Aneuploidy

Aneuploidy is defined as an abnormal number of chromosomes. Syndromes caused by an extra or missing chromosome are among the most widely recognized genetic disorders in humans. Different organisms have widely varying chromosome complements and thus the term "aneuploidy" does not refer to a particular number of chromosomes, but rather the situation in which the chromosome content within a given cell is abnormal.

Chromosomes

Every cell in the human body, apart from enucleated red blood cells and the haploid gametes, has 23 pairs of chromosomes (for a total of 46). 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 (referred to as autosomes) are numbered from 1 to 22, and are arranged from largest to smallest in a karyotype (see figure). The 23rd pair of chromosomes are the sex chromosomes. Females typically have two X chromosomes, while males typically have one X chromosome and one Y chromosome.

Complete aneuploidy for most autosomes (numbered chromosomes) is incompatible with life and will lead to spontaneous miscarriage during pregnancy. The most frequent meiotic aneuploidy in humans is trisomy 16, although fetuses affected with this chromosome abnormality do not survive to term. The most common form of meiotic aneuploidy in live-born humans is trisomy 21, which is found in Down syndrome.

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 autosomal 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.

Terminology

Strictly, 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.

Number of chromosomes	Name	Description
1	Monosomy	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 sex chromosomes (45,X) causes Turner syndrome.
2	Disomy	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 triploid 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).
3	Trisomy	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 are the two other autosomal trisomies recognized in live-born humans. Trisomy of the sex chromosomes can be seen in females (47,XXX) or males (47,XXY which is found in Klinefelter's syndrome; or 47,XYY).
4/5	tetrasomy/pentasomy	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 XXXX, XXXY, XXYY, XYYY, XXXXX, XXXXY, XXXYY, XXYYY and XYYYY.

Mechanisms

1. 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. If a checkpoint is weakened, the cell may fail to 'notice' that a chromosome pair is not lined up on the mitotic plate, for example. 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.
2. Completely inactive mitotic checkpoints may cause non-disjunction at multiple chromosomes, possibly all. Such a scenario could result in each daughter cell possessing a disjoint set of genetic material.
3. 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.
4. Multipolar spindle: more than two spindle poles form. Such a mitotic division would result in one daughter cell for each spindle pole; each cell may possess an unpredictable complement of chromosomes.
5. Monopolar spindle: only a single spindle pole forms. This produces a single daughter cell with its copy number doubled.
6. 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

It was recently discovered that mosaicism for aneuploid chromosome content may be part of the constitutional make-up of the mammalian brain. This observation was then extended to normal human brain, where brain samples from six individuals ranging from 2-86 years of age were found to have mosaicism for chromosome 21 aneuploidy (average of 4% of neurons analyzed). This low-level aneuploidy appears to arise from chromosomal segregation defects during cell division in neuronal precursor cells, and neurons containing such aneuploid chromosome content reportedly integrate into normal circuits. These results suggest the possibility that somatic mosaicism in the brain (and perhaps, by extension, other tissues) may contribute to the diversity between individuals.

Somatic mosaicism in cancer

Somatic mosaicism also occurs in many 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.

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.

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.

Detection

Example of Trisomy 21 detected via qPCR Short Tandem Repeat assay

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 chromosomes is analyzed. Other techniques include Fluorescence In Situ Hybridization (FISH), Quantitative Polymerase Chain Reaction (PCR) of Short Tandem Repeats, Quantitative Fluorescence PCR (QF-PCR), Quantitative Real-time PCR (RT-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, either through amniocentesis or chorionic villus sampling. Pregnant women of 35 years or older are offered prenatal diagnosis because the chance of chromosomal aneuploidy increases as the mother's age increases. For more information, see prenatal diagnosis.