《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,Painter TS.Studies in mammalian spermatogenesis.II.The spermatogenesis of man.J Exp Zool.1923;37:291-336,Dark Ages,Hsu TC.Mammalian chromosomes in vitro.I.The karyotype of man.J Hered.1952;43:167-172Tjio JH,Levan A.The chromosome number of man.Am J Obstet Gynecol.1956;130:723-724,Hypotonic Period,Dark Ages,Trisomy Period,Lejeune J,et al.Etude des chromosomes somatiques de neuf enfants mongoliens.G.R.Acad.Sciences.1959;248:1721-1722Ford CE,et al.A sex chromosomal anomaly in a case of gonadal dysgenesis(Turners syndrome).Lancet.1959;1:711-713Jacob PA,et al.A case of human intersexuality having a possible XXY sex determining mechanism.Nature.1959;183:302-303.,Hypotonic Period,Dark Ages,Banding Era,Caspersson T,et al.Differential banding of alkylating fluorochromes in human chromosomes.Exp Cell Res.1970;60:315-319,Hypotonic Period,Dark Ages,Trisomy Period,Molecular Era,Pardue ML,et al.Molecular hybridization of radioactive DNA to the DNA of cytological preparations.Proc.Natl.Acad.Sci.USA.1969;64:600-604 Pinkel D,et al.Cytogenetic analysis using quantitative,high-sensitivity,fluorescence hybridization.Proc.Natl.Acad.Sci.USA.1986;83:2934-2938.,Hypotonic Period,Dark Ages,Banding Era,Trisomy Period,Denver System,The 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：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。,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 System,Karyotype analysis:arranging the chromosomes of a cell into a karyotype,then analysis and compare with Denver system.,Denver System,The 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 System,Banding Pattern,Band（带）:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,Banding pattern（带型）：treated with chemical dyes,24 types of chromosomes appear its unique striations individually.,Q-banding：QM,Banding Pattern,Band:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,Q-banding：QM,G-banding：pancreatinGiemsa,Banding Pattern,Band:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,R-banding：treated specimenGiemsa or Acridine Orange,Banding Pattern,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,C-banding：Y chromosome,centromere,secondary constriction,Banding Pattern,R-banding：treated specimenGiemsa or Acridine Orange,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,T-banding：ending of chromosome,Banding Pattern,C-banding：Y chromosome,centromere,secondary constriction,R-banding：treated specimenGiemsa or Acridine Orange,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,N-banding：AgNO3Giemsa,NOR,T-banding：ending of chromosome,Banding Pattern,C-banding：Y chromosome,centromere,secondary constriction,R-banding：treated specimenGiemsa or Acridine Orange,Q-banding：QM,G-banding：pancreatinGiemsa,Band:treated with chemical dyes,the chromosome will appear as a series of alternate dark and light striations.,Landmark,Xp,Xq,Region,Band,1,1,2,2,12345678,Xq28,Banding Pattern,Development,1.High resolution banding chromosome(HRBC),FISH(fluorescence in situ hybridization),3.Molecular cytogenetics,Development,2.Microcytogenetics,1.High resolution banding chromosome(HRBC),FISH,FISH,FISH,FISH,FISH(fluorescence in situ hybridization),DNA fiber-FISH,3.Molecular cytogenetics,Development,2.Microcytogenetics,1.High resolution banding chromosome(HRBC),DNA fiber-FISH,3 cosmid from MHC locus3540 Kb/cosmid,FISH(fluorescence in situ hybridization),DNA fiber-FISH,Chromosome Painting,3.Molecular cytogenetics,Development,2.Microcytogenetics,1.High resolution banding chromosome(HRBC),Chromosome Painting,Chromosome Painting,Chromosome Painting,FISH(fluorescence in situ hybridization),DNA fiber-FISH,Chromosome Painting,CGH(comparative