Nondisjunction
Nondisjunction
Nondisjunction is the failure of two members of a homologous pair of chromosomes to separate during meiosis. It gives rise to gametes with a chromosomal content that is different from the norm. The consequences of this are usually quite severe, and a number of clinical conditions are the result of this type of chromosome mutation.
The Mechanism of Nondisjunction
Homologous chromosomes are virtually identical chromosomes that occur in pairs, one member inherited from each parent. Humans have forty-six chromosomes, or twenty-three homologous pairs. In normal meiosis, homologous chromosomes pair up and, by attachment to the spindle fibres, become aligned at the cell equator. Prior to the first meiotic division, the members of each homologous pair migrate to opposite poles of the cell by means of the pulling action of the spindle fibers. This ensures that, upon completion of meiosis, each gamete will contain one copy of every chromosome.
However, the segregation process is not error-free, and every so often it happens that two homologous chromosomes fail to separate (disjoin) and thus both migrate to the same pole. This gives rise to two types of gamete. One type possesses two copies of the chromosome, whereas the other type lacks that chromosome altogether. This condition, involving the loss or gain of a single chromosome, is referred to as aneuploidy. Fusion of an aneuploid gamete with a normal gamete gives rise to a zygote with an odd number of chromosomes.
A zygote which has one less than the normal diploid number of chromosomes (2n−1) is said to be monosomic, and such zygotes do not usually develop to term. Zygotes containing an extra chromosome (2n+1) are trisomic for the chromosome of interest, and these may develop, though usually with severe abnormalities.
Non-Fatal Human Aneuploid Conditions
The most common example of non-fatal trisomy in humans is that of Down syndrome, caused by the presence of an extra copy of chromosome 21. Affected individuals suffer from mental retardation, congenital heart disease, and increased suceptibility to infection. Physical characteristics include a short, stocky body, flattened facial features, and almond-shaped eyes.
Down syndrome is an example of an autosomal trisomy as it involves one of the autosomes ("autosome" is the term that designates all the chromosomes other than the X and Y, or sex, chromosomes). There are many human conditions that are caused by nondisjunction of the sex chromosomes, and these usually affect the individual's secondary sexual characteristics and fertility.
For example, the fusion of an XY sperm with a normal X egg, or the fusion of a Y sperm with an XX egg gives rise to an XXY individual (with normal autosomes). This condition is known as Klinefelter's syndrome. Individuals affected by this disorder usually have below-average intelligence. They are are phenotypically male, but present some female secondary sexual characteristics. They may develop breasts, and they have little facial hair, very small testes and are sterile.
Individuals with Turner's syndrome (XO) are females with a single X chromosome. They are sterile and have underdeveloped secondary sexual characteristics, and they are shorter than normal. Females with genetic constitution XXX, on the other hand, have a normal appearance and are fertile, but suffer from a mild mental handicap. Similarly, XYY males have relatively few clinical symptoms and appear phenotypically normal. They are taller than average and may show aggressive behavior and a below-average intelligence. Both XXX and XYY conditions usually pass undiagnosed.
Fatal versus Nonfatal Conditions
In order to understand why some aneuploid conditions are fatal and others (such as those mentioned above) are not, one must understand the concept of gene dosage and its importance in development. A normal human possesses twenty-two pairs of autosomes and two sex chromosomes (XY in the case of males and XX in the case of females). Such an individual develops normally because there is a situation of genetic balance: Each gene is present in the correct amount (or dose), such that its contribution towards development is appropriate and ideal. However, if a chromosome is either removed from or added to the normal set, a situation of imbalance is immediately established: The contribution (or gene dosage) of each gene contained within that chromosome is altered and as a result development is compromised. While the duplication or silencing of an individual gene is not usually fatal, the wholesale addition or loss of a chromosome, which contains a thousand or more genes, almost always is.
It is obvious from this reasoning that a small change is more likely to be tolerated (albeit at a cost) than a large one. Down syndrome is caused by trisomy of chromosome 21, which is one of the smallest human chromosomes (containing a relatively small number of genes). This provides an explanation as to why this condition is not fatal, while a trisomy involving another, larger autosome would most likely be fatal.
With the sex chromosomes, a lot more flexibility is allowed: Although the X chromosome is very large, only one is used in development (in every femalecell one of the two X chromosomes is inactivated at random). The Y chromosome, on the other hand, contains very few genes and is not necessary for normal female development. It is only required for male development. With a knowledge of these facts it is relatively easy to understand why aneuploidies involving the sex chromosomes tend not to be fatal. Note, however, that the YO condition is fatal due to the lack of the essential X chromosome.
The Causes of Nondisjunction and Its Frequency in Humans
Meiosis is a very tightly regulated process, and a whole series of control mechanisms (constituting a number of "checkpoints") exist to ensure that everything proceeds in the correct manner. If an error should occur during the process, it is usually corrected. Nondisjunction is the result of a mistake at the level of chromosome segregation, which involves the spindle fibers. In normal meiosis, there is a mechanism that monitors the correct formation of the spindle fibers, the correct attachment of the chromosomes to the spindle fibers, and the correct segregation of chromosomes. Collectively, this is referred to as the spindle checkpoint. Failure of this checkpoint to function correctly results in nondisjunction of chromosomes.
Nondisjunction is known to occur more frequently in the cells of older individuals. This is illustrated by the fact that older women are more likely to give birth to children affected by an aneuploid condition than are younger women. For instance, the risk of a twenty-year-old mother giving birth to a child with Down syndrome is about one in two thousand, compared to an approximate one in thirty risk in the case of a woman of age forty-five. The precise reason for this is not entirely certain, but a simple explanation could be that the older a cell is, the more loosely controlled are the processes occurring within that cell. This would mean that an older cell undergoing meiosis would be more likely than a younger one to ignore the constraints of the spindle checkpoint and hence give rise to aneuploid cells.
see also Chromosomal Aberrations; Crossing Over; Down Syndrome; Meiosis.
Andrea Bernasconi
Bibliography
Alberts, Bruce, et al. Molecular Biology of the Cell, 3rd ed. New York: Garland Publishing, 1994.
Lewin, Benjamin. Genes VII. New York: Oxford University Press, 2000.
Strachan, Tom, and Andrew P. Read. Human Molecular Genetics. Oxford, U.K.: BiosScientific Publishers, 1996.