Aneuploidy is the presence of an abnormal number of in a cell, for example a human somatic cell having 45 or 47 chromosomes instead of the usual 46.
An extra or missing chromosome is a common cause of some . Some cancer cells also have abnormal numbers of chromosomes.
As women age, oocytes develop defects in structure and function and have meiotic spindle dysregulation: these increase rates of aneuploidy and miscarriage.
Chromosomes
Most cells in the human body have 23 pairs of , or a total of 46 chromosomes. (The sperm and egg, or , each have 23 unpaired chromosomes, and red blood cells in bone marrow have a nucleus at first but those red blood cells that are active in blood lose their nucleus and thus they end up having no nucleus and therefore no chromosomes.)
One copy of each pair is inherited from the mother and the other copy is inherited from the father. The first 22 pairs of chromosomes (called autosomes) are numbered from 1 to 22, from largest to smallest. The 23rd pair of chromosomes are the . Typical females have two , while typical males have one X chromosome and one Y chromosome. The characteristics of the chromosomes in a cell as they are seen under a light microscope are called the karyotype.
During meiosis, when germ cells divide to create sperm and egg (gametes), each half should have the same number of chromosomes. But sometimes, the whole pair of chromosomes will end up in one gamete, and the other gamete will not get that chromosome at all.
Most embryos cannot survive with a missing or extra autosome (numbered chromosome) and are miscarried. The most frequent aneuploidy in humans is trisomy 16 and fetuses affected with the full version of this chromosome abnormality do not survive to term, although it is possible for surviving individuals to have the mosaicism, where trisomy 16 exists in some cells but not all. The most common aneuploidy that infants can survive with is trisomy 21, which is found in Down syndrome, affecting 1 in 800 births. Edwards syndrome affects 1 in 6,000 births, and Patau syndrome affects 1 in 10,000 births. 10% of infants with trisomy 18 or 13 reach 1 year of age.[ Retrieved 2009-06-21.]
Changes in chromosome number may not necessarily be present in all cells in an individual. When aneuploidy is detected in a fraction of cells in an individual, it is called chromosomal mosaicism. In general, individuals who are mosaic for a chromosomal aneuploidy tend to have a less severe form of the syndrome compared to those with full trisomy. For many of the Autosome trisomies, only mosaic cases survive to term. However, mitotic aneuploidy may be more common than previously recognized in somatic tissues, and aneuploidy is a characteristic of many types of tumorigenesis.
Mechanisms
Aneuploidy arises from errors in chromosome segregation, which can go wrong in several ways.
Nondisjunction usually occurs as the result of a weakened mitotic checkpoint, as these checkpoints tend to arrest or delay cell division until all components of the cell are ready to enter the next phase. For example, if a checkpoint is weakened, the cell may fail to 'notice' that a chromosome pair is not lined with the spindle apparatus. In such a case, most chromosomes would separate normally (with one chromatid ending up in each cell), while others could fail to separate at all. This would generate a daughter cell lacking a copy and a daughter cell with an extra copy.
Completely inactive mitotic checkpoints may cause nondisjunction at multiple chromosomes, possibly all. Such a scenario could result in each daughter cell possessing a disjoint set of genetic material.
Merotelic attachment occurs when one kinetochore is attached to both mitotic spindle poles. One daughter cell would have a normal complement of chromosomes; the second would lack one. A third daughter cell may end up with the 'missing' chromosome.
Multipolar spindles: more than two form. Such a mitotic division would result in one daughter cell for each spindle pole; each cell may possess an unpredictable complement of chromosomes.
Monopolar spindle: only a single spindle pole forms. This produces a single daughter cell with its copy number doubled.
A tetraploid intermediate may be produced as the end-result of the monopolar spindle mechanism. In such a case, the cell has double the copy number of a normal cell, and produces double the number of spindle poles as well. This results in four daughter cells with an unpredictable complement of chromosomes, but in the normal copy number.
Somatic mosaicism in the nervous system
Mosaicism for aneuploid chromosome content may be part of the constitutional make-up of the mammalian brain.
Somatic mosaicism in cancer
Aneuploidy is consistently observed in virtually all cancers.