genomic hybridization),3.Molecular cytogenetics,Development,2.Microcytogenetics,1.High resolution banding chromosome(HRBC),CGH,CGH,CGH,Advantages,Whole genome in 1 experiment,No need to culture tumor cells,Sensitive detection of gene amplification,Disadvantages,Limited resolution(10 Mb del/dup),Laborious,Only gains and losses/no balanced rearrangements,No information on the nature of the aberrations,Retrospective analysis,CGH,Heteromorphism,Banding pattern polymorphism,Chromosome heteromorphisms are normal variations in the appearance of chromosomes.,Be inherited in a Mendelian fashion,Constitutive heterochromatinNot chromosomal abnormality in clinical,Heteromorphism,Banding pattern polymorphism,Chromosomal lengthSatelliteSecondary constrictionPolymorphism of Q,G,C banding,Chromosomal Aberration,Numerical Abnormality,Structural Aberration,Numerical Abnormality,单倍体:22+X,22+Y,二倍体:44+XX,44+XY,Numerical Abnormality,Variation in chromosome number can take 2 forms:,整倍体:that which involves whole sets(genomes)of chromosomes,非整倍体:the chromosome number is not an exact multiple of the haploid（单倍体）number,整倍体,三倍体:the cell which has 3 sets(genomes)of chromosomes 3n 69,Numerical Abnormality,Numerical Abnormality,整倍体,三倍体:the cell which has 3 sets(genomes)of chromosomes 3n 69,Tripolar spindle,双雄受精:fertilization of 1 oocyte by 2 spermatozoa,双雌受精:non-expulsion of the 2nd polar body,Numerical Abnormality,整倍体,三倍体:the cell which has 3 sets(genomes)of chromosomes 3n 69,整倍体多倍体,四倍体:the cell which has 4 sets(genomes)of chromosomes 4n 92,核内复制,Numerical Abnormality,核内复制,双分染色体,Diplochromosome,整倍体多倍体,四倍体:the cell which has 4 sets(genomes)of chromosomes 4n 92,核内复制,Numerical Abnormality,核内有丝分裂,Be found more commonly than Euploid(整倍体),亚二倍体:less than the normal 2n number of chromosomes,Numerical Abnormality,非整倍体,超二倍体:more than the normal 2n number of chromosomes,单体型:is the presence of only one copy of any chromosome,Loss of autosomes is not tolerated,Turner syndrome:45,X,Numerical Abnormality,非整倍体,亚二倍体,Be found more commonly than Monosomy,Trisomy of sex chromosome is more commonly,Numerical Abnormality,非整倍体,超二倍体,三体型:is the presence of only three copy of any chromosome,Meiotic(减数分裂)non-disjunction,Mitotic(有丝分裂)non-disjunction,Chromosome non-disjunction,Numerical Abnormality,Mechanism of Aneuploid(非整倍体),Meiosis in animals.,Meiotic Non-Disjunction,Meiotic non-disjunction arises from failure of paired homologous chromosomes or sister chromatid to disjoin at meiotic anaphase.,Meiotic Non-Disjunction,Primary non-disjunction,Primary non-disjunction is the failure of chromosomes or sister chromatid 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-disjunction,Trisomy offspring arise from segregation at meiosis of an already-trisomy parent.,Meiotic Non-Disjunction,Meiotic Non-Disjunction,Meiotic non-disjunction,Mitotic non-disjunction,Chromosome non-disjunction,Numerical Abnormality,Mechanism of Aneuploid,Mitosis in animal cells.,Mitotic Non-Disjunction,Mitotic non-disjunction arises from failure of sister chromatids to disjoin at mitotic anaphase.,47/45 Mosaic,46/47/45 Mosaic,Meiotic non-disjunction,Mitotic non-disjunction,Chromosome non-disjunction,Chromosome loss,Numerical Abnormality,Mechanism of Aneuploid,The causality where a chromosome is missing from the new cell created via cell division.,Anaphase lag(染色体分裂后期延滞)may be due to delayed movement of a chromosome at anaphase.,Chromosome Loss,The Breakage and the Rejoin after breakage are the basis of chromosomal structural aberration.,Chromosomal rearrangement,Rearrangement chromosome,Structural Aberration,Terminal Deletion,Structural Aberration,Interstitial Deletion,Structural Aberration,4q13,Paracentric