What is aneuploidy and why is it important?

Aneuploidy is an error in cell division that results in the "daughter" cells having the wrong number of chromosomes. In some cases there is a missing chromosome, while in others an extra.

A great deal is known about the impacts of aneuploidy. Far less is understood about its causes.

Most cases of "meiotic" aneuploidy result in spontaneous miscarriage of the fetus. Babies that survive to birth after aneuploidy have birth defects, including Down Syndrome. Meiotic aneuploidy causes 10-20% of birth defects in people. Another type of aneuploidy, "mitotic" aneuploidy, is associated with virtually all solid tumor cancers.

Having the correct number of chromosomes in a cell is key, because chromosomes contain the body's DNA, and DNA is the chemical in which genes are encoded. When a cell is missing a particular chromosome, or has an extra copy, it doesn't have the proper mix of genes. Many cellular errors result, with the details depending upon which chromosome is absent (or present in surplus).

A normal human cell contains two nearly identical copies of 23 different chromosomes, a total of 46 chromosomes altogether. The karyotype to the right shows the pairs of each of the 22 numbered chromosome pairs plus the X and Y chromosomes.

 

adapted from Raven and Johnson 1991

Most cell division winds up with the daughter cell possessing the same number of chromosome as its parent, for example, the cell division involved in the growth of an arm or a liver or in the production of brain cells. This type of cell division is called mitosis.

To produce sperm or eggs, however, a different process is followed, called meiosis. In meiosis, the number of chromosomes after cell division is halved. Thus in humans each sperm or egg gets one copy only of each of the 23 different types of chromosomes. Then when sperm and egg combine during fertilization, the resulting embryo once again has the appropriate number of chromosomes, one copy of each type from both parents for a total of 46.

Meiotic aneuploidy causes spontaneous miscarriages in most cases. If the fetus survives to term, it usually has birth defects. The specific defect depends upon the details of the aneuploid error.

For example, when an extra copy of Chromosome 21 is present, as shown in the karyotype to the left, the baby has Down Syndrome. Alternatively, if only one copy of the X Chromosome is present, then the baby suffers from Turner Syndrome.

 

from Raven and Johnson 1991

While Turner Syndrome is relatively rare in people (about one out of 2,500 live births) studies reveal that approximately 10% of spontaneously aborted fetuses have this disorder. This indicates that most victims of Turner Syndrome don't survive fetal life. In general, lacking one or more chromosomes is usually fatal.

In general, absence of one of the autosomal chromosomes chromosomes leads to embryonic death, i.e., spontaneous miscarriage.

Extra copies of the autosomal chromosomes also usually results in death. One extra copy is called "trisomy." Trisomy of three of the smallest chromosomes (numbers 13, 18, 21) usually doesn't result in fetal death, but instead results in severe birth defects and in most cases, early childhood death. As noted above, individuals with extra copies of chromosomes 21 develop Down Syndrome. They can survive to adulthood, but have significant health problems and developmental delays and are almost always mentally retarded.

Extra copies of the sex chromosomes also cause developmental errors, although the effects are not fatal. Cases that result in an embryo with two X and one Y chromosome (which geneticists term XXY) develop Klinefelter syndrome: a sterile male with many female body characteristics and, in some cases, mental retardation. An individual with three X chromosomes (XXX) develops into a sterile female.

Extra copies of the Y chromosome (XYY) result in outwardly normal males. There is some statistical indication that XYY men are more likely to wind up in jail, suggesting an impact on neurocognitive development.

As the discussion above reveals, a great deal is known about the effects of aneuploidy. Far less is understood about the biological mechanisms that cause it.

Research on the causes of aneuploidy now focus on the pattern of alignment of the chromosomes during cell division.

Meiosis. The drawing below shows what happens to chromosomes during meiosis. People inherit a copy of each chromosome from their parent and thus have what are called "homologous pairs" of chromosomes in each cell. Prior to meiosis, each chromosome has made a copy of itself via DNA replication. Thus at the outset of meiosis, each cell begins with two copies of each pair.

In the first phase of meiosis, the chromosomes normally align with their homologous pair within the nucleus in a characteristic pattern, perpendicular to the "microtubule spindle apparatus."

 

The homologous pairs then separate from one another and migrate along the spindle apparatus toward opposite ends of the cell. A cleft then forms, separating the two poles and cell division completes. In this first phase of meiosis, the daughter cells each wind up with two copies of each chromosome. This is because prior to the onset of meiosis, each chromosome was duplicated in a process called DNA replication.

A second phase of meiosis (not shown) repeats this pattern, except it proceeds without the initial DNA replication. The result of that second phase is for the daughter cells to have only one copy of each chromosome.

In women, the process of meiosis takes place in two stages. The cells that will become a woman's eggs actually begin meiosis during fetal life, but the process is arrested during what scientist's call the "first prophase," the left-most cell in the drawing above. Then after puberty, during each menstrual cycle a small number of oocytes resume meiosis. The final stage of meiosis occurs after fertilization by a sperm.

Congression Failure

Careful study of chromosomal arrangements in human eggs prior to fertilization has revealed a high frequency of chromosomal misalignment in relation to the spindle, called congression failure, in women 35 years and older.

The risk of aneuploidy rises rapidly as women reach the age of 35 and beyond.

 

The two photomicrographs to the right show human chromosomes during meiosis, at the time that normal chromosomes are aligned perpendicular to the spindle (see diagram, above). The cells have been treated chemically so that chromosomes appear red.

The upper photomicrograph is of normal meiosis. Chromosomes are clustered along the central axis of the cell, perpendicular to the spindle.

The lower photomicrograph shows an example of congression failure, in which the chromosomes have have failed to align properly. Instead,they are scattered throughout the cell

figures adapted from Volarcik et al. 1998

It is thought that congression failure is an early sign of aneuploidy, because chromosomes that are not organized correctly on the microtubule spindle apparatus will be unlikely to migrate correctly toward the poles. Errors in migration could then place chromosomes in the wrong daughter cell, winding up with one cell having an extra copy and the other no copy.

The mechanism leading to congression failure is unknown. One explanation currently under study is that the hormonal environment of the cells surrounding the developing oocyte is involved in directing meiosis and ensuring that it unfolds normally. This interpretation suggests that variations in hormonal conditions, either because of intrinsic changes related to ageing in women, or contamination by hormonally-active compounds like bisphenol A, might lead to congression failure and thus aneuploidy. The demonstration that bisphenol A causes congression failure is consistent with this interpretation.