(醫(yī)學遺傳學)11人類染色體畸變

1、末代沙皇尼古拉二世的公主斯塔西婭,安娜-安德森,1956電影”真假公主”,10 人類染色體畸變 chromosome aberration,Any type of change in the chromosome structure or number (deficiencies, duplications, translocations, inversions, etc.).,Although it can be a mechanism for enhancing genetic diversity, such alterations are usually fatal or ill-ada

2、ptive, especially in animals.,1. factors inducing chromosome aberration,A. Ionizing radiation Ionizing radiation produces rearrangements of the genome.,When irradiation occurs during the G0/G1 phase of the cell cycle, large-scale rearrangements appear as exchange-type chromosome aberrations at the n

3、ext mitosis. Such aberrations can alter cellular phenotypes, and are important in various areas of biology:,Analyzing chromosome aberrations helps characterize repair/misrepair pathways involved in the processing of DNA damage. Ionizing radiation has some unique features as a probe of such pathways.

4、 Compared to other genotoxic agents, it produces copious quantities of DNA double strand breaks (DSBs), and its timing can be controlled more accurately.,Moreover, initial radiation damage has a discrete, stochastic character that can be modulated by using different kinds of radiation (e.g. a -parti

5、cles versus x-rays) having different ionization densities.,The spectrum of different radiation-induced chromosome aberrations is informative about the geometry of chromosomes during interphase, and vice versa.,B. chemical mutagen A kind of substances, such as drugs or toxins ,that causes chromosomal

6、 aberrations of living organisms, or increase the rate of mutation.,Drug antitumor drug（抗腫瘤藥物） 環(huán)磷酰胺、氮芥、白硝安（馬利蘭）、甲氨喋呤、阿糖胞苷等抗癌藥物 Tocolysis（子宮收縮抑制劑） drug which prevent pregnancy reaction(預防妊娠反應的藥物) anti-epileptic 苯妥英鈉可引起人淋巴細胞多倍體細胞數(shù)增高,agricultural chemicals Some agricultural chemicals can induce chromos

7、ome aberration, like phosphate pesticide.,Industrial poisons 苯、甲苯、鋁、砷、二硫化碳、氯丁二稀、氯乙烯單體,Food additive Preservative(防腐劑),pigment(色素),AF-2(硝基呋喃基糖酰胺),benzosulfimide(環(huán)己基糖精)。,C biological mutagen,toxoid sterigmatocystin(雜色曲霉素), Flavacin(黃曲霉素), clavacin(棒曲霉素)等 virus German measles virus(風疹病毒), (hepatovirus)

8、乙肝病毒, Measles virus(麻疹病毒), cytomegalovirus(巨細胞病毒),D Maternal age,Down綜合征與母親年齡,2. chromosomal aberrations,A. chromosome numerical aberration Numerical aberration is a change in the number of chromosomes from the normal number characteristic of the human beings.,euploid chromosome numerical aberration

9、 aneupliod,(1) Euploidy is the condition of having a normal number of structurally normal chromosomes. Euploid human females have 46 chromosomes (44 autosomes and two X chromosomes).,Polyploidy is a multiple of the haploid chromosome number (n) other than the diploid number (i.e., 3n, 4n and so on).

10、,Triploidy A triploid individual has three of every chromosome, that is, three haploid sets of chromosomes. A triploid human would have 69 chromosomes (3 haploid sets of 23).,Production of triploids seems to be relatively common and can occur by, for example, fertilization by two sperm.,雙雄受精和雙雌受精,Di

11、gyny(雙雌受精) Dispermy(雙雄受精) Endoreduplication（核內(nèi)復制） Endomitosis（核內(nèi)有絲分裂）,(2) Aneuploidy is the condition of having less than or more than the normal diploid number of chromosomes, and is the most frequently observed type of cytogenetic abnormality. In other words, it is any deviation from euploidy, alt

12、hough many authors restrict use of this term to conditions in which only a small number of chromosomes are missing or added.,Generally, aneuploidy is recognized as a small deviation from euploidy for the simple reason that major deviations are rarely compatible with survival, and such individuals us

13、ually die prenatally.,The two most commonly observed forms of aneuploidy are monosomy and trisomy.,Monosomy is lack of one of a pair of chromosomes. An individual having only one chromosome 6 is said to have monosomy 6. A common monosomy seen in many species is X chromosome monosomy, also known as T