Inversion,Structural Aberration,4q13,Pericentric Inversion,Structural Aberration,4p14,Structural Aberration,Pericentric Inversion,Structural Aberration,Pericentric Inversion,Inversion loop,Structural Aberration,Pericentric Inversion,Structural Aberration,Pericentric Inversion,Inversion loop,Structural Aberration,Pericentric Inversion,Ring Chromosome,Structural Aberration,Ring Chromosome,Structural Aberration,Ring Chromosome,Structural Aberration,Ring Chromosome,Structural Aberration,Reciprocal Translocation,Structural Aberration,Structural Aberration,Reciprocal Translocation,Structural Aberration,Reciprocal Translocation,Structural Aberration,Reciprocal Translocation,Robertsonian Translocation,Structural Aberration,Structural Aberration,Robertsonian Translocation,Whole Arm Translocation,Structural Aberration,Complex Translocation,Structural Aberration,Isochromosome,Structural Aberration,Isochromosome,Structural Aberration,Dicentric Chromosome,Structural Aberration,Direct Insertion,Structural Aberration,Inverse Insertion,Structural Aberration,Chromosome Disease in Clinical,Clinical feature,The general features in autosome 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(trisomy 21 syndrome),Chromosome Disease in Clinical,Characteristics,Growth retardationVarying degrees of mental retardationFlattened face Upward slanting of the eyes with epicanthal folds(内眦赘皮),1 in 600 800 newborns,Chromosome Disease in Clinical,Down Syndrome(trisomy 21 syndrome),1.Trisomy 95%,47,XX(XY),21,Caused by non-disjunction of chromosome 21,correlated with age of mother.,Chromosome Disease in Clinical,Down Syndrome(trisomy 21 syndrome),Karyotype of affected：46,XX(XY),14,t(14q21q),2.Mosaic 2%4%,46/47,3.Unbalance translocation,Karyotype of balance carrier：,45,XX(XY),14,21,t(14q21q),Chromosome Disease in Clinical,1.Trisomy 92.5%,47,XX(XY),21,Down Syndrome(trisomy 21 syndrome),1 in 3500 8000 newborns,Edwards Syndrome(trisomy 18 syndrome),Characteristics,Growth retardationMental retardationCongenital heart diseaseRocker-bottom feet fixed flexion deformity of the fingers,Chromosome Disease in Clinical,Chromosome Disease in Clinical,1 in 3500 8000 newborns,Edwards Syndrome(trisomy 18 syndrome),1 in 25 000 newborns,Patau Syndrome(trisomy 13 syndrome),Characteristics,Varying degrees of mental retardationCleft lip&Cleft palatePolydactyly(postaxial)Equinovarus,Chromosome Disease in Clinical,1 in 50000 newborns,5p-Syndrome(Cat Cry syndrome),Characteristics,Round,moon-shaped face“Cry of the cat”Varying degrees of mental retardationLow set ears,Chromosome Disease in Clinical,Turner Syndrome(45,X),1 in 5000 liveborn females,Characteristics,Short stature wide nipples,Chromosome Disease in Clinical,Trisomy X syndrome(47,XXX),1 in 1000 liveborn females,1 in 250 psychopath of females,Two of the three X chromosomes are inactivated.,Chromosome Disease in Clinical,1 2 in 1000 males,Tall with disproportionately long arms/legs,Klinefelter syndrome(47,XXY),1 in 100 mentally retarded males,1 in 10 infertile males,Poorly developed secondary sex characteristicsTesticular dysgenesis,Chromosome Disease in Clinical,1 in 900 males,Tall stature,XYY syndrome(47,XYY),1 in 30 male prison populations,Predisposition to violent,criminal behavior,180 cm:1/200190 cm:1/30200 cm:1/10,Chromosome Disease in Clinical,1 in 1250 males,Fragile X chromosome syndrome(Fra X),Characteristics,Show mild to severe mental retardationLarge,protruding earsEnlarged testesNarrow face with a prominent chinBehavioral problems,Chromosome Disease in Clinical,Denver System&Karyotype analysisNumerical Abnormality&MechanismStructural Aberration&MechanismChromosome Disease in ClinicalDisjunction of balancing chromosome,Key Points,