Post-Translation Processing

Presentation on theme: "Post-Translation Processing"— Presentation transcript:

1 Post-Translation Processing
Post-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 protein products may also be modified chemically

2 STRUCTURE OF HUMAN CHROMOSOMES
Composition of Chromatin DNA Proteins (histones and nonhistone) The basic structure unit of chromatin: Nucleosome H1, (H2A, H2B, H3, H4)2 Nucleosome:核小体

3 (H2A,H2B,H3,H4)

4 ORGANIZATION OF THE HUMAN GENOME
Single-copy or unique DNA Repetitive DNA

5 Single-Copy DNA Sequences
Once or a few times /a genome Short stretches (≤several kb) Coding portion of genes: a small proportion of all the single-copy DNA

6 Repetitive DNA Families
Definition Hundreds to millions of times in the genome Role Maintain chromosome structure Category Clustered repeated sequences Dispersed repeated sequences

7 Principles of Clinical Cytogenetics
Yuxia Yang Department of Medical Genetics, Peking University Health Science Center Cytogenetics：细胞遗传学

8 Key Points Introduction Chromosome Abnormalities Karyotype
Classification of Human Chromosome Human Chromosome Identification Karyotype：染色体组型 Chromosome Abnormalities Categories Definitions Mechanisms

9 Introduction to Cytogenetics
Cytogenetics: the study of chromosomes and their abnormalities is called cytogenetics. Clinical indications for chromasome analysis Clinical Cytogenetics：is the study of chromosomes, their structure and their inheritance, as applied to the practice of medical genetics. Chromosome disorders form a major category of genetic disease. Specific chromosome abnormalities are responsible for more than 100 identifiable syndromes. Cytogenetic disorders are present in nearly 1 percent of live births, in about 2 percent of pregnancies in women older than 35 years who undergo prenatal diagnosis, and in fully half of all spontaneous first-trimester abortions. Cytogenetic disorders are present in: 1 % live births, 2 % pregnancies in women older than 35 years, half of all spontaneous abortions.

10 The Human Karyotype 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 constriction) 、p (short arm) 、 q (long arm) 核型 (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。 核型分析 人体细胞：23对，22对常染色体，1至22号，A-G 7组；1对性染色体，X为Ｃ组，Ｙ为Ｇ组。 The condensed chromosomes of a dividing human cell are most readily analyze at metaphase or prometaphase (前中期). At these stages, the chromosomes are visible under the microscope as a chromosome spread (分裂相) and each chromosome can be seen to consist of its sister chromatids joined at the centromere. Most chromosomes can be distinguished by their length and the location of the centromere. The centromere is apparent as a primary constriction, dividing the chromosome into two arms, a short arm designated p and a long arm designated q. The staining methods originally available for human cytogenetic analysis, however, did not allow all 24 type of chromosomes (22 autosomes, X, and Y) to be individually identified. Instead, the chromosomes could be classified into seven groups, named by the letters A to G, on the basis of their overall length (全长) and the location of the centromere. With techniques now in common use, all the chromosomes can be individually identified. Fig.2-3 shows a prometaphase cell in which the chromosomes have been stained by the Giemsa-staining (G-banding) method, the technique most widely used in clinical cytogenetics laboratories. The chromosomes are treated first with trypsin (胰蛋白酶) to digest the chromosomal proteins and then with Giemsa stain. Each chromosome pair stains in a characteristic pattern of light and dark bands (G-bands). Using this method and other so-called banding techniques, all of the chromosomes can be individually distinguished. Further, the nature of any structural or numerical abnormalities can be readily determined, as we examine in great detail in Chapter 9 and 10. Centromere：着丝点 The chromosomes are classified into 7 groups (A-G) G banding

11 A chromosome at metaphase
chromatid 染色单体 ＋ ＝ 1 chromosome p q Telomere（端粒） telomere Centromere（着丝粒） (primary constriction) 上图为中期染色体模式图

12 Classification of Human Chromosomes
top a,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） 将染色体全长分为8等份，则着丝粒在染色体纵轴的1/2~5/8之间，为中着丝粒染色体。 Human chromosomes are often classified by the position of the centromere into three types that can be easily distinguished at metaphase. Metacentric, with a more or less central centromere and arms of approximately equal length; submetacentric, with an off-center centromere and arms of clearly different lengths; and acrocentric, with the centromere near one end. A potential forth type, telocentric, with the centromere at one end and only a single arm, does not occur in the normal human karyotype.

13

14 A Normal male Karyotype: 46,XY
从中期染色体涂片得到的人类染色体图像. 23对, 22对常染色体, 1对性染色体, 分A-G组, G-baning Although experts can often analyze metaphase chromosomes directly under the microcope, a common procedure is to cut out the chromosomes from a photomicrograph (显微照片) and arrange them in pairs in a standard classification as shown in Figure 2-4. The completed picture is called a karyotye. The word karyotype is also used to refer to the standard chromosome set of an individual (“a normal male karyotype”) or of a species (“the human karyotype”) and , as a verb, to refer to the process of preparing such a standard figure (“to karyotype”). A Normal male Karyotype: 46,XY

15 Chromosome Identification
Identification of Human Chromosomes stained A uniform system of chromosome classification － ISCN (An International System for Human Cytogenetic Nomenclature) ISCN: An International System for Human Cytogenetic Nomenclature Nomenclature：系统命名法 A uniform system of chromosome classification is internationally accepted for identification of human chromosomes stained by any of the three staining procedures. The figure is an ideogram of the banding pattern of a set of normal human chromosomes at metaphase, illustrating the alternating pattern of dark and light bands used for chromosome identification. The pattern of the bands on each chromosome is numbered on each arm from the centromere to the telomere. Using this numbering system, the location of any particular band, as well as the DNA sequences and genes within it, and its involvement in a chromosome abnormality can be described precisely.