14、urners syndrome. Monosomy is most commonly lethal during prenatal development.,Trisomy is having three chromosomes of a particular type. A common autosomal trisomy in humans in Down syndrome, or trisomy 21, in which a person has three instead of the normal two chromosome 21s. Trisomy is a specific i

15、nstance of polysomy, a more general term that indicates having more than two of any given chromosome.,However, birth of a live triploid is extraordinarily rare and such individuals are quite abnormal. The rare triploid that survives for more than a few hours after birth is almost certainly a mosaic,

16、 having a large proportion of diploid cells.,(3) Chromosome non-disjunction The failure of a pair of homologous chromosomes to separate properly during meiosis. The failure of homologues (at meiosis) or sister chromatids (at mitosis) to separate properly to opposite poles, that is two chromosomes or

17、 chromatids go to one pole and none to the other.,Non-disjunction can occur during meiosis I or meiosis II.,In meiosis I, the error occurs when the homologous pairs both travel into the same daughter cell. The result is two daughter cells that have two copies of the chromosome (called disomic cells)

18、 and two cells that are missing that chromosome (called nullisomic cells).,Non-disjunction in Meiosis I:,In meiosis II, the error occurs when the sister chromatids will not separate and thus travel into the same daughter cell.,單體型45,x,Non-disjunction in Meiosis II:,Fertilization following Meiosis I

19、error:,Fertilization following Meiosis II error:,三體型21三體,Non-disjunction occurs during early period of merogenesis,the result is mosaic,Chromosome loss,B. Chromosome Structural Aberration Structural aberration is a change in chromosome structure detectable by microscopic examination of the metaphase

20、 stage of cell division, observed as deletions and fragments, intrachanges or interchanges.,(1) A chromosome deletion occurs when the chromosome breaks and a piece is lost. This of course involves loss of genetic information and results in what could be considered partial monosomy for that chromosom

21、e.,缺失a：末端缺失；b：中間缺失,46,XX(XY),del(1)(q21)/ 46,XX(XY),del(1)(pterq21),46,XX(XY),del(3)(q21q31)/ 46,XX(XY),del(3)(pterq21:q31q31),(2) A related abnormality is a chromosome inversion. In this case, a break or breaks occur and that fragment of chromosome is inverted and rejoined rather than being lost. I

22、nversions are thus rearrangements that do not involve loss of genetic material and, unless the breakpoints disrupt an important gene, individuals carrying inversions have a normal phenotype.,倒位a：臂內(nèi)倒位染色體圖解；b：臂間倒位染色體圖解,46XX(XY),inv(1)(p22p34)/ 46XX(XY),inv(1)(pterp34:p22p34:p22qter),46XX(XY),inv(2)(p1

23、5q21)/ 46XX(XY),inv(2)(pterq15:q21p15:q21qter),(3) Chromosome Duplication is just that, a duplication of a section of a chromosome. A duplication is sometimes referred to as a partial trisomy. Trisomy refers to three. Therefore if a duplication exists, that individual has three copies of that area i

24、nstead of two. This means there are extra instructions (genes) present that can cause an increased risk for birth defects or developmental problems.,(4) A ring chromosome can happen in two ways. One is demonstrated in the picture; the end of the p and q arm breaks off and then stick to each other. T

25、he blue parts of each are lost thus resulting in loss of information. Second, the ends of the p and q arm stick together (fusion), usually without loss of material. However the ring can cause problems when the cell divides and can cause problems for the individual.,環(huán)狀染色體,46,XX(XY),r(2)(p21p31)/46,XX

26、(XY),r(2)(p21p31),(5) Translocations are chromosomal abnormalities which occur when chromosomes break and the fragments rejoin to other chromosomes.,There are many structurally different types of translocations. As with inversions, there is no loss of genetic material, although the breakpoint can ca

27、use disruption of a critical gene or juxtapose pieces of two genes to create a fusion gene that induces cancer.,Reciprocal translocations In a reciprocal translocation, two non-homologous chromosomes break and exchange fragments.,Individuals carrying such abnormalities still have a balanced complement of chromosomes and generally have a normal phenotype, but with varying degrees of subnormal fertility.