Nondisjunction and aneuploidy

SIGNIFICANCE: Nondisjunction is the faulty disjoining of replicated chromosomes during mitosis or meiosis, which causes an alteration in the normal number of chromosomes (aneuploidy). Nondisjunction is a major cause of Down syndrome and various sex chromosome anomalies. Understanding the mechanisms associated with cell division may provide new insight into the occurrence of these aneuploid conditions.

Background

Each cell in multicellular organisms contains all the hereditary information for that individual, in the form of DNA. In eukaryotes, DNA is packaged in rodlike structures called chromosomes, and any given species has a characteristic chromosome number. There are typically two of each kind of chromosome, which is referred to as being diploid. In humans (Homo sapiens), there are forty-six chromosomes; in corn (Zea mays), there are twenty chromosomes. A cell has half the number of chromosomes as a cell of the same species, which constitutes one of each kind of chromosome. One set of chromosomes is contributed to a new individual by each parent in through the egg and sperm, which are both haploid. Thus, a fertilized egg will contain two sets of chromosomes and will be diploid.

A karyotype is a drawing or picture that displays the number and physical appearance of the chromosomes from a single cell. A normal human contains twenty-two pairs of (chromosomes that are not sex chromosomes) and one pair of sex chromosomes. Females normally possess two X chromosomes in their cells, one inherited from each parent. Males have a single X chromosome, inherited from the mother, and a Y chromosome, inherited from the father.

The many cells of a multicellular organism are created as the fertilized egg undergoes a series of cell divisions. In each cell division cycle, the chromosomes are replicated, and, subsequently, one copy of each chromosome is distributed to two through a process called mitosis. When gametes (eggs or sperm) are produced in a mature organism, a different type of nuclear division occurs called meiosis. Gametes contain one set of chromosomes instead of two. When two gametes join (when a sperm cell fertilizes an egg cell), the diploid chromosome number for the species is restored, and, potentially, a new individual will form with repeated cell divisions.

When replicated chromosomes are distributed to daughter cells during or meiosis, each pair of chromosomes is said to disjoin from one another (disjunction). Occasionally, this process fails. When faulty disjoining (nondisjunction) of replicated chromosomes occurs, a daughter cell may result with one or more chromosomes than normal or one or more fewer than normal. This alteration in the normal number of chromosomes is called aneuploidy. One chromosome more than normal is referred to as a “trisomy.” For example, Down syndrome is caused by trisomy 21 in humans. One chromosome fewer than normal is called monosomy. Turner syndrome in humans is an example of monosomy. Turner’s individuals are women who have only one X chromosome in their cells, whereas human females normally have two X chromosomes. When nondisjunction occurs in the dividing cells of a mature organism or a developing organism, a portion of the cells of the organism may be aneuploid. If nondisjunction occurs in during formation, then a gamete will not have the correct haploid chromosome number. If that gamete joins with another, the resulting embryo will be aneuploid. Examples of human conditions occurring in live births include Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13), (more than two X chromosomes), Klinefelter syndrome (XXY), and Turner syndrome (XO). Most aneuploid embryos do not survive to birth.

Causes of Nondisjunction

There are both environmental and genetic factors associated with nondisjunction in plants and animals. Environmental factors that may induce nondisjunction include physical factors such as heat, cold, maternal age, and ionizing radiation, in addition to a wide variety of chemical agents.

In humans, it is well established that increased maternal age is a cause of nondisjunction associated with the occurrence of Down syndrome. For women who are twenty-five years of age when they conceive, the incidence of newborns with Down syndrome is 1 in 1,250 newborns. For mothers who conceive at age forty, the incidence of newborns with Down syndrome is 1 in 100. While it is clear that increased maternal age is linked to nondisjunction, it is not known what specific physiological, cellular, or molecular mechanisms or processes are associated with this increased nondisjunction. While nondisjunction in maternal meiosis may be the major source of trisomy 21 in humans, paternal nondisjunction in sperm formation does occur and may result in aneuploidy.

