《医学遗传学》第四章人类染色体与染色体病.ppt

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1、第四章第四章 人类染色体和染色体病人类染色体和染色体病Painter TSPainter TS.Studies in mammalian spermatogenesis.Studies in mammalian spermatogenesis.II.The spermatogenesis of man.II.The spermatogenesis of man.J Exp ZoolJ Exp Zool.1923;.1923;37:291-33637:291-336Dark AgesHsu TCHsu TC.Mammalian chromosomes in vitro.I.The.Mammali

2、an chromosomes in vitro.I.The karyotype of man.karyotype of man.J HeredJ Hered.1952;43:167-172.1952;43:167-172Tjio JHTjio JH,Levan ALevan A.The chromosome number of man.The chromosome number of man.Am J Obstet GynecolAm J Obstet Gynecol.1956;130:723-724.1956;130:723-724 Hypotonic PeriodDark AgesTris

3、omy PeriodLejeune JLejeune J,et al.Etude des chromosomes somatiques,et al.Etude des chromosomes somatiques de neuf enfants mongoliens.de neuf enfants mongoliens.G.R.Acad.SciencesG.R.Acad.Sciences.1959;248:1721-17221959;248:1721-1722Ford CEFord CE,et al.A sex chromosomal anomaly in a case,et al.A sex

4、 chromosomal anomaly in a case of gonadal dysgenesis(Turners syndrome).of gonadal dysgenesis(Turners syndrome).LancetLancet.1959;1:711-7131959;1:711-713Jacob PAJacob PA,et al.A case of human intersexuality having,et al.A case of human intersexuality having a possible XXY sex determining mechanism.a

5、possible XXY sex determining mechanism.NatureNature.1959;183:302-303.1959;183:302-303.Hypotonic PeriodDark AgesBanding EraCaspersson TCaspersson T,et al.Differential banding of alkylating,et al.Differential banding of alkylating fluorochromes in human chromosomes.fluorochromes in human chromosomes.E

6、xp Cell Exp Cell ResRes.1970;60:315-319.1970;60:315-319 Hypotonic PeriodDark AgesTrisomy PeriodMolecular EraPardue MLPardue ML,et al.Molecular hybridization of radioactive,et al.Molecular hybridization of radioactive DNA to the DNA of cytological preparations.DNA to the DNA of cytological preparatio

7、ns.Proc.Natl.Proc.Natl.Acad.Sci.USA.Acad.Sci.USA.1969;64:600-604 1969;64:600-604 Pinkel Pinkel D D,et et al.al.Cytogenetic Cytogenetic analysis analysis using using quantitative,quantitative,high-sensitivity,high-sensitivity,fluorescence fluorescence hybridization.hybridization.Proc.Proc.Natl.Natl.A

8、cad.Sci.USA.Acad.Sci.USA.1986;83:2934-2938.1986;83:2934-2938.Hypotonic PeriodDark AgesBanding EraTrisomy PeriodDenver SystemThe karyotype is a photograph of all of the chromosomes of an individual cell;the term covers the number,relative sizes and structure of the chromosomes.核型：核型：一个体细胞中的全部染色体，按其大一

9、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。小、形态特征顺序排列所构成的图像。Chromosome can be distinguished by the relative sizes and the position of the centromere.Metacentric(1,3,16,19,20)Submetacentric(2,4-12,17,18,X)Acrocentric(13,14,15,21,22,Y)Denver SystemKaryotype analysis:arranging the chromosomes of a cell into a ka

10、ryotype,then analysis and compare with Denver system.Denver SystemThe karyotype is a photograph of all of the chromosomes of an individual cell;the term covers the number,relative sizes and structure of the chromosomes.Denver SystemBanding PatternBandBand（带带）:treated with chemical dyes,the treated w

11、ith chemical dyes,the chromosome will appear as a series of chromosome will appear as a series of alternate dark and light striations.alternate dark and light striations.Banding patternBanding pattern（带带型）：型）：型）：型）：treated with chemical treated with chemical dyes,24 types of chromosomes dyes,24 type

12、s of chromosomes appear its unique striations appear its unique striations individually.individually.Q-bandingQ-banding：QMQMBanding PatternBand:Band:treated treated with with chemical chemical dyes,dyes,the the chromosome chromosome will will appear appear as as a a series series of of alternate alt

