What Is Nondisjunction? Definition and Examples

In genetics, nondisjunction is a failed separation of chromosomes during cell division that results in daughter cells containing an abnormal number of chromosomes (aneuploidy). It refers to either sister chromatids or homologous chromosomes improperly separating during mitosis, meiosis I, or meiosis II. The excess or deficit chromosomes alters cell function and may be lethal.

Types of Nondisjunction

Nondisjunction may occur whenever a cell divides its chromosomes. This happens during normal cell division (mitosis) and gamete production (meiosis).

Mitosis

DNA replicates prior to cell division. The chromosomes line up in the middle plane of the cell during metaphase and the kinetochores of sister chromatids attach to microtubules. At anaphase, the microtubules pull sister chromatids in opposite directions. In nondisjunction, the sister chromatids stick together, so both get pulled to one side. One daughter cell gets both sister chromatids, while the other gets none. Organisms use mitosis to grow and repair themselves, so nondisjunction affects all descendants of the affected parent cell, but not all of the cells in an organism unless it occurs in the first division of a fertilized egg.

Meiosis

As with mitosis, DNA replicates prior to gamete formation in meiosis. However, the cell divides twice to produce haploid daughter cells. When haploid sperm and egg combine at fertilization, a normal diploid zygote forms. Nondisjunction may occur during the first division (meiosis I) when homologous chromosomes fail to separate. When nondisjunction occurs during the second division (meiosis II), sister chromatids fail to separate. In either case, all of the cells in the developing embryo will be aneuploid.

Nondisjunction Causes

Nondisjunction occurs when some aspect of the spindle assembly checkpoint (SAC) fails. The SAC is a molecular complex that holds a cell in anaphase until all of the chromosomes are aligned on the spindle apparatus. Once alignment is confirmed, SAC stops inhibiting anaphase promoting complex (APC), so the homologous chromosomes separate. Sometimes the enzymes topoisomerase II or separase are inactivated, causing chromosomes to stick together. Other times, the fault is with condensin, a protein complex that assembles chromosomes on the metaphase plate. A problem may also arise when the cohesin complex holding chromosomes together degrades over time.

Risk Factors

The two main risk factors for nondisjunction are age and chemical exposure. In humans, nondisjunction in meiosis is much more common in egg production than in sperm production. The reason is that human oocytes remain arrested before completing meiosis I from before birth until ovulation. The cohesin complex holding replicated chromosomes together eventually degrades, so the microtubules and kinetochores may not properly attach when the cell finally divides. Sperm are produced continuously, so problems with the cohesin complex are rare.

Chemicals known to increase the risk of aneuploidy include cigarette smoke, alcohol, benzene, and the insecticides carbaryl and fenvalerate.

Conditions in Humans

Nondisjunction in mitosis can result in somatic mosaicism and some types of cancer, such as retinoblastoma. Nondisjunction in meiosis leads to a loss of a chromosome (monosomy) or extra single chromosome (trisomy). In humans, the only survivable monosomy is Turner syndrome, which results in an individual who is monosomic for the X chromosome. All monosomies of autosomal (non-sex) chromosomes are lethal. Sex chromosome trisomies are XXY or Klinefelter's syndrome, XXX or trisomy X, and XYY syndrome. Autosomal trisomies include trisomy 21 or Down syndrome, trisomy 18 or Edwards syndrome, and trisomy 13 or Patau syndrome. Trisomies of chromosomes aside from sex chromosomes or chromosomes 13, 18, or 21 almost always result in miscarriage. The exception is mosaicism, where the presence of normal cells may compensate for the trisomic cells.

Sources

• Bacino, C.A.; Lee, B. (2011). "Chapter 76: Cytogenetics". In Kliegman, R.M.; Stanton, B.F.; St. Geme, J.W.; Schor, N.F.; Behrman, R.E. (eds.). Nelson Textbook of Pediatrics (19th ed.). Saunders: Philadelphia. pp. 394–413. ISBN 9781437707557.
• Jones, K. T.; Lane, S. I. R. (August 27, 2013). "Molecular causes of aneuploidy in mammalian eggs". Development. 140 (18): 3719–3730. doi:10.1242/dev.090589
• Koehler, K.E.; Hawley, R.S.; Sherman, S.; Hassold, T. (1996). "Recombination and nondisjunction in humans and flies". Human Molecular Genetics. 5 Spec No: 1495–504. doi:10.1093/hmg/5.Supplement_1.1495
• Simmons, D. Peter; Snustad, Michael J. (2006). Principles of Genetics (4. ed.). Wiley: New York. ISBN 9780471699392.
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