Nondisjunction is an error in cell division where chromosomes fail to separate correctly, leading to an uneven distribution of genetic material into the resulting daughter cells. This event can occur during the formation of reproductive cells (sperm and eggs) or in the division of somatic body cells. Nondisjunction is responsible for a significant percentage of miscarriages and is the underlying cause of several well-known chromosomal syndromes.
The Mechanism of Chromosome Separation Failure
Nondisjunction is a malfunction in the highly regulated steps of cell division. When this error occurs during meiosis (the production of sperm or egg cells), the resulting gametes possess an incorrect number of chromosomes. Failure can also happen during mitosis, the division of non-reproductive body cells, but meiotic errors are typically associated with inherited disorders.
Meiosis involves two consecutive rounds of division, and nondisjunction can occur in either stage. Nondisjunction in Meiosis I happens when the pair of homologous chromosomes fails to separate, and both move into the same daughter cell. This error results in all four final gametes having an abnormal chromosome count, possessing either an extra copy or missing a copy of that chromosome.
Alternatively, the failure can happen during Meiosis II, where the sister chromatids do not separate properly. If this occurs, two of the resulting gametes will be normal, one will have an extra chromosome, and one will be missing a chromosome. Errors in Meiosis I are generally considered a more common cause of human aneuploidy.
The Immediate Result: Aneuploidy
The consequence of nondisjunction is aneuploidy, meaning an abnormal number of chromosomes in a cell. A typical human cell contains 46 chromosomes (23 pairs). A gamete formed after nondisjunction will have too many or too few chromosomes. Fertilization involving such an abnormal reproductive cell results in an embryo with an incorrect total chromosome count.
Aneuploidy most commonly presents as trisomy or monosomy. Trisomy describes the presence of three copies of a particular chromosome instead of the normal two. This condition results in a total count of 47 chromosomes, often denoted as \(2n+1\).
Monosomy is the opposite condition, where a cell is missing one chromosome from a pair, leading to only one copy. A cell with monosomy has a total of 45 chromosomes, denoted as \(2n-1\). While trisomies can sometimes lead to a live birth, the loss of an entire autosome (non-sex chromosome) in a monosomy is almost always lethal.
Common Genetic Conditions Caused by Nondisjunction
Nondisjunction affects both autosomes and sex chromosomes, causing several human genetic conditions. The most frequent autosomal aneuploidy compatible with life is Trisomy 21, commonly known as Down Syndrome. This condition is caused by an extra copy of chromosome 21, resulting in 47 chromosomes in each cell.
Individuals with Down Syndrome typically experience intellectual disability, a characteristic facial appearance, and a higher predisposition for medical issues, including congenital heart defects and thyroid conditions. This syndrome occurs in approximately 1 in every 700 to 800 live births. The extra genetic material disrupts the balance of gene products necessary for normal development.
Nondisjunction can also affect the sex chromosomes, leading to conditions like Klinefelter Syndrome and Turner Syndrome. Klinefelter Syndrome occurs in males who inherit an extra X chromosome, resulting in a 47,XXY karyotype. This condition may lead to characteristics such as tall stature, small testes, reduced testosterone, and infertility.
Turner Syndrome, affecting females, is the only known monosomy generally compatible with life, characterized by the absence of one X chromosome (45,X karyotype). Females with Turner Syndrome often experience short stature, reduced ovarian function leading to delayed puberty and infertility, and a higher risk of heart defects. These sex chromosome aneuploidies are often less severe than autosomal ones because X chromosome inactivation helps compensate for the extra or missing genetic material.
Factors Influencing Nondisjunction Risk
The likelihood of a nondisjunction event is influenced by biological and environmental factors. Advanced maternal age is the primary risk factor for nondisjunction in the egg cell. The risk for conditions like Down Syndrome increases notably as a woman ages; incidence rises from about 1 in 1,250 at age 25 to about 1 in 100 at age 40.
This increased risk relates to the long arrest time of egg cells in the first stage of meiosis, which can last for decades. The cellular machinery responsible for chromosome separation, such as the cohesin proteins that hold chromosomes together, may degrade over time, leading to errors when meiosis is finally completed.
The influence of paternal age is less pronounced, but some studies suggest advanced paternal age may increase the risk for nondisjunction. Environmental factors, such as exposure to radiation or certain chemical agents, may also play a role. The primary focus remains on the age-related breakdown of the meiotic process.