Aneuploidy

Aneuploidy is the presence of an aberrant number of chromosomes in a cell, such as 45 or 47 instead of the usual 46 in a human cell. A difference of one or more entire sets of chromosomes is not included. A euploid cell is one that has any number of full chromosomal sets.

Some genetic abnormalities are caused by an extra or missing chromosome. Atypical chromosomal counts can also be found in cancer cells. Aneuploid solid tumours account for roughly 68 percent of all human tumours. When the chromosomes do not separate properly between the two cells during cell division, aneuploidy occurs (nondisjunction). The majority of cases of autosomal aneuploidy result in miscarriage.

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 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.

Monopolar spindle: only a single spindle pole forms. This produces a single daughter cell with its copy number doubled.

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. In the normal human brain, brain samples from six individuals ranging from 2–86 years of age had 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.However, recent research using single-cell sequencing has challenged these findings, and has suggested that aneuploidy in the brain is actually very rare.

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.

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