13、ernate dark dark and and light striations.light striations.Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGiemsaBanding PatternBand:Band:treated treated with with chemical chemical dyes,dyes,the the chromosome chromosome will will appear appear as as a a series series of of alte

14、rnate alternate dark dark and and light striations.light striations.R-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orange cridine Orange Banding PatternQ-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGiemsaBand:Band:treated treated with with chem

15、ical chemical dyes,dyes,the the chromosome chromosome will will appear appear as as a a series series of of alternate alternate dark dark and and light striations.light striations.C-bandingC-banding：Y chromosome,centromere,secondary constrictionY chromosome,centromere,secondary constrictionBanding P

16、atternR-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orange cridine Orange Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGiemsaBand:Band:treated treated with with chemical chemical dyes,dyes,the the chromosome chromosome will will appear appear

17、 as as a a series series of of alternate alternate dark dark and and light striations.light striations.T-bandingT-banding：ending of chromosomeending of chromosomeBanding PatternC-bandingC-banding：Y chromosome,centromere,secondary constrictionY chromosome,centromere,secondary constrictionR-bandingR-b

18、anding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orange cridine Orange Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGiemsaBand:Band:treated treated with with chemical chemical dyes,dyes,the the chromosome chromosome will will appear appear as as a a series

19、series of of alternate alternate dark dark and and light striations.light striations.N-bandingN-banding：AgNOAgNO3 3Giemsa,NORGiemsa,NORT-bandingT-banding：ending of chromosomeending of chromosomeBanding PatternC-bandingC-banding：Y chromosome,centromere,secondary constrictionY chromosome,centromere,se

20、condary constrictionR-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orangecridine Orange Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGiemsaBand:Band:treated treated with with chemical chemical dyes,dyes,the the chromosome chromosome will will

21、appear appear as as a a series series of of alternate alternate dark dark and and light striations.light striations.LandmarkXpXqRegionBand1 1 1 1 2 2 2 2 1 12 23 34 45 56 67 78 8Xq28Xq28Banding PatternDevelopment1.High resolution banding chromosome(HRBC)1.High resolution banding chromosome(HRBC)vv F

22、ISH FISH(fluorescence in situ hybridization)(fluorescence in situ hybridization)3.Molecular cytogenetics3.Molecular cytogeneticsDevelopment2.Microcytogenetics2.Microcytogenetics1.High resolution banding chromosome(HRBC)1.High resolution banding chromosome(HRBC)FISHX染色体染色体Y染色体染色体13号染色体号染色体18号染色体号染色体2

23、1号染色体号染色体FISHvv FISH FISH(fluorescence in situ hybridization)(fluorescence in situ hybridization)vv DNA fiber-FISHDNA fiber-FISH3.Molecular cytogenetics3.Molecular cytogeneticsDevelopment2.Microcytogenetics2.Microcytogenetics1.High resolution banding chromosome(HRBC)1.High resolution banding chromos

24、ome(HRBC)DNA fiber-FISH3 cosmid from MHC locus3540 Kb/cosmidvv FISH FISH(fluorescence in situ hybridization)(fluorescence in situ hybridization)vv DNA fiber-FISH DNA fiber-FISHvv Chromosome PaintingChromosome Painting3.Molecular cytogenetics3.Molecular cytogeneticsDevelopment2.Microcytogenetics2.Mic

25、rocytogenetics1.High resolution banding chromosome(HRBC)1.High resolution banding chromosome(HRBC)Chromosome PaintingChromosome PaintingChromosomal AberrationvvNumerical AbnormalityvvStructural AberrationNumerical Abnormality单倍体单倍体:22+X,22+Y二倍体二倍体:44+XX,44+XYNumerical AbnormalityVariation in chromos

26、ome number can take 2 forms:整整整整倍倍倍倍体体体体:that that which which involves involves whole whole setssets (genomes)(genomes)of of chromosomeschromosomes非非非非整整整整倍倍倍倍体体体体:the the chromosome chromosome number number is is notnot an an exact exact multiple of the haploidmultiple of the haploid（单倍体单倍体单倍体单倍体）

27、numbernumber整倍体整倍体三三三三倍倍倍倍体体体体:the the cell cell which which has has 3 3 sets sets(genomes)(genomes)of of chromosomeschromosomes 3n 3n 69 69Numerical AbnormalityNumerical Abnormality整倍体整倍体三三三三倍倍倍倍体体体体:the the cell cell which which has has 3 3 sets sets(genomes)(genomes)of of chromosomeschromosomes 3