Somatic mosaicism occurs in virtually all cancer cells, including trisomy 12 in chronic lymphocytic leukemia (CLL) and trisomy 8 in acute myeloid leukemia (AML). However, these forms of mosaic aneuploidy occur through mechanisms distinct from those typically associated with genetic syndromes involving complete or mosaic aneuploidy, such as chromosomal instability
Alteration of normal mitotic checkpoints are also important tumorigenic events, and these may directly lead to aneuploidy.
In addition, genetic syndromes in which an individual is predisposed to breakage of chromosomes (chromosome instability syndromes) are frequently associated with increased risk for various types of cancer, thus highlighting the role of somatic aneuploidy in carcinogenesis.
The ability to evade the immune system appears to be enhanced in tumoral cells with strong aneuploidy. This has therefore suggested that the presence of an abnormal number of chromosomes might be an effective predictive biomarker for response to precise immunotherapy. For example, in melanoma patients, high somatic copy number alterations are associated with less effective response to immune checkpoint blockade anti–CTLA4 (cytotoxic T lymphocyte–associated protein 4) therapy.[
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A research work published in 2008 focuses on the mechanisms involved in aneuploidy formation, specifically on the Epigenetics origin of aneuploid cells. Epigenetic inheritance is defined as cellular information other than the DNA sequence itself, that is still heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular lesion in cancer-cells, even more frequent than gene mutations. Tumor suppressor gene silencing by CpG island promoter hypermethylation is supposed to be the most frequent epigenetic modification in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, deficiencies of certain nutrients, radiation, etc. Some of the alterations have been correlated with the formation of aneuploid cells in vivo. In this study it is suggested on a growing basis of evidence, that not only genetics but also epigenetics, contribute to aneuploid cell formation.
Partial aneuploidy
The terms "partial monosomy" and "partial trisomy" are used to describe an imbalance of genetic material caused by loss or gain of part of a chromosome. In particular, these terms would be used in the situation of an unbalanced translocation, where an individual carries a derivative chromosome formed through the breakage and fusion of two different chromosomes. In this situation, the individual would have three copies of part of one chromosome (two normal copies and the portion that exists on the derivative chromosome) and only one copy of part of the other chromosome involved in the derivative chromosome. Robertsonian translocations, for example, account for a very small minority of Down syndrome cases (<5%). The formation of one isochromosome results in partial trisomy of the genes present in the isochromosome and partial monosomy of the genes in the lost arm.
Aneugens
Agents capable of causing aneuploidy are called aneugens. Many mutagenic carcinogens are aneugens. , for example, may cause aneuploidy by fragmenting the chromosome; it may also target the spindle apparatus.
Exposure of males to lifestyle, environmental and/or occupational hazards may increase the risk of Spermatozoon aneuploidy.
Occupational exposure to benzene is associated with a 2.8-fold increase of XX disomy and a 2.6-fold increase of YY disomy in spermatozoa.
are released to the environment in sufficiently large quantities that most individuals have some degree of exposure. The fenvalerate and carbaryl have been reported to increase spermatozoa aneuploidy. Occupational exposure of pesticide factory workers to fenvalerate is associated with increased spermatozoa DNA damage.
Humans are exposed to perfluorinated compounds (PFCs) in many commercial products.
Diagnosis
Germline aneuploidy is typically detected through karyotyping, a process in which a sample of cells is fixed and stained to create the typical light and dark chromosomal banding pattern and a picture of the is analyzed. Other techniques include fluorescence in situ hybridization (FISH), quantitative PCR of short tandem repeats, quantitative fluorescence PCR (QF-PCR), quantitative PCR dosage analysis, Quantitative Mass Spectrometry of Single Nucleotide Polymorphisms, and comparative genomic hybridization (CGH).
These tests can also be performed prenatally to detect aneuploidy in a pregnancy, through either amniocentesis or chorionic villus sampling. Pregnant women of 35 years or older are offered prenatal testing because the chance of chromosomal aneuploidy increases as the mother's age increases.
Recent advances have allowed for less invasive testing methods based on the presence of fetal genetic material in maternal blood. See Triple test and Cell-free fetal DNA.