16 Chromosome Identification
G Banding: trypsin(胰蛋白酶) 、 Giemsa(姬姆萨) Q Banding: quinacrine mustard(喹吖因氮芥) R Banding: special treatmemt (heating) 、 staining 、 the reverse of G or Q banding G带与Q带的带型非常一致，G深带=Q亮带; G浅带=Q暗带；R带：染色体染色后，呈现出与G带或Q带相反的带纹。 The 24 types of human chromosome can be readily identified by a number of specific staining procedures. There are three commonly used staining methods that can distinguish among human chromosomes. Giemsa banding (G banding) is the most common used in clinical laboratories. Other procedures used in some laboratories or for specific purposes, or both. The chromosomes stain in a specific pattern of bright and dim bands (Q bands), the bright Q bands corresponding almost exactly to the dark G bands. These methods are useful for detecting variants in chromosome morphology. These variants (detecting by Q and C banding ) are generally benign and reflect differences in the amount or type of satellite DNA sequences at a particular location along a chromosome. R banding: the chromosomes received special treatment before staining, the resulting dark and light bands (R bands) are the reverse of those produced by G or Q banding. G带深，Q带亮；G带浅，Q带暗。quinacrine mustard:喹吖因氮芥

17 G Banding

18 Q Banding

19 R banding

20 Ideogram showing G banding patterns for human chromosomes at metaphase
人类染色体模式图. 23对, 22对常染色体, 1对性染色体, 分A-G组, Ideogram：表意文字,意符

21 Chromosome Identification
Identification of Human Chromosomes stained A uniform system of chromosome classification － ISCN (An International System for Human Cytogenetic Nomenclature) ISCN: An International System for Human Cytogenetic Nomenclature Nomenclature：系统命名法 A uniform system of chromosome classification is internationally accepted for identification of human chromosomes stained by any of the three staining procedures. The figure is an ideogram of the banding pattern of a set of normal human chromosomes at metaphase, illustrating the alternating pattern of dark and light bands used for chromosome identification. The pattern of the bands on each chromosome is numbered on each arm from the centromere to the telomere. Using this numbering system, the location of any particular band, as well as the DNA sequences and genes within it, and its involvement in a chromosome abnormality can be described precisely. ISCN规定的界标：着丝粒、端粒、明显的带

22 Xq13 Arm Region Band Sub-band
每条显带染色体根据ISCN规定的界标（着丝粒、端粒、明显的带作为界标）划分为若干区，各区又包括若干带。区带的编号都是从着丝粒或近着丝粒的一侧开始，向长臂、短臂的末端依次分别编号为1区、2区、…..以及1带、2带……等。在标定一条染色体特定带时，需用符号表示，如1p36表示一号染色体短臂3区6带。

23 Chromosome Identification
C Banding: staining the centromeric region、 other constitutive heterochromatin regions High-Resolution Banding: chromosomes stained at the stage of prophase or prometaphase, detecting a subtle structural abnormality(前中期、晚前期的单倍染色体带纹数可达 条带;典型中期染色体，一套单倍染色体带纹数约 条带 ) C带：染色体标本通过特殊的预处理核Giemsa染色后，只在染色体局部区域着色深染，主要是染色体的着丝粒区结构异染色质深带。此外，1、9、16号染色体次缢痕及Yq远侧1/2~2/3的区段深染.异染色质（heterochromatin） C banding: this method involves staining the centromeric region of each chromosome and other regions containing constitutive heterochromatin: sections of chromosomes 1q,9q,16q adjacent to the centromere and the distal part of Yq. High-resolution banding : this type of banding is achieved through G-banding or R-banding techniques to stain chromosomes that have been obtained at an early stage of mitosis (prophase or prometaphase), when they are still in a relatively uncondensed state. High-resolution banding is useful when a subtle structural abnormality of a chromosome is suspected. Prometaphase chromosomes reveal 550 to 850 bands in a haploid set. （早中期，前中期，晚前期）。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。

24 C Banding

25 High-Resolution Banding
A comparative of the banding patterns of the X chromosome at three different stages of resolution is shown in the picture. The increase in diagnostic precision obtained with those longer chromosome is evident.

26 Fluorescence In Situ Hybridization (FISH:荧光原位杂交)
Chromosome Identification 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 interphase chromosomes Hybridization Visualizing the location of hybridization under a fluorescence microscope a labeled chromosome-specific DNA segment (probe) is exposed to denatured metaphase, prophase, or interphase chromosomes. It undergoes complementary base pairing (hybridization) with the DNA sequence that corresponds to its location on a specific chromosome. Because the probe is labeled with a fluorescent dye, the location at which it hybridizes with the patient’s chromosomes can be visualized under a fluorescence microscope. (FISH can typically detect deletions as small as 1million base pairs ( 1Mb) in size ).

27 荧光原位（FISH）杂交的原理是将间期或中期的染色体的DNA固定在载玻片上，“原位”变性为两条DNA单链，再用变性的标记探针与染色体DNA进行杂交。用激发荧光燃料的波长光照射观察染色体，如有杂交信号便可看到荧光。杂交信号的位置就是探针与染色体DNA片段结合的位置。 DNA分子杂交实质上是双链DNA的变性和具有同源序列的两条单链的复性过程。