28、n 3n 69 69Tripolar spindleTripolar spindle双双双双雄雄雄雄受受受受精精精精:fertilization fertilization of of 1 1 oocyte oocyte by by 2 2 spermatozoa spermatozoa 双双双双雌雌雌雌受受受受精精精精:non-expulsion non-expulsion of of the the 2nd 2nd polar polar bodybodyNumerical Abnormality整倍体整倍体三三三三倍倍倍倍体体体体:the the cell cell which whic

29、h has has 3 3 sets sets(genomes)(genomes)of of chromosomeschromosomes 3n 3n 69 69整倍体整倍体多倍体多倍体四四四四倍倍倍倍体体体体:the the cell cell which which has has 4 4 sets sets(genomes)(genomes)of of chromosomes chromosomes 4n 4n 92 92vv核内复制核内复制核内复制核内复制Numerical Abnormality核内复制核内复制双分染色体双分染色体双分染色体双分染色体OO Diplochromosom

30、eDiplochromosome整倍体整倍体多倍体多倍体四四四四倍倍倍倍体体体体:the the cell cell which which has has 4 4 sets sets(genomes)(genomes)of of chromosomes chromosomes 4n 4n 92 92vv核内复制核内复制核内复制核内复制Numerical Abnormalityvv核内有丝分裂核内有丝分裂核内有丝分裂核内有丝分裂BeBe found more commonly than found more commonly than Euploid(Euploid(整倍体整倍体整倍体整倍体)

31、亚亚亚亚二二二二倍倍倍倍体体体体:less less than than the the normal normal 2n 2n number number of of chromosomeschromosomesNumerical Abnormality非整倍体非整倍体超超超超二二二二倍倍倍倍体体体体:more more than than the the normal normal 2n 2n number number of of chromosomeschromosomes单单单单体体体体型型型型:is is the the presence presence of of only o

32、nly one one copy copy of of any chromosomeany chromosomeLoss of autosomes is not toleratedLoss of autosomes is not toleratedTurner syndrome:45,XTurner syndrome:45,XNumerical Abnormality非整倍体非整倍体亚二倍体亚二倍体亚二倍体亚二倍体Be found more commonly than Be found more commonly than MonosomyMonosomyTrisomyTrisomy of s

33、ex chromosome is more commonlyof sex chromosome is more commonlyNumerical Abnormality非整倍体非整倍体超二倍体超二倍体超二倍体超二倍体三三三三体体体体型型型型:is is the the presence presence of of only only three three copy copy of any chromosomeof any chromosomeMeiotic(Meiotic(减数分裂减数分裂减数分裂减数分裂)non-disjunction)non-disjunctionMitotic(Mi

34、totic(有丝分裂有丝分裂有丝分裂有丝分裂)non-disjunction)non-disjunctionChromosome non-disjunctionChromosome non-disjunctionNumerical AbnormalityMechanism of Aneuploid(非整倍体非整倍体)Meiosis in animals.Meiotic Non-DisjunctionMeiotic non-disjunction arises from failure of paired homologous chromosomes or sister chromatid to

35、 disjoin at meiotic anaphase.Meiotic Non-Disjunction2N2NN NN N1 1N N1 12N2N1 12N2N1 12N2N1 12N2N1 1N N1 1N N1 1N N1 1N N1 12N2N2N2N2N2N1 12N2N1 12N2NN NN NN NN NN N1 1N N1 1Primary non-disjunctionPrimary non-disjunction is the failure of chromosomes or sister sister chromatidchromatid to separate in

36、 meiosis.The gamete thus has two copies of a chromosome.Fertilization adds another copy to give a total of 3 copies.Secondary non-disjunctionTrisomy offspring arise from segregation at meiosis of an already-trisomy parent.Meiotic Non-DisjunctionMeiotic Non-Disjunction2N+12N+1N N2N2N2N2N2N2N1 12N2N1

37、1N NN N1 1N NN NN N1 1N N1 1Meiotic non-disjunctionMeiotic non-disjunctionMitotic non-disjunctionMitotic non-disjunctionChromosome non-disjunctionChromosome non-disjunctionNumerical AbnormalityMechanism of AneuploidMitosis in animal cells.Mitotic Non-DisjunctionMitotic non-disjunction arises from fa

