![Nondisjunction Diagrams](https://upload.wikimedia.org/wikipedia/commons/0/0e/Nondisjunction_Diagrams.svg)
Nondisjunction is the failure of
homologous chromosomes
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...
or
sister chromatids
A sister chromatid refers to the identical copies (chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the dup ...
to separate properly during
cell division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
(
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
/
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
). There are three forms of nondisjunction: failure of a pair of
homologous chromosomes
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...
to separate in
meiosis I
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
, failure of sister chromatids to separate during
meiosis II
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
, and failure of sister chromatids to separate during
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
.
Nondisjunction results in daughter cells with abnormal chromosome numbers (
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
).
Calvin Bridges
Calvin Blackman Bridges (January 11, 1889 – December 27, 1938) was an American scientist known for his contributions to the field of genetics. Along with Alfred Sturtevant and H.J. Muller, Bridges was part of Thomas Hunt Morgan's famous "Fl ...
and
Thomas Hunt Morgan
Thomas Hunt Morgan (September 25, 1866 – December 4, 1945) was an American evolutionary biologist, geneticist, embryologist, and science author who won the Nobel Prize in Physiology or Medicine in 1933 for discoveries elucidating the role tha ...
are credited with discovering nondisjunction in ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
'' sex chromosomes in the spring of 1910, while working in the Zoological Laboratory of Columbia University.
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
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
and
meiosis II
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
are specialized forms of cell division occurring during generation of
gametes
A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...
(eggs and sperm) for sexual reproduction,
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
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
Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...
triggers the second meiotic division.
Similar to the segregation events of
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
, the pairs of sister
chromatids
A chromatid (Greek ''khrōmat-'' 'color' + ''-id'') is one half of a duplicated chromosome. Before replication, one chromosome is composed of one DNA molecule. In replication, the DNA molecule is copied, and the two molecules are known as chro ...
resulting from the separation of bivalents in
meiosis I
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
are further separated in
anaphase
Anaphase () is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes (daughter chromatids) are moved to opposite poles of the cell. Chromosomes also reach their overall maxim ...
of
meiosis II
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
. In oocytes, one sister chromatid is segregated into the second polar body, while the other stays inside the egg. During
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
, each meiotic division is symmetric such that each primary
spermatocyte
Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and s ...
gives rise to 2 secondary spermatocytes after meiosis I, and eventually 4
spermatids
The spermatid is the haploid male gametid that results from division of secondary spermatocytes. As a result of meiosis, each spermatid contains only half of the genetic material present in the original primary spermatocyte.
Spermatids are c ...
after meiosis II. Meiosis II-nondisjunction may also result in
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
syndromes, but only to a much smaller extent than do
segregation Segregation may refer to:
Separation of people
* Geographical segregation, rates of two or more populations which are not homogenous throughout a defined space
* School segregation
* Housing segregation
* Racial segregation, separation of humans ...
failures in meiosis I.
Mitosis
Division of
somatic
Somatic may refer to:
* Somatic (biology), referring to the cells of the body in contrast to the germ line cells
** Somatic cell, a non-gametic cell in a multicellular organism
* Somatic nervous system, the portion of the vertebrate nervous sys ...
cells through mitosis is preceded by replication of the genetic material in
S phase
S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
. As a result, each chromosome consists of two sister
chromatids
A chromatid (Greek ''khrōmat-'' 'color' + ''-id'') is one half of a duplicated chromosome. Before replication, one chromosome is composed of one DNA molecule. In replication, the DNA molecule is copied, and the two molecules are known as chro ...
held together at the
centromere
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers a ...
. In the
anaphase
Anaphase () is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes (daughter chromatids) are moved to opposite poles of the cell. Chromosomes also reach their overall maxim ...
of
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
, sister
chromatids
A chromatid (Greek ''khrōmat-'' 'color' + ''-id'') is one half of a duplicated chromosome. Before replication, one chromosome is composed of one DNA molecule. In replication, the DNA molecule is copied, and the two molecules are known as chro ...
separate and migrate to opposite cell poles before the cell divides. Nondisjunction during
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
leads to one daughter receiving both sister
chromatids
A chromatid (Greek ''khrōmat-'' 'color' + ''-id'') is one half of a duplicated chromosome. Before replication, one chromosome is composed of one DNA molecule. In replication, the DNA molecule is copied, and the two molecules are known as chro ...
of the affected chromosome while the other gets none.
This is known as a
chromatin bridge or an anaphase bridge. Mitotic nondisjunction results in somatic
mosaicism
Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
, since only daughter cells originating from the cell where the nondisjunction event has occurred will have an abnormal number of
chromosomes
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
.