28 Probes: three types gene-specific or locus-specific probes,
repetitive DNA probes (satellite DNA probes) chromosome painting probes (probes for entire chromosomes or chromosome arms) －one-color, two-color, three-color, multicolor 根据原位杂交所检测的目的序列，FISH探针可以大致分为： Locus-specific probe:基因座特异性探针 （单一拷贝序列探针） Repetitive DNA probes: 重复序列探针(重复序列的拷贝数10个～几百个（rRNA基因即rDNA）～几百万个（satellite DNA，重复次数超过106，位于着丝粒，端粒，及Yq远端2/3的结构异染色质区。如1，9，16号染色体的长臂近端的结构异染色质区及Yq远端2/3为结构异染色质区；Alu序列，重复拷贝数50万），最常见的重复序列探针是着丝粒探针：α-satellite family of DNA is composed of tandem arrays of different copies of an 171 bp unit, found at the centromeric region of each human chromosome. This repeat family is believed to play a role in centromere function, ensuring proper chromosome segregation in mitosis and meiosis.)。 Probes for entire chromosomes or chromosome arms:染色体涂抹探针，整条染色体探针或染色体臂探针（染色体特异性基因组文库作为探针，或利用染色体显微切割获得整条染色体探针，或流式分选获得目标染色体，以适当载体克隆或PCR扩增制成探针） DNA probes specific for individual chromosomes, chromosomal regions, or genes can be used to identify particular chromosomal rearrangements or to rapidly diagnose the existence of an abnormal chromosome number in clinical material. Gene-specific or locus-specific probes can be used to detect the presence, absence, or location of a particular gene, both in metaphase chromosomes and interphase cells. Repetitive DNA probes allow detection of satellite DNA or other repeat DNA elements (such as the repeat TTAGGG DNA hexamer found at human telomere) at specific chromosomal loci including centromere, telomere, or regions of heterochromatin; satellite DNA , especially those belonging to the alpha satellite family of centromere repeats, are extremely useful for detecting the number of copies of a particular chromosome. Probes for entire chromosomes or chromosome arms contain a mixture of single-copy DNA sequences that map along the length of the entire chromosome (or arm). These probes “paint” the target chromosome (both in metaphase and in interphase). One of the more important applications of FISH in clinical cytogenetics involves the use of different fluorochromes to detect multiple probes simultaneously. Two-color and three-color applications are routinely used to diagnose specific deletion, duplication, or rearrangements（< 1Mb）, both in prometaphase, or metaphase, as well as interphase. With highly specialized imaging procedures, it is even possible to detect and distinguish 24 different colors simutaneously by spectral karyotyping (SKY), allowing dramatic evaluation of the karyotype in a single expeiment. SKY utilize varying combinations of five different fluorescent probes in conjunction with special cameras and image-processing software so that each chromosome is uniquely colored (“paint”) for ready identification. Such images are especially useful for identifying chromosome rearrangements. FISH探针通常是染色体特异位点上的DNA片段。FISH探针也可以是整条染色体臂或臂的一部分DNA片段，甚至可以是整条染色体DNA。根据探针的序列组成不同，荧光探针或与整条染色体杂交，或与部分片段杂交。这种探针混合体称为染色体“涂染”探针。将人类染色体24个探针联合应用，与中期染色体进行FISH杂交，就成为图谱核型分析（SKY）。

29 Chromosome specific painting probe:涂染探针。相关染色体的拷贝数能通过这些探针中的任何一个检测出来。

30 Metaphase：中期 Interphase:间期
A single-copy DNA probe specific for the factor VIII gene on the X chromosome Metaphase：中期 Interphase:间期 Locus-specific probe The following figures show fluorescence in situ hybridization in human chromosomes at metaphase and interphase, using three different types of DNA probe.

31 A repetitive alpha satellite DNA probe specific for the centromere of chromosome 17
Metaphase Interphase Satellite DNA probe

32 A whole chromosome “paint” probe specific for the X chromosome
Metaphase Interphase

33 Spectral karyotyping (SKY：光谱核型分析)
创新的染色体数目和结构异常检查工具：24种全染色体涂染探针先用不同的荧光素组合进行不同的标记，之后探针混合物与中期染色体进行原位杂交，最后用荧光显微镜分析，结果分为显色和分色图像两部分，前者可分析探针杂交质量，后者用SKY软件参照每条染色体特有的信息特征进行分析。SKY技术可同时观察和分析人24条染色体特征，同一张图像显示不同颜色。可发现传统显色及FISH技术所不能发现的细微的染色体异常，清楚的鉴别染色体的重排，特别是易位 插入及 可以产生标记染色体的许多复杂的染色体结构改变，对于各种标记染色体的来源也能一部了然 Epifluorescence microscope: 落射荧光显微镜 spectracube: visualise: 使可见；normalise: 使标准化 With highly specialized imaging procedures, it is even possible to detect and distinguish 24 different colors simutaneously by spectral karyotyping (SKY), allowing dramatic evaluation of the karyotype in a single expeiment. SKY utilize varying combinations of five different fluorescent probes in conjunction with special cameras and image-processing software so that each chromosome is uniquely colored (“paint”) for ready identification. Such images are especially useful for identifying chromosome rearrangements.

34 Spectral karyotyping (SKY)光谱核型分析
Spectral karyotyping (SKY)光谱核型分析. Twenty-four individual chromosome painting probes are labeled with different fluorescent dyes and used as a total genome chromosome paint. The fluorescent signals are analyzed by sophisticated imaging software and store in a computer. To generate the photograph, the computer assigns a different color to each of the 24 different fluorescence spectra generated by the individual chromosome painting probes. Numerous structural and numerical abnormalities are evident and can be identified by image analysis of the 24 different chromosome painting probes used.