38、ilure of sister chromatids to disjoin at mitotic anaphase.2N2N2N2N2N2N2N2N2N2N2N2N1 12N2N1 12N2N2N2N1 12N2N1 147/45 Mosaic46/47/45 MosaicMeiotic non-disjunctionMeiotic non-disjunctionMitotic non-disjunctionMitotic non-disjunctionChromosome non-disjunctionChromosome non-disjunctionChromosome lossChro

39、mosome lossNumerical AbnormalityMechanism of AneuploidThe causality where a chromosome is missing from the new cell created via cell division.Anaphase lag(染染色色体体分分裂裂后后期期延延滞滞)may be due to delayed movement of a chromosome at anaphase.Chromosome LossThe Breakage and the Rejoin after breakage are the b

40、asis of chromosomal structural aberration.Chromosomal rearrangementRearrangement chromosomeStructural AberrationTerminal DeletionStructural Aberration4q274q27Interstitial DeletionStructural Aberration4q134q134q254q25Paracentric InversionStructural Aberration4q134q134q244q24Pericentric InversionStruc

41、tural Aberration4p144p144q214q21Structural AberrationPericentric InversionStructural AberrationPericentric InversionInversion loopStructural AberrationPericentric InversionStructural AberrationPericentric InversionInversion loopStructural AberrationPericentric InversionRing ChromosomeStructural Aber

42、ration2q312q312p212p21Ring ChromosomeStructural Aberration2q312q312p212p21p21p21q31q31Ring ChromosomeStructural AberrationRing ChromosomeStructural AberrationReciprocal TranslocationStructural Aberration4q254q2520q1220q12Structural AberrationReciprocal TranslocationStructural AberrationReciprocal Tr

43、anslocationRobertsonian TranslocationStructural AberrationStructural AberrationRobertsonian TranslocationWhole Arm TranslocationStructural AberrationComplex TranslocationStructural AberrationIsochromosomeStructural AberrationIsochromosomeStructural AberrationDicentric ChromosomeStructural Aberration

44、6q2211p15Direct InsertionStructural AberrationInverse InsertionStructural AberrationChromosome Disease in ClinicalClinical featureThe general features in autosome abnormalities are a triad of growth retardation,mental retardation,and specific somatic abnormalities.Change of sex chromosome also have

45、the abnormalities and malformations of internal or external genital organs.Down Syndrome Down Syndrome(trisomy 21 syndrome)Chromosome Disease in ClinicalCharacteristicsCharacteristicsoGrowth retardationoVarying degrees of mental retardationoFlattened face oUpward slanting of the eyes with epicanthal

46、 folds(内眦赘皮内眦赘皮)1 in 600 800 newbornsChromosome Disease in ClinicalDown Syndrome Down Syndrome(trisomy 21 syndrome)1.Trisomy 95%,47,XX(XY),21Caused by non-disjunction of chromosome 21,correlated with age of mother.Chromosome Disease in ClinicalDown Syndrome Down Syndrome(trisomy 21 syndrome)Karyotyp

47、e of affected：46,XX(XY),14,t(14q21q)2.Mosaic 2%4%,46/473.Unbalance translocationKaryotype of balance carrier：45,XX(XY),14,21,t(14q21q)Chromosome Disease in Clinical1.Trisomy 92.5%,47,XX(XY),21Down Syndrome Down Syndrome(trisomy 21 syndrome)1 in 3500 8000 newbornsEdwards Syndrome Edwards Syndrome(tri

48、somy 18 syndrome)CharacteristicsCharacteristicsoGrowth retardationoMental retardationoCongenital heart diseaseoRocker-bottom feet ofixed flexion deformity of the fingers Chromosome Disease in ClinicalChromosome Disease in Clinical1 in 3500 8000 newbornsEdwards Syndrome Edwards Syndrome(trisomy 18 sy

49、ndrome)1 in 25 000 newbornsPatau Syndrome Patau Syndrome(trisomy 13 syndrome)CharacteristicsCharacteristicsoVarying degrees of mental retardationoCleft lip&Cleft palateoPolydactyly(postaxial)oEquinovarusChromosome Disease in Clinical1 in 50000 newborns5p5p-Syndrome Syndrome(Cat Cry syndrome)Characte

50、risticsCharacteristicso oRound,moon-shaped faceRound,moon-shaped faceo o“Cry of the cat”“Cry of the cat”o oVarying Varying degrees degrees of of mental mental retardationretardationo oLow set earsLow set earsChromosome Disease in ClinicalTurner Syndrome Turner Syndrome(45,X)1 in 5000 liveborn female