[ Nondisjunction during mitosis can contribute to the development of some forms of ]cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, e.g., retinoblastoma
Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively fo ...
(see below). Chromosome nondisjunction in mitosis can be attributed to the inactivation of topoisomerase II
Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP, unlike Type I topoisomerase. In this process, these enzymes change th ...
, condensin
Condensins are large protein complexes that play a central role in chromosome assembly and segregation during mitosis and meiosis (Figure 1). Their subunits were originally identified as major components of mitotic chromosomes assembled in ''Xeno ...
, or separase
Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded ...
. Meiotic nondisjunction has been well studied in ''Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
''. This yeast undergoes mitosis similarly to other eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
. Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and the cohesion complex. During anaphase, cohesin
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3 ( SA1 or SA2 in humans). Cohesin holds sister chromatids together after DNA rep ...
is cleaved by separase. Topoisomerase II and condensin are responsible for removing catenation
In chemistry, catenation is the bonding of atoms of the same element into a series, called a ''chain''. A chain or a ring shape may be ''open'' if its ends are not bonded to each other (an open-chain compound), or ''closed'' if they are bonded ...
s.
Molecular mechanisms
Central role of the spindle assembly checkpoint
The spindle assembly checkpoint
The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separa ...
(SAC) is a molecular safe-guarding mechanism that governs proper chromosome segregation
Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregati ...
in eukaryotic cells. SAC inhibits progression into anaphase until all homologous chromosomes (bivalents, or tetrads) are properly aligned to the spindle apparatus
In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a pr ...
. Only then, SAC releases its inhibition of the anaphase promoting complex
Anaphase-promoting complex (also called the cyclosome or APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin ...
(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. 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 of prophase I
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately res ...
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
Crossover may refer to:
Entertainment
Albums and songs
* ''Cross Over'' (Dan Peek album)
* ''Crossover'' (Dirty Rotten Imbeciles album), 1987
* ''Crossover'' (Intrigue album)
* ''Crossover'' (Hitomi Shimatani album)
* ''Crossover'' (Yoshino ...
, 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.
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 segregation Segregation may refer to:
Separation of people
* Geographical segregation, rates of two or more populations which are not homogenous throughout a defined space
* School segregation
* Housing segregation
* Racial segregation, separation of humans ...
control. The cohesin
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3 ( SA1 or SA2 in humans). Cohesin holds sister chromatids together after DNA rep ...
complex is responsible for keeping together sister chromatids and provides binding sites for spindle attachment. Cohesin is loaded onto newly replicated chromosomes in oogonia
An oogonium (plural oogonia) is a small diploid cell which, upon maturation, forms a primordial follicle in a female fetus or the female (haploid or diploid) gametangium of certain thallophytes.
In the mammalian fetus
Oogonia are formed in lar ...
during fetal development. Mature oocytes
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female g ...
have only limited capacity for reloading cohesin after completion of S phase
S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
. 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
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
-kinetochore
A kinetochore (, ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and ...
attachment and chromosome segregation errors during meiotic divisions.
Consequences
The result of this error is a cell with an imbalance of chromosomes. Such a cell is said to be aneuploid
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
. 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
Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing.
Human monosomy
Human conditions due to monosomy:
* Turner syndrome – People wit ...
. 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
A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes).
Description and causes
Most organisms that reprodu ...
. In the event that an aneuploidic gamete is fertilized, a number of syndromes might result.
Monosomy
The only known survivable monosomy in humans is Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
, where the affected individual is monosomic for the X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
(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 a mosaicism
Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
(see below), or if the normal number of chromosomes is restored via duplication of the single monosomic chromosome ("chromosome rescue").
Turner syndrome (X monosomy) (45, X0)
Complete loss of an entire X chromosome accounts for about half the cases of Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
. 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
A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
45, X0) are spontaneously aborted.[
]
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.
Down syndrome (trisomy 21)
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
, a trisomy of chromosome 21, is the most common anomaly of chromosome number in humans.[ The majority of cases result from nondisjunction during maternal meiosis I.] Trisomy occurs in at least 0.3% of newborns and in nearly 25% of spontaneous abortions
Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is fetal viability, able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE a ...
. It is the leading cause of pregnancy wastage and is the most common known cause of mental retardation
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signific ...
. It is well documented that advanced maternal age
Advanced maternal age, in a broad sense, is the instance of a woman being of an older age at a stage of reproduction, although there are various definitions of specific age and stage of reproduction.[Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...]
(trisomy 21), are Edwards syndrome
Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features in ...
