Nondisjunction

Chromosomal aberrations Gene mutation Dominant lethal mutation Micronucleus formation Micronucleus formation Micronucleus formation Chromosomal aberrations Sister chromatid exchange Micronucleus formation Chromosomal aberrations Sister chromatid exchange DNA-protein cross-links Nondisjunction of Y chromosome in sperm DNA damage (single-strand breaks)... 

Drosophila melanogaster Chromosome loss or nondisjunction - Ramel and Magnusson 1979... 

Ramel C. Magnusson J. 1979. Chemical induction of nondisjunction in Drosophila. Environ Health Perspect 3 59-66. 

Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body s cells. 

Aneuploidy, which indicates a deviation from the euploid number of chromosomes, is the term used to describe the loss or gain of specific chromosomes. Two major types of aneuploidy are observed trisomy (three copies of a specific chromosome) and monosomy (one copy of a specific chromosome). Monosomies and trisomies are usually caused by nondisjunction (the failure of the two members of the chromosome pair to disjoin or separate) during meiosis (Fig II-3-2). All autosomal monosomies are lethal, but trisomies of three different autosomes (13,18, and 21) are compatible with survival to term in at least some cases. This difference illustrates the fact that the body tolerates extra genetic material more successfiiUy than a loss of genetic material. 

Heavy irradiation has been shown to induce nondisjunction in some experimental animals, but there is no good evidence for a detectable effect on human trisomy (choice E). 

Stoler, S., Keith, K.C., Curnick, K.E., and Fitzgerald-Hayes, M. (1995) A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis. Gene Dev. 9, 573-586. 

Positive results from the in vitro micronucleus test indicate that the test substance induces chromosome damage and/or damage to the cell division apparams, in cultured mammahan somatic cells. Immunochemical labehng (FISH fluorescence in sim hybridization) of kinetochores, or hybridization with general or chromosome specific centromeric/telomeric probes can provide useful information on the mechanism of micronucleus formation. Use of cytokinesis block facilitates the acquisition of the additional mechanistic information (e.g., chromosome nondisjunction) that can be obtained by FISH techniques. The micronucleus assay has a number of advantages over metaphase analysis performed to measure chromosome aberrations (see OECD TG 487 draft). 

Careie, A., Conti, G, Conti, L. Crebelli, R. (1985) Assays in Aspergillus nidulans for the indnction of forward-mutation in haploid strain 35 and for mitotic nondisjunction, haploidization and crossing-over in diploid strain PI. In Ashby, J., de Serres, F.J., Draper, M., Ishidate, M., Jr, Margolin, B.H., Matter, B.E. Shelby, M.D., eds. Progress in Mutation Research, Volume 5, Evaluation of Short-Term Tests for Carcinogens. Report of the International Programme on Chemical Safety s Collaborative Study on in vitro assays, Amsterdam, Elsevier Science, pp. 307-312... 

Clearly, this complex process must be controlled by the cell such that there are checkpoint controls, which make sure that there are two centrosomes and two half spindles, that the correct chromatids associate with the correct half-spindle and that separation does not occur until all of the chromatids are in the correct place. Failure of any part of this system could lead to the wrong number of chromosomes in one daughter cell. This uneven segregation is known as chromosomal nondisjunction. A number of chemicals, including some drugs, will interfere with this process. Thus, spindle formation can be disrupted, so the chromosomes may segregate in a random fashion. 

The result of nondisjunction, loss of one chromosome, for example, may be incompatible with survival of the cell, so aneugens are often cytotoxic. This obviously only occurs in cells, which are actively dividing, therefore such compounds find use as anticancer drugs. Two examples are vincristine and vinblastine, two vinca alkaloids, derived from a plant. 

The unequal partition of chromosomes or nondisjunction is a serious effect if the affected daughter cells survive. Down syndrome or Trisomy 21 is the result of chromosome nondisjunction in humans, those affected having 47 chromosomes instead of 46. This unequal partitioning of chromosomes can occur at mitosis in germ cells or during meiosis in the production of sperm or ova. 

The four types of mutagenic change are base-pair transformations, base-pair additions or deletions, large deletions and rearrangements, and unequal partition or nondisjunction. 

Carere, A., Conti, G, Conti, L. Crebelli, R. (1985) Assays in Aspergillus nidulans for the induction of forward-mutation in haploid strain 35 and for mitotic nondisjunction, haploidization and crossing-over in diploid strain Pl. Prog. Mutat. Res., 5, 307-312... 

Toluene did not induce sex-linked recessive lethal mutations or translocations, but did induce sex-chromosome loss and nondisjunction in male Drosophila melanogaster and induced mitotic arrest (C-mitosis) in embryos of the grasshopper, Melanoplus sanguinipes. 

MATa hie4 ade2-40 ade3 leul tryS ouh2 met 13 Mitotic nondisjunction 345... 

MATa adeS 4 aro2 4 oyh2 4 leul 4 ade3 Msiotic nondisjunction... 

D9J9 especially designed to measure meiotic nondisjunction has been tested with a variety of chemical agents.31 1 ... 

A specially constructed cross (1-41-5 x 1-34-8) of N. crassa has been used to determine the ability of agents to produce meiotic nondisjunction.11+7 The parental strains were heterozygous for four auxotrophic markers on chromosome 1 prototrophic disomies can be selected by plating ascospores on minimal medium. 

FIGURE 5-2 Diagram of a chromosome-loss test for the sex chromosomes when the male is the treated parent. The regular progeny are shown as classes (a) and (b). Class (c) is a presumptive loss of either the X or Y chromosome, but a portion of such a sex chromosome lacking marker mutants may still remain. Classes (d) and (e) represent loss of the and Bs marked regions, respectively, of the Y chromosome. Class (f) is a rare class and arises from nondisjunction of the X and Y chromosome in the parental male. Classes (g) and (h) are rare classes that arise from primary nondisjunction of the X chromosomes in the parental female. Reprinted with permission from Abrahamson and Lewis.5... 

The nondisjunction test developed by Craymer75 involves an X Y translocation stock that is mated to a standard female line with appropriate genetic markers. 

Convenient methods378 exist in the mouse for detecting whole-chromosome aneuploidy, as determined by sex-chromosome loss and nondisjunction, ttiese methods are possible because XO female mice and XXY male mice are viable. 

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