35 Application: to examine the presence or absence of a particular DNA sequence to diagnose the existence of an abnormal chromosome number in clinical material to detect chromosome rearrangements with combinations of FISH probes FISH dramatically expanded both the range and precision of routine chromosome analysis. A common use of FISH is to determine whether a portion of a chromosome is deleted in a patient. In a normal individual, a probe hybridizes in two places, reflecting the presence of two homologous chromosomes in a somatic cell nucleus. If a probe from the chromosome segment in question hybridizes to only one of the patient’s chromosomes, then the patient probably has the deletion on the copy of the chromosome to which the probe fails to hybridize. FISH provides considerably better solution than high-resolution banding approaches; it can typically detect deletions as small as 1 million base pairs (1 Mb) in size. Excess chromosome material can also be detected using FISH. In this case, the probe hybridizes in three places. Combination of FISH probes can also be used to detect chromosome rearrangements such as translocation

36 chromosome 18 aqua, X chromosome green, Y chromosome red
Multicolor fluorescence in situ hybridization analysis of interphase amniotic fluid cells. Left panel, 46,XY cells (chromosome 18 aqua, X chromosome green, Y chromosome red). Middle panel, 47, XX, +18 cell (chromosome 18 aqua, X chromosome green). Right panel, trisomy 21 cells (chromosome 13 green, chromosome 21 red). chromosome 18 aqua, X chromosome green, Y chromosome red chromosome 18 aqua, X chromosome green chromosome 13 green, chromosome 21 red

37 Prader-Willi syndrome
demonstrating deletion of 15q11-q13 Green：alpha satellite DNA at the chromosome 15 centromere Two-color fluorescence in situ hybridization analysis of proband with Prader-Willi syndrome, demonstrating deletion of 15q11-q13 on one homolog. Green signal is hybridization to alpha satellite DNA at the chromosome 15 centromere. Red signal on distal 15q is a control single-copy probe. Red signal on proximal 15q is a probe for the SNRPN gene, which is present on one chromosome 15 (white arrow), but is deleted from the other (dark arrow). Red：SNRPN gene

38 Chromosome Abnormalities
Abnormalities of Chromosome Number Abnormalities of Chromosome Structure 染色体畸变: 体细胞或性细胞内染色体发生异常改变，称染色体畸变。 Abnormalities of chromosomes may be either numerical or structural and may be one or more autosomes, sex chromosomes, or both. The most common type of chromosome abnormality is aneuploidy, an abnormal chromosome number due to an extra or missing chromosome, which is always associated with physical or mental maldevelopment. Reciprocal tanslocation (an exchange of segments between nonhomologous chromosomes) are also common but usually have no phenotypic effect, there may be an associated increased risk of abnormal offspring.

39 Abnormalities 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。 染色体数目畸变：细胞内整个染色体组或整条染色体数量上的增减称为染色体数目异常。染色体数目畸变分类：整倍性改变和非整倍性改变。整倍体性改变：以染色体组为单位发生的染色体成倍的增减。整倍体：染色体数为n的倍数的细胞或个体称整倍体。多倍体：一个细胞内有三个以上的染色体组。非整倍性改变：细胞内染色体数目增加或减少一条或几条。非整倍体：体细胞的染色体数增加或减少一条或几条，这样的细胞或个体称非整倍体。亚二倍体：细胞中染色体数较二倍体少时，称亚二倍体。2n-1, 2n-2,……单体型：体细胞中染色体数为45条，即某号染色体少一条。 如 45, X。超二倍体：细胞中染色体数较二倍体数多时，称超二倍体。三体型：体细胞内染色体数为47，即某号染色体有三条。如 47, XX(XY), +21。部分三体型或部分单体型：有时核型中增加或减少了某条染色体的一部分。 A complete set of chromosomes: a chromosome complement, 一个染色体组 Eukaryotic organisms that are normally diploid (2n) (such as humans) and eukaryotic organisms that are normally haploid (such as yeast) are all euploid. Chromosome mutations that result in variations in the number of chromosome sets occur in nature, and the resulting organism or cells are also euploid. Chromosome mutations resulting in variations in the number of individual chromosomes are examples of aneuploidy. Both euploid and aneuploid variations affecting whole chromosomes. Euploid: an organism or cell has one complete set of chromosomes, or an exact multiple of complete sets, that organism or cell is said to be euploid. Aneuploid: an organism or cell has a chromosome number that is not an exact multiple of the haploid (n) set of chromosomes

40 Triploidy and Tetraploidy
Definition: 3n Reason: dispermy(双受精) (most common)、 digyny(双雌受精) Phenotypic expression: paternal-abnormal placenta; maternal-abortion Haploid (n), diploid (2n): the number characteristic of normal somatic cells. Triploid (3n) and tetraploid (4n) have been seen in fetuses， although triploid infants can be liveborn, they do not survive long. Triploidy most results from fertilization by two sperm (dispermy). Failure of one of the meiotic divisions, resulting in a diploid egg or sperm, can also account for a portion of cases. The phenotypic expression of a triploid karyotype depends on the source of the extra chromosome set; triploids with an extra set of paternal chromosomes typically have an abnormal placenta and are classified as partial hydatidiform moles (部分葡萄胎三倍体)(葡萄胎：人类胎盘肿瘤，它有两套父源性单倍体染色体而无母源性的染色体). Those with an additional set of maternal chromosomes are spontaneouly aborted earlier in pregnancy. Digyny:双雌受精; dispermy:双受精

41 karyotypes: 69,XXX; 69,XXY; 69,XYY
dispermy digyny Triploidy most results from fertilization by two sperm (dispermy). Failure of one of the meiotic divisions, resulting in a diploid egg or sperm, can also account for a portion of cases. karyotypes: 69,XXX; 69,XXY; 69,XYY

42 Tetraploid(四倍体) Definition: 4n
Reason: endoreduplication (核内复制), endomitosis (核内的有丝分裂) Karyotypes: 92,XXXX or 92,XXYY Endoreduplication：Replication of chromosomes without subsequent cell division. Endomitosis：Endomitosis is a variant of mitosis without nuclear division.

