Aneuploidy

Aneuploidy
Classification and external resources
ICD-10	Q90-Q98
ICD-9	758
MeSH	D000782

"XXXY" redirects here. It is not to be confused with XX/XY.

Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders (birth defects). Some cancer cells also have abnormal numbers of chromosomes.^[1] Aneuploidy occurs during cell division when the chromosomes do not separate properly between the two cells. Chromosome abnormalities occur in 1 of 160 live births. The most common extra chromosomes among live births are 21, 18 and 13.^[2]

Different species have different numbers of normal chromosomes and thus the term "aneuploidy" refers to the chromosome number being different for that species.

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. Normal females have two X chromosomes, while normal males have one X chromosome and one Y chromosome.

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 spontaneously aborted. The most frequent aneuploidy in humans is trisomy 16, although fetuses affected with the full version of this chromosome abnormality do not survive to term (it is possible for surviving individuals to have the mosaic form, 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. Trisomy 18 (Edwards syndrome) affects 1 in 6,000 births, and trisomy 13 (Patau syndrome) affects 1 in 10,000 births. 10% of infants with trisomy 18 or 13 reach 1 year of age.^[3]

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 (see below).

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.

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, known as Edwards and Patau Syndrome, respectively, are the two other autosomal trisomies recognized in live-born humans. Trisomy of the sex chromosomes is possible, such as in (47,XXX), (47,XXY), and (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, XXXXX, XXXXY and XYYYY.[4]

Mechanisms

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.

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.

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.

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.^[5] 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).^[6] This low-level aneuploidy appears to arise from chromosomal segregation defects during cell division in neuronal precursor cells,^[7] and neurons containing such aneuploid chromosome content reportedly integrate into normal circuits.^[8] These results suggest the possibility that somatic mosaicism in the brain (and perhaps, by extension, other tissues) may contribute to the diversity between individuals^{[citation needed]}.

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.

Loss of p53 creates genomic instability that most often results in the aneuploidy phenotype.^[9]

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. Studies indicate that aneuploidy directly contributes to carcinogenesis by disrupting the asymmetric division of adult stem cells.^[10][11]

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.

Diagnosis

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, through either 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.

Recent advances have allowed for less invasive testing methods based on the presence of fetal genetic material in maternal blood.

Types

key

color	significance
	lethal
	normal female phenotype
	normal male phenotype
	Turner's syndrome (abnormal female)
	Klinefelter's syndrome (abnormal male)

Non-autosomal

	0	X	XX	XXX	XXXX	XXXXX
0	00	X0	XX	XXX	XXXX	XXXXX
Y	Y0	XY	XXY	XXXY	XXXXY	XXXXXY
YY	YY	XYY	XXYY	XXXYY	XXXXYY	XXXXXYY
YYY	YYY	XYYY	XXYYY	XXXYYY	XXXXYYY	XXXXXYYY
YYYY	YYYY	XYYYY	XXYYYY	XXXYYYY	XXXXYYYY	XXXXXYYYY
YYYYY	YYYYY	XYYYYY	XXYYYYY	XXXYYYYY	XXXXYYYYY	XXXXXYYYYY

key

color	significance
	case where complete non-mosaic trisomy can never survive to term
	case where complete non-mosaic trisomy can occasionally (barring other complications) survive to term
	case where complete non-mosaic trisomy can always (barring other complications) survive to term

Autosomal

#	monosomy	trisomy
1		Trisomy 1
2		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		Warkany syndrome 2
9		Trisomy 9
10		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	18q deletion syndrome	Edwards syndrome
19		Trisomy 19
20		Trisomy 20
21		Down syndrome
22	DiGeorge syndrome	Cat eye syndrome Trisomy 22

See also

• Ploidy
• Polyploidy
• Chromosome abnormalities

References

1. ^ Sen S (January 2000). "Aneuploidy and cancer". Current Opinion in Oncology 12 (1): 82–8. doi:10.1097/00001622-200001000-00014. PMID 10687734. 
2. ^ Driscoll DA, Gross S (June 2009). "Clinical practice. Prenatal screening for aneuploidy". The New England Journal of Medicine 360 (24): 2556–62. doi:10.1056/NEJMcp0900134. PMID 19516035. 
3. ^ Griffiths, Anthony JF; Miller, Jeffrey H; Suzuki, David T; Lewontin, Richard C; Gelbart, William M (2000). "Chromosome Mutation II: Changes in Chromosome Number". An Introduction to Genetic Analysis (7th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3520-5. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=iga.section.3080. Retrieved 2009-06-21. 
4. ^ Linden MG, Bender BG, Robinson A (October 1995). "Sex chromosome tetrasomy and pentasomy". Pediatrics 96 (4 Pt 1): 672–82. PMID 7567329. 
5. ^ Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J (November 2001). "Chromosomal variation in neurons of the developing and adult mammalian nervous system". Proceedings of the National Academy of Sciences of the United States of America 98 (23): 13361–6. doi:10.1073/pnas.231487398. PMC 60876. PMID 11698687. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=60876. 
6. ^ Rehen SK, Yung YC, McCreight MP, et al. (March 2005). "Constitutional aneuploidy in the normal human brain". The Journal of Neuroscience 25 (9): 2176–80. doi:10.1523/JNEUROSCI.4560-04.2005. PMID 15745943. 
7. ^ Yang AH, Kaushal D, Rehen SK, et al. (November 2003). "Chromosome segregation defects contribute to aneuploidy in normal neural progenitor cells". The Journal of Neuroscience 23 (32): 10454–62. PMID 14614104. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=14614104. 
8. ^ Kingsbury MA, Friedman B, McConnell MJ, et al. (April 2005). "Aneuploid neurons are functionally active and integrated into brain circuitry". Proceedings of the National Academy of Sciences of the United States of America 102 (17): 6143–7. doi:10.1073/pnas.0408171102. PMC 1087909. PMID 15837924. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1087909. 
9. ^ Clemens A. Schmitt; Fridman, JS; Yang, M; Baranov, E; Hoffman, RM; Lowe, SW (April 2002). "Dissecting p53 tumor suppressor functions in vivo". Cancer Cell 1 (3): 289–298. doi:10.1016/S1535-6108(02)00047-8. PMID 12086865. 
10. ^ Zhang F, Zhao D, Wang S, Hong L, Li Q (2007). "Aneuploidy directly contribute to carcinogenesis by disrupting the asymmetric division of adult stem cells". Medical Hypotheses 68 (1): 237–8. doi:10.1016/j.mehy.2006.06.007. PMID 16890378. 
11. ^ Zhang F, Zhao D, Chen G, Li Q (2006). "Gene mutation and aneuploidy might cooperate to carcinogenesis by dysregulation of asymmetric division of adult stem cells". Medical Hypotheses 67 (4): 995–6. doi:10.1016/j.mehy.2006.04.043. PMID 16790321. 

External links

• Aneuploidy Testing
• Aneuploidy FAQ
• Genetics of Aneuploids