeswithepicanthalfolds(内眦赘皮)1in600~800newbornsChromosomeDiseaseinClinicalDownSyndrome(trisomy21syndrome)《医学遗传学》第四章人类染色体与染色体病1.

Trisomy

——

95%,47,XX(XY),＋21Causedbynon-disjunctionofchromosome21,correlatedwithageofmother.ChromosomeDiseaseinClinicalDownSyndrome(trisomy21syndrome)《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病Karyotypeofaffected：46,XX(XY),－14,＋t(14q21q)2.

Mosaic

——

2%~4%,46/473.

UnbalancetranslocationKaryotypeofbalancecarrier：45,XX(XY),－14,－21,＋t(14q21q)ChromosomeDiseaseinClinical1.

Trisomy

——

92.5%,47,XX(XY),＋21DownSyndrome(trisomy21syndrome)《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病1in3500~8000newbornsEdwardsSyndrome(trisomy18syndrome)CharacteristicsGrowthretardationMentalretardationCongenitalheartdiseaseRocker-bottomfeetfixedflexiondeformityofthefingersChromosomeDiseaseinClinical《医学遗传学》第四章人类染色体与染色体病ChromosomeDiseaseinClinical1in3500~8000newbornsEdwardsSyndrome(trisomy18syndrome)《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病1in25000newbornsPatauSyndrome(trisomy13syndrome)CharacteristicsVaryingdegreesofmentalretardationCleftlip&CleftpalatePolydactyly(postaxial)EquinovarusChromosomeDiseaseinClinical《医学遗传学》第四章人类染色体与染色体病《医学遗传学》第四章人类染色体与染色体病1in50000newborns5p-

Syndrome(CatCrysyndrome)CharacteristicsRound,moon-shapedface“Cryofthecat”VaryingdegreesofmentalretardationLowsetearsChromosomeDiseaseinClinical《医学遗传学》第四章人类染色体