Nondisjunction

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Fertilization
  • Zygote
    • 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

    meiosis II, and failure of sister chromatids to separate during mitosis.[1][2][3] 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.[4]

    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:

    gametes (eggs and sperm) for sexual reproduction, mitosis is the form of cell division used by all other cells of the body.[citation needed
    ]

    Meiosis II

    Ovulated eggs become arrested in metaphase II until

    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.[6]

    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.

    Mitosis

    Division of

    eukaryotes. Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and the cohesion complex.[9] During anaphase, cohesin is cleaved by separase.[10] Topoisomerase II and condensin are responsible for removing catenations.[11]

    Molecular mechanisms

    Central role of the spindle assembly checkpoint

    The

    anaphase promoting complex (APC), which in turn irreversibly triggers progression through anaphase.[citation needed
    ]

    Sex-specific differences in meiosis

    Surveys of cases of human aneuploidy syndromes have shown that most of them are maternally derived.

    prophase I for many years up to several decades. Male gametes on the other hand quickly go through all stages of meiosis I and II. Another important difference between male and female meiosis concerns the frequency of recombination between homologous chromosomes: In the male, almost all chromosome pairs are joined by at least one crossover, while more than 10% of human oocytes contain at least one bivalent without any crossover event. Failures of recombination or inappropriately located crossovers have been well documented as contributors to the occurrence of nondisjunction in humans.[5]

    Age-related loss of cohesin ties

    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

    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.[6]

    Consequences

    The result of this error is a cell with an imbalance of chromosomes. Such a cell is said to be

    aneuploid. Loss of a single chromosome (2n-1), in which the daughter cell(s) with the defect will have one chromosome missing from one of its pairs, is referred to as a monosomy. Gaining a single chromosome, in which the daughter cell(s) with the defect will have one chromosome in addition to its pairs is referred to as a trisomy.[3] In the event that an aneuploidic gamete is fertilized, a number of syndromes might result.[citation needed
    ]

    Monosomy

    The only known survivable monosomy in humans is

    mosaicism (see below), or if the normal number of chromosomes is restored via duplication of the single monosomic chromosome ("chromosome rescue").[2]

    Turner syndrome (X monosomy) (45, X0)

    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).

    Complete loss of an entire X chromosome accounts for about half the cases of Turner syndrome. The importance of both X chromosomes during embryonic development is underscored by the observation that the overwhelming majority (>99%) of fetuses with only one X chromosome (karyotype 45, X0) are spontaneously aborted.[14]

    Autosomal trisomy

    The term autosomal trisomy means that a chromosome other than the sex chromosomes X and Y is present in 3 copies instead of the normal number of 2 in diploid cells.[citation needed]

    Down syndrome (trisomy 21)

    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).

    spontaneous abortions. It is the leading cause of pregnancy wastage and is the most common known cause of intellectual disability.[15] 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.[13]

    Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13)

    Human autosomal trisomies compatible with live birth, other than

    mosaicism, the presence of a normal cell line, in addition to the trisomic cell line, may support the development of a viable trisomy of the other chromosomes.[2]

    Sex chromosome aneuploidy

    The term sex chromosome aneuploidy summarizes conditions with an abnormal number of sex chromosomes, i.e., other than XX (female) or XY (male). Formally, X chromosome monosomy (Turner syndrome, see above) can also be classified as a form of sex chromosome aneuploidy.[citation needed]

    Klinefelter syndrome (47, XXY)

    Klinefelter syndrome is the most common sex chromosome aneuploidy in humans. It represents the most frequent cause of hypogonadism and infertility in men. Most cases are caused by nondisjunction errors in paternal meiosis I.[2] About eighty percent of individuals with this syndrome have one extra X chromosome resulting in the karyotype XXY. The remaining cases have either multiple additional sex chromosomes (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY), or structural chromosome abnormalities.[2]

    XYY Male (47, XYY)

    The incidence of XYY syndrome is approximately 1 in 800–1000 male births. Many cases remain undiagnosed because of their normal appearance and fertility, and the absence of severe symptoms. The extra Y chromosome is usually a result of nondisjunction during paternal meiosis II.[2]

    Trisomy X (47,XXX)

    Trisomy X is a form of sex chromosome aneuploidy where females have three instead of two X chromosomes. Most patients are only mildly affected by neuropsychological and physical symptoms. Studies examining the origin of the extra X chromosome observed that about 58–63% of cases were caused by nondisjunction in maternal meiosis I, 16–18% by nondisjunction in maternal meiosis II, and the remaining cases by post-zygotic, i.e., mitotic, nondisjunction.[16]

    Uniparental disomy

    Prader-Willi syndrome and Angelman syndrome.[14]

    Mosaicism syndromes

    Hypomelanosis of Ito.[14]

    Mosaicism in malignant transformation

    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.

    Development of cancer often involves multiple alterations of the cellular genome (

    Knudson hypothesis). Human retinoblastoma is a well studied example of a cancer type where mitotic nondisjunction can contribute to malignant transformation: Mutations of the RB1 gene, which is located on chromosome 13 and encodes the tumor suppressor retinoblastoma protein, can be detected by cytogenetic analysis in many cases of retinoblastoma. Mutations of the RB1 locus in one copy of chromosome 13 are sometimes accompanied by loss of the other wild-type chromosome 13 through mitotic nondisjunction. By this combination of lesions, affected cells completely lose expression of functioning tumor suppressor protein.[7]

    Diagnosis

    Preimplantation genetic diagnosis

    Pre-implantation genetic diagnosis (PGD or PIGD) is a technique used to identify genetically normal embryos and is useful for couples who have a family history of genetic disorders. This is an option for people choosing to procreate through IVF. PGD is considered difficult due to it being both time consuming and having success rates only comparable to routine IVF.[17]

    Karyotyping

    Light microscopy can be used to visually determine if aneuploidy is an issue.[18]

    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.[19]

    Blastomere biopsy

    Blastomere biopsy is a technique in which blastomeres are removed from the zona pellucida. It is commonly used to detect aneuploidy.[20] Genetic analysis is conducted once the procedure is complete. Additional studies are needed to assess the risk associated with the procedure.[21]

    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.[22][23] Other studies indicate factors such as alcohol consumption,[24] occupational exposure to benzene,[25] and exposure to the insecticides fenvalerate[26] and carbaryl[27] also increase aneuploidy.

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