遗传往届肽链从核蛋白体释放后经过细胞内各种修饰处理成为有活性的成熟蛋

1、Post-Translation ProcessingPost-translational modifications:肽链从核蛋白体释放后，经过细胞内各种修饰处理成为有活性的成熟蛋白质的过程。Primary translation product is folded and bonded into a specific three-dimensional structure.Two or more polypeptide chains combine to form a single mature protein complex.Cleavage of the protein The pro

2、tein products may also be modified chemicallySTRUCTURE OF HUMAN CHROMOSOMES Composition of ChromatinDNAProteins (histones and nonhistone) The basic structure unit of chromatin: Nucleosome H1, (H2A, H2B, H3, H4)2(H2A,H2B,H3,H4)ORGANIZATION OF THE HUMAN GENOMESingle-copy or unique DNARepetitive DNASin

3、gle-Copy DNA SequencesOnce or a few times /a genomeShort stretches (several kb)Coding portion of genes: a small proportion of all the single-copy DNARepetitive DNA FamiliesDefinition Hundreds to millions of times in the genomeRole Maintain chromosome structureCategoryClustered repeated sequencesDisp

4、ersed repeated sequencesPrinciples of Clinical CytogeneticsYuxia YangDepartment of Medical Genetics, Peking University Health Science CenterKey Points Introduction Karyotype Classification of Human Chromosome Human Chromosome Identification Categories Definitions Mechanisms Chromosome AbnormalitiesI

5、ntroduction to CytogeneticsClinical indications for chromasome analysis Cytogenetics: the study of chromosomes and their abnormalities is called cytogenetics.The Human KaryotypeThe chromosomes are classified into 7 groups (A-G) Karyotype：是指一个体细胞中的全部染色体，按照大小、形态特征顺序排列所构成的图像Centromere (primary constric

6、tion) 、p (short arm) 、 q (long arm) G bandingA chromosome at metaphase chromatid 染色单体 chromatid 1 chromosome p qTelomere（端粒）telomereCentromere（着丝粒）(primary constriction)topa,b: metacentric（中央着丝粒） c,d: submetacentric（亚中着丝粒） e: acrocentric（近端着丝粒） f: telocentric（端着丝粒）Classification of Human Chromosomes

7、A Normal male Karyotype: 46,XYChromosome Identification Identification of Human Chromosomes stained A uniform system of chromosome classification ISCN (An International System for Human Cytogenetic Nomenclature)Chromosome IdentificationG Banding: trypsin(胰蛋白酶) 、 Giemsa(姬姆萨)Q Banding: quinacrine must

8、ard(喹吖因氮芥) R Banding: special treatmemt (heating) 、 staining 、 the reverse of G or Q bandingG BandingQ BandingR bandingIdeogram showing G banding patterns for human chromosomes at metaphaseChromosome Identification Identification of Human Chromosomes stained A uniform system of chromosome classifica

9、tion ISCN (An International System for Human Cytogenetic Nomenclature)ISCN规定的界标：着丝粒、端粒、明显的带Arm Region Band Sub-bandXq13Chromosome Identification C Banding: staining the centromeric region、 other constitutive heterochromatin regionsHigh-Resolution Banding: chromosomes stained at the stage of prophase

10、 or prometaphase, detecting a subtle structural abnormality(前中期、晚前期的单倍染色体带纹数可达550-850条带;典型中期染色体，一套单倍染色体带纹数约320-400条带 )C BandingHigh-Resolution Banding Fluorescence In Situ Hybridization (FISH:荧光原位杂交)Principles: Labeling probe with a fluorescent dye Denature of the probe and metaphase、prophase or int

11、erphase chromosomes Hybridization Visualizing the location of hybridization under a fluorescence microscopeChromosome Identification Probes: three typesgene-specific or locus-specific probes, repetitive DNA probes (satellite DNA probes) chromosome painting probes (probes for entire chromosomes or ch

12、romosome arms)one-color, two-color, three-color, multicolorA single-copy DNA probe specific for the factor VIII gene on the X chromosomeMetaphase：中期Interphase:间期A repetitive alpha satellite DNA probe specific for the centromere of chromosome 17MetaphaseInterphaseA whole chromosome “paint” probe spec

13、ific for the X chromosomeMetaphaseInterphaseSpectral karyotyping (SKY：光谱核型分析) Application: to examine the presence or absence of a particular DNA sequence to diagnose the existence of an abnormal chromosome number in clinical materialto detect chromosome rearrangements with combinations of FISH prob