43 四倍体形成的原因 1 核内复制: 是指在一次细胞分裂时，DNA复制了两次，形成的两个子细胞是四倍体或其它。 2核内有丝分裂: 染色体正常复制一次，但细胞未分裂。

44 Aneuploidy Trisomy Definition: a trisomic cell involves a single extra chromosome; that is, the cell has three copies of a particular chromosomes and two copies of other chromosomes. A trisomic cell is 2n+1 Example: trisomy 21 (karyotype: 47,XX/XY,+21) In aneuploidy, one or more chromosomes are lost from or added to the normal set of chromosomes. In most cases, autosomal aneuploidy is lethal in animals, so in mammals it is detected mainly in aborted fetuses. Aneuploidy is the most common and clinical significant type of human chromosome disorder, occurring in at least 3 to 4 percent of all clinically recognized pregnancies. Most aneuploid patients have either trisomy or, less often, monosomy (only one representative of a particular chromosome). Both can have severe phenotypic consequences. Trisomy for a whole chromosome is rarely compatible with life. The most common type of trisomy in liveborn infants is trisomy 21.

45 Monosomy Definition: a monosomic cell involves a loss of a single chromosome; that is, the cell is 2n-1. Example: Turner syndrome (Turner syndrome karyotype: 45, X) Monosomy: only one representative of a particular chromosome. Monosomy for an entire chromosome is almost always lethal; an important exception is monosomy for the X chromosome, as seen in Turner syndrome.

46 Mechanism Meiotic(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 frequency or placement, or both, of recombination events in meiosis I. Mechanism of aneuploidy. Meiotic nondisjunction: a pair of chromosomes to disjoin properly during one of the two meiotic divisions. The consequences of nondisjunction during meiosis I and meiosis II are different. If the error occurs during meiosis I, the gamete with 24 chromosomes contains both the paternal and the maternal members of the pair. If it occurs during meiosis II, the gamete with the extra chromosome contains both copies of either the paternal or the maternal chromosome. The propensity of a chromosome pair to nondisjunction has been strongly associated with aberrations in the frequency or placement, or both of recombination events. A chromosome pair with too few recombinations or with recombination too close to the centromere or telomere may be more susceptible to nondisjunction than a chromosome pair with a more typical number and distribution of recombination events. Many errors can occur in cell division. Anaphase of meiosis I is the most error-prone step, the error resulting in both homologs of a chromosome pair going to the same, rather than opposite, poles. This pathogenic process is termed nondisjunction. Meiotic nondisjunction, particularly in oogenesis, is the most common mutational mechanism in our species, responsible for chromosomally abnormal fetuses in at least several percent of all recognized pregnencies.

47 Normal meiosis, 在减数分裂I的前期的偶线期发生联会(pairing), 粗线期发生互换（crossing-over）.

48

49 The propensity of a chromosome pair to nondisjunction has been strongly associated with aberrations in the frequency or placement, or both of recombination events. A chromosome pair with too few recombinations or with recombination too close to the centromere or telomere may be more susceptible to nondisjunction than a chromosome pair with a more typical number and distribution of recombination events.

50 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). Oocyte:卵母细胞 gamete：配子

51 Mitotic (有丝分裂)nondisjunction: 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. Mitotic nondisjunction: nondisjunction can occur in a mitotic division after formation of the zygote. If this happens at an early cleavage division, clinically significant mosaicism may result. In some malignant cell lines and some cell cultures, mitotic nondisjunction can lead to highly abnromal karyotype.

52 mitotic nondisjunction-mosaicism
46 47 45 nondisjunction mitotic nondisjunction-mosaicism

53 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3，6，7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

54 Abnormalities of Chromosome Structure
Mechanism: chromosome breakage 、 reconstitution in an abnormal combination Incidence: 1 in 375 newborns Types of structure rearrangements Balanced Unbalanced Balanced rearrangements : if the chromosome set has the normal complement of chromosome material. unbalanced rearrangements: if there is additional or missing material. Mechanism: there are four common types of chromosomal mutations involving changes in chromosome structure: deletions and duplications, inversions and translocations. All four classes of chromosomal structure mutations begin by one or more breaks in the chromosome. If a break occurs within a gene, then the function of that gene may be lost. Wherever the break occurs, the breakage process leaves broken ends without the specialized sequences found at the ends of chromosomes that prevent their degradation and “stickiness”. As a result, the broken end of a chromosome is “sticky” and may adhere to other broken chromosome ends. This stickiness can help us understand the formation of the types of chromosomal structure mutations. Rearrangement can take place in many ways, which together are less common than aneuploidy, structural abnormalities are present in about 1 in 375 newborns. Chromosome exchange occurs spotaneously at a low frequency and may also be induced by breaking agents. Like numerical abnormalities, structural rearrangements may be present in all cells of a person or in mosaic form. Some rearrangements are stable, capable of passing through mitotic and meiotic cell divisions unaltered, whereas others are unstable. To be stable, a rearranged chromosome must have normal structural elements, including a functional centromere and two telomeres.

55 Unbalanced Rearrangements
Deletion (del) Definition: is a chromosomal mutation in which part of a chromosome is missing Incidence of autosomal deletions: 1/7000 live birth Types: terminal, interstitial Deletions: 染色体片段丢失。Deletions: is the loss of a DNA segment, deletions involve loss of a chromosome segment, resulting in chromosome imbalance. A carrier of a chromosome deletion (one normal homolog and one deleted homolog) is monosomic for the genetic information on the corresponding segment of the normal homolog. The clinical consequences reflect haploinsufficiency (单倍不足)(the inability of a single copy of the genetic material to carry out the functions normally performed by two copies) and appear to depend on the size of the deleted segment and the number and function of the genes that it contains.

