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1、医学遗传学第四章人类染色体与染色体病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 AgesMolecular EraPardue MLPardue ML,et al.Molecular hybridization of r
2、adioactive,et al.Molecular hybridization of radioactive DNA to the DNA of cytological preparations.DNA to the DNA of cytological preparations.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 us
3、ing quantitative,quantitative,high-sensitivity,high-sensitivity,fluorescence fluorescence hybridization.hybridization.Proc.Proc.Natl.Natl.Acad.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
4、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,
5、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 karyotype,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 t
6、he number,relative sizes and structure of the chromosomes.Denver SystemBanding PatternBandBand（带带）:treated with chemical dyes,the treated with 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 st
7、riations.Banding patternBanding pattern（带带型）：型）：型）：型）：treated with chemical treated with chemical dyes,24 types of chromosomes dyes,24 types of chromosomes appear its unique striations appear its unique striations individually.individually.Q-bandingQ-banding：QMQMBanding PatternBand:Band:treated trea
8、ted with with chemical 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.Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGiemsaBanding PatternBand:Band:tre
9、ated treated with with chemical 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.R-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orange cridi
10、ne Orange Banding PatternQ-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 series of of alternate alternate dark dark and and light striation
11、s.light striations.C-bandingC-banding：Y chromosome,centromere,secondary constrictionY chromosome,centromere,secondary constrictionBanding PatternR-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orange cridine Orange Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatin
12、pancreatinGiemsaGiemsaBand: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 alternate dark dark and and light striations.light striations.T-bandingT-banding：ending of chromosomeending of chromosom
13、eBanding PatternC-bandingC-banding：Y chromosome,centromere,secondary constrictionY chromosome,centromere,secondary constrictionR-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orange cridine Orange Q-bandingQ-banding：QMQMG-bandingG-banding：pancreatinpancreatinGiemsaGi
14、emsaBand: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 alternate dark dark and and light striations.light striations.N-bandingN-banding：AgNOAgNO3 3Giemsa,NORGiemsa,NORT-bandingT-banding：ending
15、of chromosomeending of chromosomeBanding PatternC-bandingC-banding：Y chromosome,centromere,secondary constrictionY chromosome,centromere,secondary constrictionR-bandingR-banding：treated specimentreated specimenGiemsa or AGiemsa or Acridine Orangecridine Orange Q-bandingQ-banding：QMQMG-bandingG-bandi
16、ng：pancreatinpancreatinGiemsaGiemsaBand: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 alternate dark dark and and light striations.light striations.LandmarkXpXqRegionBand1 1 1 1 2 2 2 2 1 12 23
17、 34 45 56 67 78 8Xq28Xq28Banding PatternDevelopment1.High resolution banding chromosome(HRBC)1.High resolution banding chromosome(HRBC)vv FISH FISH(fluorescence in situ hybridization)(fluorescence in situ hybridization)3.Molecular cytogenetics3.Molecular cytogeneticsDevelopment2.Microcytogenetics2.M
18、icrocytogenetics1.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21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.Molecul
19、ar cytogeneticsDevelopment2.Microcytogenetics2.Microcytogenetics1.High resolution banding chromosome(HRBC)1.High resolution banding chromosome(HRBC)DNA fiber-FISH3 cosmid from MHC locus3540 Kb/cosmidvv FISH FISH(fluorescence in situ hybridization)(fluorescence in situ hybridization)vv DNA fiber-FISH
20、 DNA fiber-FISHvv Chromosome PaintingChromosome Painting3.Molecular cytogenetics3.Molecular cytogeneticsDevelopment2.Microcytogenetics2.Microcytogenetics1.High resolution banding chromosome(HRBC)1.High resolution banding chromosome(HRBC)Chromosome PaintingChromosome PaintingChromosomal AberrationvvN
21、umerical 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 chromosome 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
22、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）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 Abnormality
23、Numerical 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 3n 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
24、: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 which 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(gen
25、omes)(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 DiplochromosomeDiplochromosome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
26、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)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 mor
27、e 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 only one one copy copy of of any chromosomeany chromosomeLoss of autosomes is not toleratedLoss of autosomes is not toleratedTurner syndrome:45,XTurner syndrome:4
28、5,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 sex 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 o
29、nly 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(Mitotic(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)Me