14、eschromosome 18 aqua, X chromosome green, Y chromosome redchromosome 18 aqua, X chromosome greenchromosome 13 green, chromosome 21 redPrader-Willi syndromedemonstrating deletion of 15q11-q13 Green：alpha satellite DNA at the chromosome 15 centromereRed：SNRPN geneChromosome AbnormalitiesAbnormalities

15、of Chromosome NumberAbnormalities of Chromosome StructureAbnormalities of Chromosome Number Euploid Variation：以染色体组为单位发生的染色体成倍的增减。 Aneuploid Variation：细胞内染色体数目增加或减少一条或几条。Triploidy and Tetraploidy Triploid(三倍体) Definition: 3nReason: dispermy(双受精) (most common)、 digyny(双雌受精)Phenotypic expression: pate

16、rnal-abnormal placenta; maternal-abortionkaryotypes: 69,XXX; 69,XXY; 69,XYYdispermydigyny Tetraploid(四倍体)Definition: 4nReason: endoreduplication (核内复制), endomitosis (核内的有丝分裂) Karyotypes: 92,XXXX or 92,XXYYAneuploidy TrisomyDefinition: a trisomic cell involves a single extra chromosome; that is, the

17、cell has three copies of a particular chromosomes and two copies of other chromosomes. A trisomic cell is 2n+1Example: trisomy 21 (karyotype: 47,XX/XY,+21) MonosomyDefinition: a monosomic cell involves a loss of a single chromosome; that is, the cell is 2n-1.Example: Turner syndrome (Turner syndrome

18、 karyotype: 45, X)MechanismMeiotic(减数分裂)nondisjunction (most common): the failure of a pair of chromosomes to disjoin properly during one of the two meiotic divisions, usually during meiosis I. The propensity of a chromosome pair to nondisjunction has been strongly associated with aberrations in the

19、 frequency or placement, or both, of bination events in meiosis I.Premature separation of sister chromatids : in meiosis I in stead of meiosis II, the separated chromatids may by chance segregate to the oocyte(卵母细胞)or to the polar body, leading to an unbalanced gamete(配子).Mitotic (有丝分裂)nondisjunctio

20、n: nondisjunction can occur in a mitotic division after formation of the zygote (受精卵). If this happens at an early cleavage division, clinically significant mosaicism may result.46464646464745nondisjunctionmitotic nondisjunction-mosaicism医学遗传学实验调课通知实验课时间为第2，4，5周下午（医实、临床7班、临床9班、预防、口腔-2班、医检）实验课时间为第3，6

21、，7周下午（口腔-1班、临床8班）注意：医实、临床7班、9班时间调整为周二下午13：30 医检调整为周五下午13：30 口腔-1班、临床8班调整为周五下午13：30 地点：细胞楼三层，具体教室分配见三层宣传栏 Abnormalities of Chromosome StructureMechanism: chromosome breakage 、 reconstitution in an abnormal combinationIncidence: 1 in 375 newborns Types of structure rearrangementsBalancedUnbalancedUnba

22、lanced RearrangementsDeletion (del)Definition: is a chromosomal mutation in which part of a chromosome is missingIncidence of autosomal deletions: 1/7000 live birthTypes: terminal, interstitialKaryotype: 46,XX,del(1)(q21) 46,XX,del(1)(pterq21:)Terminal deletionLoss常见染色体结构畸变的描述方法：按国际规定的要求，依次先写明染色体总数，

23、性染色体组成，然后用一个字母（如t）或三联字符号（如del）说明重排染色体类型的名称，其后在括号内写明有关的染色体号数，接着在另一括号内注明区、带号以表示断裂点。简式：只用其断点来表示： 46, XX, del(1)(q21)；繁式：在最后括弧内，描述染色体重排的带的组成： 46, XX, del(1)(pterq21:)Karyotype: 46,XX(XY),del(3)(q21q31) 46,XX(XY),del(3)(pterq21:q31qter) LossInterstitial deletionReasons: Deletions may originate simply by

24、chromosome breakage and loss of the acentric segment. Unequal crossing over between misaligned homologous chromosomes or sister chromatids.Deletions can also be generated by abnormal segregation from a balanced translocation or inversionDuplication (dup)Definition: is a chromosomal mutation that res

25、ults in the doubling of a segment of a chromosome.正位重复反位重复Duplication (dup)Reasons: Can originate by unequal crossing overBy abnormal segregation from meiosis in a carrier of a translocation or inversion.Marker and Ring ChromosomesMarker Chromosome (mar)Definition: very small unidentified chromosome