56 Karyotype: 46,XX,del(1)(q21) 46,XX,del(1)(pter→q21:)
Terminal deletion Loss Terminal deletion: a single break leading to a loss that includes the chromosome’s tip is called terminal deletion. 发生了结构畸变的染色体即称重排染色体（rearrangement chromosome）。 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，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)(pter→q21:) Karyotype: 46,XX,del(1)(q21) 46,XX,del(1)(pter→q21:) 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，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)(pter→q21:)

57 Karyotype: 46,XX(XY),del(3)(q21q31)
Loss Interstitial deletion Interstitial deletion: when two breaks occur and the material between. 中间缺失：一条染色体的同一个臂上发生两次断裂，两断点之间的片段丢失。 Karyotype: 46,XX(XY),del(3)(q21q31) 46,XX(XY),del(3)(pter→q21::q31→qter)

58 Reasons: Deletions may originate simply by 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 inversion Numerous deletions have been identified in the investigation of dysmorphic (畸形的) patients and in prenatal diagnosis, but knowledge of the functional genes lost in the deleted segments and their relation to the phenotypic consequences is still limited.

59 Unequal crossing over between segments of homologous chromosomes or between sister chromatids (duplicated or deleted segment indicated by the brackets).

60 Duplication (dup) Definition: is a chromosomal mutation that results in the doubling of a segment of a chromosome. 重复：染色体上某一区段增加一份或一份以上，即为重复。包括正位重复（重复片段的方向与原片段方向一致），反位重复（重复片段的方向与原片段方向相反）。 Duplication is the addition of one or more extra copies of a DNA segment. In general, duplication appears to be less harmful than deletion. Because duplication in a gamete results in chromosomal imbalance (i.e., partial trisomy), and because the chromosome breaks that generate it may disrupt genes, duplications often leads to some phenotypic abnormality.

61 正位重复 反位重复

62 Duplication (dup) Reasons: Can originate by unequal crossing over
By abnormal segregation from meiosis in a carrier of a translocation or inversion.

63 Unequal crossing over between segments of homologous chromosomes or between sister chromatids (duplicated or deleted segment indicated by the brackets).

64 Marker and Ring Chromosomes
Marker Chromosome (mar) Definition: very small unidentified chromosomes, called marker chromosomes, are also referred to as supernumerary chromosomes or extra structurally abnormal chromosomes (ESACs) Marker chromosome: Synonym(s), supernumary chromosome（超数染色体）. 形态上可辨认，但又无法完全识别其来源和特征的染色体，称标志染色体。标志染色体通常作为正常染色体的补充，称为超数染色体（supernumerary chromosomes）或额外结构异常染色体（ extra structurally abnormal chromosomes (ESACs) ）。 A small chromosome containing a centromere occasionally seen in tissue culture, often in a mosaic state (present in some cells but not in others). A marker chromosome may be of little clinical significance or, if it contains material from one or both arms of another chromosome, may create an imbalance for whatever genes are present; assessment to establish clinical significance, particularly if found in a fetal karyotype, is often difficult. Tiny marker chromosomes often consist of little more than centric heterochromatin that can be identified using a variety of chromosome-specific satellite or “paint” FISH probes. Larger marker chromosomes contain material from one or both chromosome arms, creating an imbalance for whatever genes are present. Because of the problem of identification, the clinical significance of a marker is difficult to assess, and the finding of a marker in a fetal karyotype can present a serious problem in assessment and genetic counseling. Depending on the origin of the marker, the risk of a fetal abnormality can range from very low to as high as 100%, relatively high proportion of such markers derives from chromosome 15 and from sex chromosomes. An intriguing subclass of marker chromosomes lack identifiable centromeric DNA sequences. These markers represent small fragments of chromosome arms that have somehow acquired centromere activity. Such markers are said to contain neocentromeres.

65 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 chromosomes are quite rare. If the centromere is within the ring, a ring chromosome would be expected to be mitotically stable.

66 loss loss ring chromosome

67 Isochromosomes (i) Definition: is a chromosome in which one arm is missing and the other duplicated in a mirror-image fashion.

68 after replication isochromosomes replication isochromosome

69 Isochromosomes (i) Mechanisms:
Misdivision through the centromere in meiosis II Exchange involving one arm of a chromosome and its homolog (or sister chromatid) at the proximal edge of the arm, adjacent to the centromere. More commonly, exchange involving one arm of a chromosome and its homolog (or sister chromatid) at the proximal edge of the arm.

70 Isochromosomes (i) Common Isochromosomes: i(Xq) i(18p) i(12p)
The most common isochromosome is an isochromosome of the long arm of the X chromosome, i(Xq), in some individuals with Turner sydrome. Isochromosomes for a number of autosomes have also been described, i18(p), i(12p) Isochromosomes are also frequently seen in karyotypes of both solid tumors and hematological malignancies.

71 Dicentric(双着丝粒 ) Chromosomes (dic)
Definition: a dicentric is a rare type of abnormal chromosome in which two 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. Dicentrics, despite their two centromeres, may be mitotically stable if one of the two centromeres is inactivated or if the two centromeres coordinate their movement to one or the other pole during anaphase. Such chromosomes are formally called pseudodicentrics. The most common pseudodicentrics involve the sex chromosomes or the acrocentric chromosomes (Robertsonian translocations).