Types
| +key
!color
!significance |
| | lethal |
| | typical male phenotype |
| | Klinefelter syndrome (non-typical male) |
| | polysomy X and/or Y (non-typical male) |
| | typical female phenotype |
| | Turner's syndrome (non-typical female) |
| | polysomy X (non-typical female) |
| +Non-autosomal
! scope="col" | ! scope="col"0
! scope="col" | X
! scope="col" | XX
! scope="col" | XXX
! scope="col" | XXXX
! scope="col" | XXXXX |
|
|
|
|
|
|
| +key
!color
!significance |
| | case where complete non-mosaic trisomy can never survive to term |
| | case where complete non-mosaic trisomy can rarely (barring other complications) survive to term |
| | case where complete non-mosaic trisomy can frequently |
| +Autosomal
!#
!monosomy
!trisomy |
| 1 | 1p36 deletion syndrome
1q21.1 deletion syndrome | Trisomy 1 |
| 2 | 2q37 deletion syndrome | Trisomy 2 |
| 3 | | Trisomy 3 |
| 4 | Wolf–Hirschhorn syndrome | Trisomy 4 |
| 5 | Cri du chat
5q deletion syndrome | Trisomy 5 |
| 6 | | Trisomy 6 |
| 7 | Williams syndrome | Trisomy 7 |
| 8 | Monosomy 8p
Monosomy 8q | Trisomy 8 |
| 9 | Alfi's syndrome
Kleefstra syndrome | Trisomy 9 |
| 10 | Monosomy 10p
Monosomy 10q | Trisomy 10 |
| 11 | Jacobsen syndrome | Trisomy 11 |
| 12 | | Trisomy 12 |
| 13 | | Patau syndrome |
| 14 | | Trisomy 14 |
| 15 | Angelman syndrome
Prader–Willi syndrome | Trisomy 15 |
| 16 | | Trisomy 16 |
| 17 | Miller–Dieker syndrome
Smith–Magenis syndrome | Trisomy 17 |
| 18 | Distal 18q-
Proximal 18q- | Edwards syndrome |
| 19 | | Trisomy 19 |
| 20 | | Trisomy 20 |
| 21 | | Down syndrome |
| 22 | DiGeorge syndrome
Phelan–McDermid syndrome
22q11.2 distal deletion syndrome | Cat eye syndrome
Trisomy 22 |
|
Terminology
In the strict sense, a chromosome complement having a number of chromosomes other than 46 (in humans) is considered heteroploid while an exact multiple of the haploid chromosome complement is considered euploid.
|
| Monosomy refers to lack of one chromosome of the normal complement. Partial monosomy can occur in unbalanced translocations or deletions, in which only a portion of the chromosome is present in a single copy (see deletion (genetics)). Monosomy of the (45,X) causes Turner syndrome. |
| Disomy is the presence of two copies of a chromosome. For organisms such as humans that have two copies of each chromosome (those that are diploid), it is the normal condition. For organisms that normally have three or more copies of each chromosome (those that are ploidy or above), disomy is an aneuploid chromosome complement. In uniparental disomy, both copies of a chromosome come from the same parent (with no contribution from the other parent). |
| Trisomy refers to the presence of three copies, instead of the normal two, of a particular chromosome. The presence of an extra chromosome 21, which is found in Down syndrome, is called trisomy 21. Trisomy 18 and Trisomy 13, known as Edwards syndrome and Patau syndrome, respectively, are the two other autosomal trisomies recognized in live-born humans. Trisomy of the sex chromosomes is also possible, for example (47,XXX), (47,XXY), and XYY syndrome. |
Tetrasomy and pentasomy are the presence of four or five copies of a chromosome, respectively. Although rarely seen with autosomes, sex chromosome tetrasomy and pentasomy have been reported in humans, including tetrasomy X, XXXY syndrome, XXYY syndrome, Pentasomy X, XXXXY, and XYYYY syndrome. |
See also
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Chromosome abnormality
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Chromosome segregation
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Mosaic variegated aneuploidy syndrome
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Nondisjunction
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Ploidy
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Robertsonian translocation
External links
