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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. Most cases of aneuploidy result in termination of the developing fetus, but there can be cases of live birth; 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[link]

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[link]

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.

Mechanisms[link]

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[link]

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]

Somatic mosaicism in cancer[link]

Aneuploidy is consistently observed in all cancers.^[9] 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 ^[10] (due to mitotic segregation defects in cancer cells). Therefore the molecular processes that lead to aneuploidy are targets for the development of cancer drugs.

Alteration of normal mitotic checkpoints are also important tumorogenic events, and these may directly lead to aneuploidy.^[11] Loss of p53 creates genomic instability that most often results in the aneuploidy genotype.^[12]

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.^[13][14]

Partial aneuploidy[link]

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.

Aneuploidogens[link]

Agents capable of causing aneuploidy are called aneuploidogens. Many mutagenic carcinogens are aneuploidogens. X-rays, for example, may cause aneuploidy by fragmenting the chromosome; it may also target the spindle apparatus.^[15] Non-mutagenic chemicals such as colchicine can produce aneuploidy by affecting microtubule polymerization.

Diagnosis[link]

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[link]

See also[link]

• Ploidy
• Polyploidy
• Chromosome abnormalities
• Edward's Syndrome
• Down Syndrome

References[link]

External links[link]

• Aneuploidy Testing
• Aneuploidy FAQ
• Genetics of Aneuploids

Angelika Amon, Ph.D. (b. 1967) is an Austrian American molecular and cell biologist and professor at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts, United States. Amon's research centers on how chromosomes are regulated, duplicated, and partitioned in the cell cycle.^[1]

Background[link]

Amon had an early interest in plant and animal biology as a child, keeping a notebook full of newspaper clippings, and was motivated to study biology after learning about Mendelian genetics in middle school.^[2] She received her B.S. from the University of Vienna and continued her doctoral work there under Professor Kim Nasmyth at the Research Institute of Molecular Pathology, receiving the Ph.D. in 1993. She completed a two year post-doctoral fellowship at the Whitehead Institute in Cambridge, Massachusetts and was subsequently named a Whitehead Fellow for three years.^[2] She joined the MIT Center for Cancer Research and MIT's Department of Biology in 1999 and was promoted to full professor in 2007.^[3][4]

Amon won a Presidential Early Career Award for Scientists and Engineers in 1998,^[5] was named an associate investigator at the Howard Hughes Medical Institute in 2000,^[6] and was the 2003 recipient of the National Science Foundation's Alan T. Waterman Award.^[7][8] Amon also shared the 2007 Paul Marks Prize for Cancer Research and won the 2008 National Academy of Sciences Award in Molecular Biology.^[9][10][11]

Amon is married and has two daughters.^[2]

Research[link]

Amon's research has investigated how cells control and organize the segregation of their chromosomes during cell division. More specifically, her research examines the regulation of exit from mitosis, the regulation of the meiotic cell cycle, and effects of aneuploidy on normal physiology and tumorigenesis.^[1]

As a student under Nasmyth, Amon demonstrated that CDC28 protein kinase is not required for the metaphase to anaphase transition and CLB2 proteolysis continues until reactivation of CDC28 toward the end of G1.^[12][13]

The Amon lab primarily investigates yeast (Saccharomyces cerevisiae) as a model for understanding the controls that govern cell-cycle progression.^[7] As a Whitehead Fellow, her team discovered that CDC20 plays a crucial role in cell division.^[14] Her Whitehead team identified an interaction between phosphatase and CDC14 which initiates the exit of cells from mitosis to the G1 phase.^[15] Amon's team demonstrated that CDC20 is the target protein in the spindle checkpoint during mitosis.^[16]

Amon's more recent work has investigated the regulation of chromosome segregation and how chromosomes are accurately transmitted to gametes in meiosis by examining gene regulatory networks. She identified two regulatory networks (FEAR and MEN) that promote the release of CDC14 which have the potential to identify the mechanisms that control the final stages of the mitotic cell cycle.^{[17][18][19][20]}

Her research group recently created haploid yeast cells containing extra copies of chromosomes and discovered that these aneuploid strains elicit phenotypes independent of the identity of the additional chromosome such as defects in cell cycle progression, increased energy demands, and interference with protein biosynthesis.^[21] Amon has also examined trisomy in the mouse as a model of mammalian cell growth and physiology and demonstrated that mammalian aneuploidy results in a stress response analogous to yeast aneuploidy.^[22] Amon's aneuploidy research has potential applications to cancer research.^[23]

References[link]

External links[link]

• MIT Department of Biology homepage
  • Amon Lab homepage
• Koch Institute homepage
• Howard Hughes Medical Institute homepage