72 dicentric chromosome

73 Balanced Rearrangements
Inversions (inv) Definition: occurs when a single chromosome undergoes two breaks and is reconstituted with the segment between the breaks inverted. Types: Paracentric (not including centromere) Pericentric (including centromere) Paracentric: 臂内倒位， Pericentric: 臂间倒位 Chromosomal rearrangements do not usually have a phenotypic effect if they are balanced, because all the chromosomal material is present. Even when structural rearrangements are truly balanced, they can pose a threat to the subsequent generation, because carriers are likely to produce a high frequency of unbalanced gametes and therefore have unbalanced karyotypes

74 Paracentric Karyotypes: 46,XX,inv(1)(p22p34)
46,XX,inv(1)(pter→p34::p22→p34::p22→qter)

75 Pericentric Karyotypes: 46,XX,inv(2)(p15q21)
46,XX,inv(2)(pter→p15::q21→p15::q21→qter)

76 Inversion carrier: a carrier of either type of inversion is at risk of producing abnormal gametes that may lead to unbalanced offspring An inversion does not usually cause an abnormal phenotype in carriers, because it is a balanced rearrangement. Its medical significance is at risk of producing abnormal gametes that may lead to unbalanced offspring.

77 A B C D When an inversion is present, a loop is formed when the chromosomes pair in meiosis I. although recombination is somewhat suppressed within inversion loops, when it occurs it can lead to the production of unbalanced gametes. Both gametes with balanced chromosome complements (either normal or possessing the inversion) and gametes with unbalanced complements are formed, depending on the location of recombination events. When the inversion is paracentric, the unbalanced recombinant chromosomes are typically acentric or dicentric and may not lead to viable offspring. The risk that a carrier of a paracentric inversion will have a liveborn child with an abnormal karyotype is very low indeed. The risk that a carrier of a paracentric inversion will have a liveborn child with an abnormal karyotype is very low indeed.

78 A B C D 臂间倒位携带者在形成生殖细胞的减数分裂过程中，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 A pericentric inversion can lead to the production of unbalanced gametes with both duplication and deficiency of chromosome segments. The duplicated and deficient segments are the segments that are distal to the inversion. The risk of a carrier of a pericentric inversion producing a child with an unbalanced karyotype is 5-10%. Each pericentric inversion is associated with a particular risk, and large pericentric inversions are more likely than are smaller ones to lead to viable recombinant offspring because the unbalanced segments in the recombinant progeny (后代) are smaller in the case of large inversions. 臂间倒位携带者在形成生殖细胞的减数分裂过程中，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。

79 Translocations (t) Definition: involves the exchange of chromosome segments between two, usually nonhomologous chromosomes Main types: reciprocal, Robertsonian Translocation: is the movement of a DNA segment to another chromosomal location in the genome. 易位：两条染色体同时发生断裂，一条染色体的断片移接到另一条非同源染色上，这种结构畸变称易位。

80 Reciprocal Translocations (rcp)
Definition: this type of rearrangement results from breakage of nonhomologous chromosomes, with reciprocal exchange of the broken-off segments. Reciprocal translocation: usually only two chromosomes are involved, and because the exchange is reciprocal, the total chromosome number is unchanged (Fig. 9-12A). Reciprocal translocations are relatively common and are found in approximately 1 in 600 newborns. Such translocation are usually harmless, although they are more common in institutionalized mentally retarded individuals than in general population. Like other balanced structural rearrangements, they are associated with a high risk of unbalanced gametes and abnormal progeny(后代)。They come to attention either during prenatal diagnosis or when the parents of an abnormal child with an unbalanced translocation are karyotyped. Balanced translocations are more commonly found in couples who have had two or more spontaneous abortions and infertile males than in general population.

81 reciprocal translocation
Karyotypes: 46, XX, t(2;5)(q21;q31) 46, XX, t(2;5)(2pter→2q21::5q31→5qter;5pter→5q31::2q21→2qter)

82 Carriers of balanced reciprocal translocation: are associated with a high risk of unbalanced gametes and abnormal progeny Quadrivalent figure: 四射体 Carrier of balanced reciprocal translocation: when the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis, a quadrivalent figure is formed. At anaphase, the chromosomes usually segregate from this figuration in one of three ways, as shown in Figure 9-12 B. Like other balanced structural rearrangements, they are associated with a high risk of unbalanced gametes and abnormal progeny(后代).

83 Figure A, Diagram of a balanced translocation 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。

84 Pairing at meiosis Segregation
Unbalanced Unbalanced Normal balanced Unbalanced Unbalanced When the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis, a quadrivalent (四价体) (cross-shaped) figure is formed ( shown in Fig. 9-12B). At anaphase, the chromosomes segregate from this configuration in one of three ways, described as alternate (相间分离), adjacent-1 (相邻-1), adjacent-2 (相邻-2) segregation. Alternate segregation, the usual type of meiotic segregation, produces gametes that either a normal chromosome complement or the two reciprocal chromosomes; both types of gamete are balanced (occurs 50%; each contains complete set of genes; viable). In adjacent-1 segregation, homologous centromeres go to separate daughter cells (occurs frequently, 50%; each contains duplications and deletions; usually inviable), whereas in adjacent-2 segregation (which is rare), homologous centromeres pass to the same daughter cells (seldom occurs; each contains duplications and deletions; always inviable). Both adjacent-1 and adjacent-2 segregation yield unbalanced gametes (partial trisomy and partial monosomy) (see Fig. 9-12B). In addition to the examples mentioned of 2:2 segregation (i.e. two chromosomes to each pole), balanced translocation chromosomes can also segregate 3:1, leading to gametes with 22 or 24 chromosomes. Although monosomy in a resulting fetus is rare, trisomy can result. Such 3:1 segregation is observed in 5 to 20 percent of sperm from balanced translocation carrier, depending on the specific translocation. 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，结果可形成18种配子。其中，仅有一种配子是正常的，一种是平衡易位的，其余16种都是不平衡的。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。 (inviable) (viable) (inviable) (50%) (50%) (rare)

