Nondisjunction is the failure ofhomologous chromosomes orsister chromatids to separate properly duringcell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair ofhomologous chromosomes to separate inmeiosis I, failure of sister chromatids to separate duringmeiosis II, and failure of sister chromatids to separate duringmitosis.[1][2][3] Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).
Calvin Bridges andThomas Hunt Morgan are credited with discovering nondisjunction inDrosophila 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. Higher animals have three distinct forms of such cell divisions:Meiosis I andmeiosis II are specialized forms of cell division occurring during generation ofgametes (eggs and sperm) for sexual reproduction,mitosis is the form of cell division used by all other cells of the body.[citation needed]
Ovulated eggs become arrested in metaphase II untilfertilization triggers the second meiotic division.[5] Similar to the segregation events ofmitosis, the pairs of sisterchromatids resulting from the separation of bivalents inmeiosis I are further separated inanaphase ofmeiosis II. In oocytes, one sister chromatid is segregated into the second polar body, while the other stays inside the egg. Duringspermatogenesis, each meiotic division is symmetric such that each primaryspermatocyte gives rise to 2 secondary spermatocytes after meiosis I, and eventually 4spermatids after meiosis II. Meiosis II-nondisjunction may also result inaneuploidy syndromes, but only to a much smaller extent than dosegregation failures in meiosis I.[6]
Division ofsomatic cells through mitosis is preceded by replication of the genetic material inS phase. As a result, each chromosome consists of two sisterchromatids held together at thecentromere. In theanaphase ofmitosis, sisterchromatids separate and migrate to opposite cell poles before the cell divides. Nondisjunction duringmitosis leads to one daughter receiving both sisterchromatids of the affected chromosome while the other gets none.[2][3] This is known as achromatin bridge or an anaphase bridge. Mitotic nondisjunction results in somaticmosaicism, since only daughter cells originating from the cell where the nondisjunction event has occurred will have an abnormal number ofchromosomes.[3] Nondisjunction during mitosis can contribute to the development of some forms ofcancer, e.g.,retinoblastoma (see below).[7] Chromosome nondisjunction in mitosis can be attributed to the inactivation oftopoisomerase II,condensin, orseparase.[8] Meiotic nondisjunction has been well studied inSaccharomyces cerevisiae. This yeast undergoes mitosis similarly to othereukaryotes. Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and thecohesion complex.[9] During anaphase,cohesin is cleaved by separase.[10] Topoisomerase II and condensin are responsible for removingcatenations.[11]
Thespindle assembly checkpoint (SAC) is a molecular safe-guarding mechanism that governs properchromosome segregation in eukaryotic cells.[12] SAC inhibits progression into anaphase until all homologous chromosomes (bivalents, or tetrads) are properly aligned to thespindle apparatus. Only then, SAC releases its inhibition of theanaphase promoting complex (APC), which in turn irreversibly triggers progression through anaphase.[citation needed]
Surveys of cases of human aneuploidy syndromes have shown that most of them are maternally derived.[5] This raises the question: Why is female meiosis more error prone? The most obvious difference between female oogenesis and male spermatogenesis is the prolonged arrest of oocytes in late stages ofprophase 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 onecrossover, 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]
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 insegregation control.[6][13] Thecohesin complex is responsible for keeping together sister chromatids and provides binding sites for spindle attachment. Cohesin is loaded onto newly replicated chromosomes inoogonia during fetal development. Matureoocytes have only limited capacity for reloading cohesin after completion ofS 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 incorrectmicrotubule-kinetochore attachment and chromosome segregation errors during meiotic divisions.[6]
The result of this error is a cell with an imbalance of chromosomes. Such a cell is said to beaneuploid. 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 amonosomy. 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 atrisomy.[3] In the event that an aneuploidic gamete is fertilized, a number of syndromes might result.[citation needed]
The only known survivable monosomy in humans isTurner syndrome, where the affected individual is monosomic for theX chromosome (see below). Other monosomies are usually lethal during early fetal development, and survival is only possible if not all the cells of the body are affected in case of amosaicism (see below), or if the normal number of chromosomes is restored via duplication of the single monosomic chromosome ("chromosome rescue").[2]
Complete loss of an entire X chromosome accounts for about half the cases ofTurner 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]
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, a trisomy of chromosome 21, is the most common anomaly of chromosome number in humans.[2] The majority of cases result from nondisjunction during maternal meiosis I.[14] Trisomy occurs in at least 0.3% of newborns and in nearly 25% ofspontaneous abortions. It is the leading cause of pregnancy wastage and is the most common known cause ofintellectual disability.[15] It is well documented thatadvanced 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]
Human autosomal trisomies compatible with live birth, other thanDown syndrome (trisomy 21), areEdwards syndrome (trisomy 18) andPatau syndrome (trisomy 13).[1][2] Complete trisomies of other chromosomes are usually not viable and represent a relatively frequent cause of miscarriage. Only in rare cases of amosaicism, 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]
The termsex 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 is the most common sex chromosome aneuploidy in humans. It represents the most frequent cause ofhypogonadism andinfertility 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 thekaryotype 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]
The incidence ofXYY 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 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 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 ofPrader-Willi syndrome andAngelman syndrome.[14]
Mosaicism syndromes can be caused by mitotic nondisjunction in early fetal development. As a consequence, the organism evolves as a mixture of cell lines with differingploidy (number of chromosomes). Mosaicism may be present in some tissues, but not in others. Affected individuals may have a patchy or asymmetric appearance. Examples of mosaicism syndromes includePallister-Killian syndrome andHypomelanosis of Ito.[14]
Development of cancer often involves multiple alterations of the cellular genome (Knudson hypothesis). Humanretinoblastoma 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 suppressorretinoblastoma 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]
Pre-implantation genetic diagnosis (PGD or PIGD) is a technique used to identify genetically normalembryos and is useful for couples who have a family history of genetic disorders. This is an option for people choosing to procreate throughIVF. PGD is considered difficult due to it being both time consuming and having success rates only comparable to routine IVF.[17]
Karyotyping involves performing anamniocentesis 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.[18]
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 is a technique in which blastomeres are removed from thezona 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]
Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a knownaneugen (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 tobenzene,[25] and exposure to the insecticidesfenvalerate[26] andcarbaryl[27] also increase aneuploidy.
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