(trisomy 18) and Patau syndrome
Patau syndrome is a syndrome caused by a chromosome, chromosomal abnormality, in which some or all of the Cell (biology), cells of the body contain Trisomy, extra genetic material from chromosome 13 (human), chromosome 13. The extra genetic mater ...
(trisomy 13).[ Complete trisomies of other chromosomes are usually not viable and represent a relatively frequent cause of miscarriage. Only in rare cases of a ]mosaicism
Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
, 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.[
]
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
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
, see above) can also be classified as a form of sex chromosome aneuploidy.
Klinefelter syndrome (47, XXY)
Klinefelter syndrome
Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are su ...
is the most common sex chromosome aneuploidy in humans. It represents the most frequent cause of hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
and infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
in men. Most cases are caused by nondisjunction errors in paternal meiosis I. About eighty percent of individuals with this syndrome have one extra X chromosome resulting in the karyotype
A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
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.
XYY Male (47, XYY)
The incidence of XYY syndrome
XYY syndrome, also known as Jacobs syndrome, is an aneuploid genetic condition in which a male has an extra Y chromosome. There are usually few symptoms. These may include being taller than average, acne, and an increased risk of learning disa ...
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.
Trisomy X (47,XXX)
Trisomy X
Trisomy X, also known as triple X syndrome and characterized by the karyotype 47,XXX, is a chromosome disorder in which a female has an extra copy of the X chromosome. It is relatively common and occurs in 1 in 1,000 women but it is rarely dia ...
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.
Uniparental disomy
Uniparental disomy
Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or of part of a chromosome, from one parent and no copy from the other parent. UPD can be the result of heterodisomy, in which a pair of non-identical chromosomes ar ...
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
Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...
.[
]
Mosaicism syndromes
Mosaicism
Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
syndromes can be caused by mitotic nondisjunction in early fetal development. As a consequence, the organism evolves as a mixture of cell lines with differing ploidy
Ploidy () is the number of complete sets of chromosomes in a cell (biology), cell, and hence the number of possible alleles for Autosome, autosomal and Pseudoautosomal region, pseudoautosomal genes. Sets of chromosomes refer to the number of mat ...
(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 include Pallister-Killian syndrome and Hypomelanosis of Ito
Albinism is the congenital absence of melanin in an animal or plant resulting in white hair, feathers, scales and skin and pink or blue eyes. Individuals with the condition are referred to as albino.
Varied use and interpretation of the term ...
.[
]
Mosaicism in malignant transformation
Development of cancer often involves multiple alterations of the cellular genome (Knudson hypothesis The Knudson hypothesis, also known as the two-hit hypothesis, is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change. It was ...
). Human retinoblastoma
Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively fo ...
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
The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
, 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.
Diagnosis
Preimplantation genetic diagnosis
Pre-implantation genetic diagnosis (PGD or PIGD) is a technique used to identify genetically normal embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
s and is useful for couples who have a family history of genetic disorders. This is an option for people choosing to procreate through IVF
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...
. PGD is considered difficult due to it being both time consuming and having success rates only comparable to routine IVF.
Karyotyping
Karyotyping
A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
involves performing an amniocentesis
Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is ne ...
in order to study the cells of an unborn fetus during metaphase 1. Light microscopy
Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of micr ...
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
In biology, a blastomere is a type of cell produced by cell division (cleavage) of the zygote after fertilization; blastomeres are an essential part of blastula formation, and blastocyst formation in mammals.
Human blastomere characteristics
In h ...
biopsy is a technique in which blastomeres are removed from the zona pellucida
The zona pellucida (plural zonae pellucidae, also egg coat or pellucid zone) is a specialized extracellular matrix that surrounds the plasma membrane of mammalian oocytes. It is a vital constitutive part of the oocyte. The zona pellucida first ...
. 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 An aneugen is a substance that causes a daughter cell to have an abnormal number of chromosomes or aneuploidy. A substance's aneugenicity reflects its ability to induce aneuploidy. Unlike clastogens, aneugenic events do not damage the physical stru ...
(aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
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
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...
, and exposure to the insecticides fenvalerate
Fenvalerate is a synthetic pyrethroid insecticide. It is a mixture of four optical isomers which have different insecticidal activities. The 2-S ''alpha'' (or SS) configuration, known as esfenvalerate, is the most insecticidally active isomer. F ...
and carbaryl
Carbaryl (1-naphthyl methylcarbamate) is a chemical in the carbamate family used chiefly as an insecticide. It is a white crystalline solid previously sold under the brand name Sevin, which was a trademark of the Bayer Company. The Sevin tradem ...
also increase aneuploidy.
References
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Genetics