85 Robertsonian Translocations (rob)
Definition: this type of rearrangement involves two acrocentric chromosomes that fuse near the centromere region with loss of the short arms The resulting balanced karyotype has only 45 chromosomes, including the translocation chromosome, which is made of long arms of two chromosomes. Because the short arms of all five pairs of acrocentric (近端着丝粒) chromosome have multiple copies of genes for ribosomal RNA, loss of the short arms of two acrocentric chromosomes is not deleterious. Robertsonian translocation can be either monocentric(单着丝粒) or pseudodicentric, depending on the location of the breakpoint on each acrocentric chromosome. 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色质构成所致。 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色质构成所致。

86 Robertsonian translocation
loss Robertsonian translocation 14p11 21q11

87 Two (13q14q , 14q21q ) of Robertsonian translocations are common
Although Robertsonian translocation involving all combinations of the acrocentric chromosomes have been detected, two (13q14q and 14q21q) are common. The translocation involving 13q and 14q is found in about 1person in 1300 and is the single most common chromosome rearrangement in our species.

88 Carrier of Robertsonian translocation: a carrier of a Robertsonian translocation is phenotypically normal, there is a risk of unbalanced gametes and therefore offspring. A carrier of a Robertsonian translocation involving chromosome 21 are at risk of producing a child with translocation Down syndrome.

89 14q21q Translocation Germ cell Gamete Normal gamete Zygotes Balanced
Trisomy 21 Monosomy Monosomy Trisomy 14q21q 14

90 Insertions (ins) Definition: an insertion is a nonreciprocal type of translocation that occurs when a segment removed from one chromosome is inserted into a different chromosome, either in its usual orientation or inverted. Because they require three chromosome breaks, insertions are relatively rare. 包括：正位插入（插入片段在新位置上保持原来带序），倒位插入（插入片段的带序颠倒了）。 插入：单方易位。两条非同源染色体同时发生断裂，但只有其中一条染色体的片段插入到另一条染色体的非末端部位。只有发生了三次断裂时，才可能发生插入易位。

91 insertion

92 Mosaicism (mos) Definition: two or more different chromosome complements are present in an individual, this situation is called mosaicism Types: numerical (most common type), structural Mosaicism：一个个体同时表现2种或2种以上的染色体核型，这种现象称镶嵌现象，镶嵌性。同一个体的细胞有不同的遗传组成、染色体结构或染色体数目的现象。 医药. 1. 镶嵌性，镶嵌现象：遗传学上指个体中存在两个以上的细胞系，它们源于一个合子，但其遗传型和染色体组型明显不同 嵌合体：一个个体内同时存在两种或两种以上的核型的细胞系，这种个体称嵌合体。 When a person has a chromosome abnormality, the abnormality is usually present in all of his or her cells. Sometimes, two or more different chromosome complements are present in an individual. This situation is called mosaicism.

93 Mosaicism (mos) Examples: 46, XX/47, XX, +21 45, X/46, XX
Reasons: mosaicism is nondisjunction in an early postzygotic mitotic division. 正常受精卵在胚胎发育的最早阶段－卵裂初期的细胞，如发生某一条染色体的姐妹染色单体不分离，可产生嵌合体。这种嵌合体个体中各细胞系的类型和其数量的比例决定于发生染色体不分离的时期的早晚。如果染色体不分离发生在受精卵的第一次卵裂时期，则形成具有两个细胞系的嵌合体，两个细胞系的比例各占50％。如果染色体不分离发生在受精卵的第二次卵裂时期，则形成具有三个细胞系的嵌合体（46/47/45）。不分离发生的越晚，正常二倍体的细胞系所占的比例越大，而异常细胞系的比例就越少，临床症状相对较轻。亚二倍体（45）细胞由于缺失一条染色体，特别是缺失的是一条常染色体时，其细胞活力降低，往往被淘汰、消失，不能形成细胞系 (原因是染色体的减少会造成基因间遗传物质的严重失衡而使细胞难以存活。但总数45条染色体的细胞中所缺少的是X染色体，则该种细胞存活的机会较大。)。所以，在临床病例的核型分析中，常见的为46/47型嵌合型。 For example, a zygote with additional chromosome 21 might lose the extra chromosome in a mitotic division and continue to develop as a 46/47, +21 mosaic. The significance of a finding of mosaicism is often difficult to assess, especially if it is identified prenatally. The effects of mosaicism on development vary with the timing of the nondisjunctional event, the nature of the chromosome abnormality, the proportion of the different chromosome complements present, and the tissues affected. An additional problem is that the proportions of the different chromosome complements seen in the tissue being analyzed may not necessarily reflect the proportions present in other tissues or in the embryo during its early developmental stages. In laboratory studies, cytogeneticists attempt to differentiate between true mosaicism, present in individuals, and pseudomosaicism, in which the mosaicism probably arose in cell culture. The distinction is not easy or certain. Mosaicism is relatively common in cytogenetic studies of chorionic villus （绒毛膜）cultures and can lead to major interpretive difficulties in prenatal diagnosis.

94 mitotic nondisjunction-mosaicism
46 47 45 nondisjunction mitotic nondisjunction-mosaicism

95 Mosaic (同源嵌合体) have two or more genetically different cell lines derived from a single zygote. The genetic changes may be a gene mutation, a numerical or structural chromosomal change, or in the special case of lyonization (莱昂作用，莱昂化), X-inactivation. A chimera (异源嵌合体) is derived from two zygotes, which are usually both normal but genetically distinct.

96 Parent-of-origin effects
Genomic imprinting: difference in gene expression between allele inherited from the mother and the allele inherited from the father father mother 15q11-q13 15q11-q13 Angelman Prader-Willi syndrome

97 Principles of Clinical Cytogenetics
Introduction Karyotype Classification of Human Chromosome Human Chromosome Identification Chromosome Abnormalities Categories Definitions Mechanisms

98 Thank you and see you next time!