600px|thumb| The left image at the blue arrow is nondisjunction taking place during meiosis II. The right image at the green arrow is nondisjunction taking place during meiosis I. Nondisjunction is when chromosomes fail to separate normally resulting in a gain or loss of chromosomes.
Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).
Calvin Bridges and Thomas Hunt Morgan are credited with discovering nondisjunction in Drosophila melanogaster sex chromosomes in the spring of 1910, while working in the Zoological Laboratory of Columbia University. Proof of the chromosome theory of heredity emerged from these early studies of chromosome non-disjunction.
Types
In general, nondisjunction can occur in any form of cell division that involves ordered distribution of chromosomal material. Higher animals have three distinct forms of such cell divisions: Meiosis I and meiosis II are specialized forms of cell division occurring during generation of gametes (eggs and sperm) for sexual reproduction, mitosis is the form of cell division used by all other cells of the body.
Meiosis II
Ovulated eggs become arrested in metaphase II until fertilization triggers the second meiotic division. Similar to the segregation events of mitosis, the pairs of sister chromatids resulting from the separation of bivalents in meiosis I are further separated in anaphase of meiosis II. In oocytes, one sister chromatid is segregated into the second polar body, while the other stays inside the egg. During spermatogenesis, each meiotic division is symmetric such that each primary spermatocyte gives rise to 2 secondary spermatocytes after meiosis I, and eventually 4 spermatids after meiosis II. Meiosis II-nondisjunction may also result in aneuploidy syndromes, but only to a much smaller extent than do segregation failures in meiosis I.
[[File:Mitotic nondisjunction.png|600px|thumb|Nondisjunction of sister chromatids during mitosis: <br />
Left: Metaphase of mitosis. Chromosome line up in the middle plane, the mitotic spindle forms and the kinetochores of sister chromatids attach to the microtubules. <br />
Right: Anaphase of mitosis, where sister chromatids separate and the microtubules pull them in opposite directions. <br />
The chromosome shown in red fails to separate properly, its sister chromatids stick together and get pulled to the same side, resulting in mitotic nondisjunction of this chromosome. ]]
Mitosis
Division of somatic cells through mitosis is preceded by replication of the genetic material in S phase. As a result, each chromosome consists of two sister chromatids held together at the centromere. In the anaphase of mitosis, sister chromatids separate and migrate to opposite cell poles before the cell divides. Nondisjunction during mitosis leads to one daughter receiving both sister chromatids of the affected chromosome while the other gets none. Chromosome nondisjunction in mitosis can be attributed to the inactivation of topoisomerase II, condensin, or separase. Meiotic nondisjunction has been well studied in Saccharomyces cerevisiae. This yeast undergoes mitosis similarly to other eukaryotes. Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and the cohesion complex. During anaphase, cohesin is cleaved by separase. Topoisomerase II and condensin are responsible for removing catenations.
Molecular mechanisms
Central role of the spindle assembly checkpoint
The spindle assembly checkpoint (SAC) is a molecular safe-guarding mechanism that governs proper chromosome segregation in eukaryotic cells. SAC inhibits progression into anaphase until all homologous chromosomes (bivalents, or tetrads) are properly aligned to the spindle apparatus. Only then, SAC releases its inhibition of the anaphase promoting complex (APC), which in turn irreversibly triggers progression through anaphase.
Sex-specific differences in meiosis
Surveys of cases of human aneuploidy syndromes have shown that most of them are maternally derived. The cohesin complex is responsible for keeping together sister chromatids and provides binding sites for spindle attachment. Cohesin is loaded onto newly replicated chromosomes in oogonia during fetal development. Mature oocytes have only limited capacity for reloading cohesin after completion of S phase. The prolonged arrest of human oocytes prior to completion of meiosis I may therefore result in considerable loss of cohesin over time. Loss of cohesin is assumed to contribute to incorrect microtubule-kinetochore attachment and chromosome segregation errors during meiotic divisions. Trisomy occurs in at least 0.3% of newborns and in nearly 25% of spontaneous abortions. It is the leading cause of pregnancy wastage and is the most common known cause of intellectual disability. It is well documented that advanced maternal age is associated with greater risk of meiotic nondisjunction leading to Down syndrome. This may be associated with the prolonged meiotic arrest of human oocytes potentially lasting for more than four decades.
Uniparental disomy
Uniparental disomy denotes the situation where both chromosomes of a chromosome pair are inherited from the same parent and are therefore identical. This phenomenon most likely is the result of a pregnancy that started as a trisomy due to nondisjunction. Since most trisomies are lethal, the fetus only survives because it loses one of the three chromosomes and becomes disomic. Uniparental disomy of chromosome 15 is, for example, seen in some cases of Prader-Willi syndrome and Angelman syndrome.
Karyotyping
Karyotyping involves performing an amniocentesis in order to study the cells of an unborn fetus during metaphase 1. Light microscopy can be used to visually determine if aneuploidy is an issue.
Polar body diagnosis
Polar body diagnosis (PBD) can be used to detect maternally derived chromosomal aneuploidies as well as translocations in oocytes. The advantage of PBD over PGD is that it can be accomplished in a short amount of time. This is accomplished through zona drilling or laser drilling.
Blastomere biopsy
Blastomere biopsy is a technique in which blastomeres are removed from the zona pellucida. It is commonly used to detect aneuploidy. Genetic analysis is conducted once the procedure is complete. Additional studies are needed to assess the risk associated with the procedure.
Lifestyle/environmental hazards
Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a known aneugen (aneuploidy inducing agent). It is associated with increases in aneuploidy ranging from 1.5 to 3.0-fold. Other studies indicate factors such as alcohol consumption, occupational exposure to benzene, and exposure to the insecticides fenvalerate and carbaryl also increase aneuploidy.