30、iosis in animals.Meiotic Non-DisjunctionMeiotic non-disjunction arises from failure of paired homologous chromosomes or sister chromatid to 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 N
31、N N1 1N N1 1Primary non-disjunctionPrimary non-disjunction is the failure of chromosomes or sister sister chromatidchromatid to separate in 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 ar
32、ise from segregation at meiosis of an already-trisomy parent.Meiotic Non-DisjunctionMeiotic Non-Disjunction2N+12N+1N N2N2N2N2N2N2N1 12N2N1 1N NN N1 1N NN NN N1 1N N1 1Meiotic non-disjunctionMeiotic non-disjunctionMitotic non-disjunctionMitotic non-disjunctionChromosome non-disjunctionChromosome non-
33、disjunctionNumerical AbnormalityMechanism of AneuploidMitosis in animal cells.Mitotic Non-DisjunctionMitotic non-disjunction arises from failure of sister chromatids to disjoin at mitotic anaphase.2N2N2N2N2N2N2N2N2N2N2N2N1 12N2N1 12N2N2N2N1 12N2N1 147/45 Mosaic46/47/45 MosaicMeiotic non-disjunctionM
34、eiotic non-disjunctionMitotic non-disjunctionMitotic non-disjunctionChromosome non-disjunctionChromosome non-disjunctionChromosome lossChromosome 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
35、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 basis of chromosomal structural aberration.Chromosomal rearrangementRearrangement chromosomeStructural AberrationTerminal DeletionStructural Aberration4q274q27Int
36、erstitial DeletionStructural Aberration4q134q134q254q25Paracentric InversionStructural Aberration4q134q134q244q24Pericentric InversionStructural Aberration4p144p144q214q21Structural AberrationPericentric InversionStructural AberrationPericentric InversionInversion loopStructural AberrationPericentri
37、c InversionStructural AberrationPericentric InversionInversion loopStructural AberrationPericentric InversionRing ChromosomeStructural Aberration2q312q312p212p21Ring ChromosomeStructural Aberration2q312q312p212p21p21p21q31q31Ring ChromosomeStructural AberrationRing ChromosomeStructural AberrationRec
38、iprocal TranslocationStructural Aberration4q254q2520q1220q12Structural AberrationReciprocal TranslocationStructural AberrationReciprocal TranslocationRobertsonian TranslocationStructural AberrationStructural AberrationRobertsonian TranslocationWhole Arm TranslocationStructural AberrationComplex Tran
39、slocationStructural AberrationIsochromosomeStructural AberrationIsochromosomeStructural AberrationDicentric ChromosomeStructural Aberration6q2211p15Direct InsertionStructural AberrationInverse InsertionStructural AberrationChromosome Disease in ClinicalClinical featureThe general features in autosom
40、e abnormalities are a triad of growth retardation,mental retardation,and specific somatic abnormalities.Change of sex chromosome also have the abnormalities and malformations of internal or external genital organs.Down Syndrome Down Syndrome(trisomy 21 syndrome)Chromosome Disease in ClinicalCharacte
41、risticsCharacteristicsoGrowth retardationoVarying degrees of mental retardationoFlattened face oUpward slanting of the eyes with epicanthal 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-disjun
42、ction of chromosome 21,correlated with age of mother.Chromosome Disease in ClinicalDown Syndrome Down Syndrome(trisomy 21 syndrome)Karyotype 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 Clini
43、cal1.Trisomy 92.5%,47,XX(XY),21Down Syndrome Down Syndrome(trisomy 21 syndrome)1 in 3500 8000 newbornsEdwards Syndrome Edwards Syndrome(trisomy 18 syndrome)CharacteristicsCharacteristicsoGrowth retardationoMental retardationoCongenital heart diseaseoRocker-bottom feet ofixed flexion deformity of the
44、 fingers Chromosome Disease in ClinicalChromosome Disease in Clinical1 in 3500 8000 newbornsEdwards Syndrome Edwards Syndrome(trisomy 18 syndrome)1 in 25 000 newbornsPatau Syndrome Patau Syndrome(trisomy 13 syndrome)CharacteristicsCharacteristicsoVarying degrees of mental retardationoCleft lip&Cleft
45、 palateoPolydactyly(postaxial)oEquinovarusChromosome Disease in Clinical1 in 50000 newborns5p5p-Syndrome Syndrome(Cat Cry syndrome)CharacteristicsCharacteristicso 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 re
46、tardationretardationo oLow set earsLow set earsChromosome Disease in ClinicalTurner Syndrome Turner Syndrome(45,X)1 in 5000 liveborn femalesCharacteristicsCharacteristicso oShort stature&Short stature&Webbed neckWebbed necko oOvarian dysgenesis,Ovarian dysgenesis,primary primary amenorrhea,amenorrhe
47、a,infertilityinfertilityo oAbsence of secondary sex Absence of secondary sex characteristicscharacteristicso oUnderdeveloped breasts;Underdeveloped breasts;wide nippleswide nipplesChromosome Disease in ClinicalTrisomy X syndrome(47,XXX)1 in 1000 liveborn females1 in 250 psychopath of femalesTwo of t
48、he three X chromosomes are inactivated.Chromosome Disease in Clinical1 2 in 1000 malesoTall with disproportionately long arms/legsKlinefelter syndrome(47,XXY)1 in 100 mentally retarded males1 in 10 infertile malesoPoorly developed secondary sex characteristicsoTesticular dysgenesisChromosome Disease
49、 in Clinical1 in 900 malesoTall statureXYY syndrome(47,XYY)1 in 30 male prison populations oPredisposition to violent,criminal behavior180 cm:1/200190 cm:1/30200 cm:1/10Chromosome Disease in Clinical1 in 1250 malesFragile X chromosome syndrome(Fra X)CharacteristicsCharacteristicsoShow mild to severe
50、 mental retardationoLarge,protruding earsoEnlarged testesoNarrow face with a prominent chinoBehavioral problemsChromosome Disease in ClinicalvvDenver System&Karyotype analysisvvNumerical Abnormality&MechanismvvStructural Aberration&MechanismvvChromosome Disease in ClinicalvvDisjunction of balancing