In a study conducted by Karl Sperling and colleagues published in the British Medical Journal (July 16, 1994), low-dose radiation in the form of radioactive fallout from the Chernobyl nuclear accident (April 1986) was linked to a significant increase in trisomy 21 in West Berlin in January 1987: twelve births of trisomy 21 compared to the expected two or three births. This study suggests that, at least under certain circumstances, ionizing radiation may affect the occurrence of nondisjunction. Researchers have shown that ethanol (the alcohol in alcoholic beverages) causes nondisjunction in mouse-egg formation, suggesting a similar possibility in humans. Other researchers have found that human cells in tissue culture (cells growing on nutrient media) had an increased occurrence of nondisjunction if the media was deficient in folic acid. This implies that folic acid may be necessary for normal chromosome or distribution during cell division.

Scientists know from genetics research that mutations (changes in specific genes) in the fruit fly result in the occurrence of nondisjunction. This genetic component of nondisjunction is further supported by the observation that an occasional family gives birth to more than one child with an aneuploid condition. In these instances, it is likely that genetic factors are contributing to repeated nondisjunction.

Impact and Applications

There are several reasons scientists are devoting research efforts to understanding the consequences of nondisjunction and aneuploidy. First, at least 15 to 20 percent of all recognized human pregnancies end in spontaneous abortions. Of these aborted fetuses, between 50 and 60 percent are aneuploid. Second, of live births, 1 in 700 is an individual with Down syndrome. Mental retardation is a major symptom in individuals with Down syndrome. Thus, nondisjunction is one cause of mental retardation. Finally, aneuploidy is common in cancerous cells. Scientists do not know whether nondisjunction is part of the multistep process of tumor formation, or whether aneuploidy is a consequence of tumor growth. Continued research into the mechanics of cell division and the various factors that influence that process will increase the understanding of the consequences of nondisjunction and possibly provide the means to prevent its occurrence.

Key terms

• meiosisa series of two nuclear divisions that occur in gamete formation in sexually reproducing organisms
• mitosisnuclear division of chromosomes, usually accompanied by cytoplasmic division; two daughter cells are formed with identical genetic material

Bibliography

Bellenir, Karen, ed. Genetic Disorders Sourcebook. 3d ed. Detroit: Omnigraphics, 2004. Print.

Bender, Bruce G., and Robert J. Harmon. “Psychosocial Adaptation of Thirty-nine Students with Sex Chromosome Abnormalities.” Pediatrics 96.2 (1995): 302–08. Print.

Berch, Daniel B., and Bruce G. Bender, eds. Sex Chromosome Abnormalities and Human Behavior. Boulder: Westview, 1990. Print.

Cunningham, Cliff. Understanding Down Syndrome: An Introduction for Parents. 1988. Reprint. Cambridge: Brookline Books, 1999. Print.

Delhanty, Joy D. A., Franck Pellestor, and S. Karger. Aneuploidy. New York: Karger, 2011. Print.

Gardner, R. J. McKinlay, and Grant R. Sutherland. Chromosome Abnormalities and Genetic Counseling. 4th ed. New York: Oxford UP, 2012. Print.

Gersen, Steven L., and Martha B. Keagle, eds. The Principles of Clinical Cytogenetics. 2d ed. Totowa: Humana, 2005. Print.

Miller, Orlando J., and Eeva Therman. Human Chromosomes. 4th ed. New York: Springer, 2001. Print.

Nagaoka, So I., et al. "Human Aneuploidy: Mechanism and New Insights into an Age-Old Problem." Nature Reviews Genetics 13.7 (2012): 493–504. Print.

Orr-Weaver, Terry L., and Robert A. Weinberg. “A Checkpoint on the Road to Cancer.” Nature (19 Mar. 1998): 223. Print.

Pai, G. Shashidhar, Raymond C. Lewandowski, and Digamber S. Borgaonkar. Handbook of Chromosomal Syndromes. New York: Wiley, 2002. Print.

Patterson, D. “The Causes of Down Syndrome.” Scientific American 257.2 (1987): 52. Print.

"Risks of Pregnancy Over Age 30." Stanford Medicine, www.stanfordchildrens.org/en/topic/default?id=risks-of-pregnancy-over-age-30-90-P02481. Accessed 5 Sept. 2024.

Verdyck, P., et al. "Aneuploidy in Oocytes from Women of Advanced Maternal Age: Analysis of the Causal Meiotic Errors and Impact on Embryo Development." Human Reproduction, vol. 38, no. 12, 2023, pp. 2526-2535, doi.org/10.1093/humrep/dead201. Accessed 5 Sept. 2024.

Vig, Baldev K., ed. Chromosome Segregation and Aneuploidy. New York: Springer-Verlag, 1993. Print.