Nondisjunction

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.

[4] In general, nondisjunction can occur in any form of cell division that involves ordered distribution of chromosomal material.

[citation needed] Ovulated eggs become arrested in metaphase II until fertilization triggers the second meiotic division.

Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and the cohesion complex.

[11] The spindle assembly checkpoint (SAC) is a molecular safe-guarding mechanism that governs proper chromosome segregation in eukaryotic cells.

[12] SAC inhibits progression into anaphase until all homologous chromosomes (bivalents, or tetrads) are properly aligned to the spindle apparatus.

[citation needed] Surveys of cases of human aneuploidy syndromes have shown that most of them are maternally derived.

The most obvious difference between female oogenesis and male spermatogenesis is the prolonged arrest of oocytes in late stages of prophase I for many years up to several decades.

Failures of recombination or inappropriately located crossovers have been well documented as contributors to the occurrence of nondisjunction in humans.

[5] Due to the prolonged arrest of human oocytes, weakening of cohesive ties holding together chromosomes and reduced activity of the SAC may contribute to maternal age-related errors in segregation control.

[6][13] The cohesin complex is responsible for keeping together sister chromatids and provides binding sites for spindle attachment.

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.

[citation needed] The only known survivable monosomy in humans is Turner syndrome, where the affected individual is monosomic for the X chromosome (see below).

[15] It is well documented that advanced maternal age is associated with greater risk of meiotic nondisjunction leading to Down syndrome.

As a consequence, the organism evolves as a mixture of cell lines with differing ploidy (number of chromosomes).

By this combination of lesions, affected cells completely lose expression of functioning tumor suppressor protein.

PGD is considered difficult due to it being both time consuming and having success rates only comparable to routine IVF.

[17] Karyotyping involves performing an amniocentesis in order to study the cells of an unborn fetus during metaphase 1.

[18] Polar body diagnosis (PBD) can be used to detect maternally derived chromosomal aneuploidies as well as translocations in oocytes.

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 of sister chromatids during mitosis:
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.
Right: Anaphase of mitosis, where sister chromatids separate and the microtubules pull them in opposite directions.
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.
Karyotype of X monosomy (Turner syndrome)
This condition is characterized by the presence of only one X chromosome and no Y chromosome (see bottom right corner).
Karyotype of trisomy 21 (Down syndrome)
Note that chromosome 21 is present in 3 copies, while all other chromosomes show the normal diploid state with 2 copies. Most cases of trisomy of chromosome 21 are caused by a nondisjunction event during meiosis I (see text).
Loss of a tumor suppressor gene locus according to the two-hit model :
In the first hit, the tumor suppressor gene on one of the two chromosomes is affected by a mutation that makes the gene product non-functional. This mutation may arise spontaneously as a DNA replication error or may be induced by a DNA damaging agent. The second hit removes the remaining wild-type chromosome, for example through a mitotic nondisjunction event. There are several other potential mechanisms for each of the two steps, for example an additional mutation, an unbalanced translocation, or a gene deletion by recombination. As a result of the double lesion, the cell may become malignant because it is no longer able to express the tumor suppressor protein.