26、s, called marker chromosomes, are also referred to as supernumerary chromosomes or extra structurally abnormal chromosomes (ESACs)Ring Chromosome (r)Definition: deletions sometimes occur at both tips of a chromosome. The remaining chromosome ends can then fuse, forming a ring chromosome.ring chromos

27、omelosslosslossIsochromosomes (i)Definition: is a chromosome in which one arm is missing and the other duplicated in a mirror-image fashion.isochromosomereplicationafter replicationafter replicationisochromosomesIsochromosomes (i)Mechanisms: Misdivision through the centromere in meiosis II Exchange

28、involving one arm of a chromosome and its homolog (or sister chromatid) at the proximal edge of the arm, adjacent to the centromere.Isochromosomes (i)Common Isochromosomes: i(Xq) i(18p) i(12p) Dicentric(双着丝粒 ) Chromosomes (dic)Definition: a dicentric is a rare type of abnormal chromosome in which tw

29、o chromosome segments (from different chromosomes or from the two chromatids of a single one), each with a centromere, fuse end to end, with loss of their acentric fragments.dicentric chromosomeBalanced RearrangementsInversions (inv)Definition: occurs when a single chromosome undergoes two breaks an

30、d is reconstituted with the segment between the breaks inverted.Types: Paracentric (not including centromere) Pericentric (including centromere)ParacentricKaryotypes: 46,XX,inv(1)(p22p34) 46,XX,inv(1)(pterp34:p22p34:p22qter)PericentricKaryotypes: 46,XX,inv(2)(p15q21) 46,XX,inv(2)(pterp15:q21p15:q21q

31、ter)Inversion carrier: a carrier of either type of inversion is at risk of producing abnormal gametes that may lead to unbalanced offspringABACDBCDThe risk that a carrier of a paracentric inversion will have a liveborn child with an abnormal karyotype is very low indeed.ABACDBCD臂间倒位携带者在形成生殖细胞的减数分裂过程

32、中，根据在配子形成中同源染色体节段相互配对的规律，它将形成倒位圈，并且，经过在倒位圈内的交换，形成4种不同的配子，一种为正常染色体，一种为倒位染色体，另外两种均带有部分重复及部分缺失的重排染色体。这两种异常重排染色体各有一个着丝粒，属于稳定性畸变而可往后传递。因此其遗传效应主要决定于重复和缺失片段的长短及其所含基因的致死效应。一般来说，其倒位片段越短，则重复和缺失部分越长，形成配子和合子正常发育的可能性越小，临床表现为婚后不育、早期流产和死产的比例越高，娩出子女的可能性相对低；而倒位片段越长，则其重复和缺失部分越短，其配子和合子正常发育的可能性越大，娩出畸形胎儿的危险性相对较高Transloc

33、ations (t)Definition: involves the exchange of chromosome segments between two, usually nonhomologous chromosomesMain types: reciprocal, RobertsonianReciprocal Translocations (rcp)Definition: this type of rearrangement results from breakage of nonhomologous chromosomes, with reciprocal exchange of t

34、he broken-off segments.Karyotypes:46, XX, t(2;5)(q21;q31)46, XX, t(2;5)(2pter2q21:5q315qter;5pter5q31:2q212qter)reciprocal translocationCarriers of balanced reciprocal translocation: are associated with a high risk of unbalanced gametes and abnormal progenyFigure 9-12. A, Diagram of a balanced trans

35、location between chromosome 3 and chromosome11, t(3;11)(q12;p15.5)平衡易位携带者在形成生殖细胞的减数分裂的前期I时，易位染色体将在联会时配对形成四射体。至后期I时，相关染色体可进行对位分离和邻位1和邻位2分离以及3:1分离。其中，仅有一种配子是正常的，一种是平衡易位的，其余都是不平衡的。与正常配子受精后所形成的合子中，大部都形成单体或部分单体、三体或部分三体患胎而导致流产、死胎或畸形儿。Pairing at meiosisSegregationUnbalanced Unbalanced Normal balancedUnbala

36、nced Unbalanced(50%)(50%)(rare)(inviable)(inviable)(viable)Robertsonian Translocations (rob)Definition: this type of rearrangement involves two acrocentric chromosomes that fuse near the centromere region with loss of the short arms罗伯逊易位：又称着丝粒融合。两条近端着丝粒染色体在着丝粒部位或着丝粒附近部位发生断裂后，两者的长臂在着丝粒处结合在一起，形成一条由长臂构成的衍生染色体，两个短臂则构成一个小染色体，小染色体往往在第二次细胞分裂时丢失，这可能是由于缺乏着丝粒或其完全由异染