Aneuploidy: What is it? Extra Chromosomes, Nondisjunction, Genetic Disorders and Chromosomal Rearrangements

Some things only work well in pairs. Examples of everyday include shoes, gloves, and headphones on a music player.

If you are missing a member of a pair, it is likely a nuisance, and could even be a serious problem (for example, if you are already late for school). Pairs are also important in genetics.

Most of your cells contain 46 chromosomes, rod-like structures made of DNA and proteins, which come in 23 perfectly matched pairs.

These chromosomes carry tens of thousands of genes, which told your body how to develop it and keep it functioning from moment to moment during your life.

If a pair of chromosomes loses or gains a limb, or even part of a limb, the delicate balance of the human body can be affected.

In this article, we will examine how changes in the number and structure of chromosomes occur, and how they can affect human health.

Aneuploidy: extra or missing chromosomes

Changes in the genetic material of a cell are called mutations. In a form of mutation, cells can end up with an extra or missing chromosome.

Each species has a characteristic chromosome number, such as 46 chromosomes for a typical cell in the human body.

In organisms with two complete sets of chromosomes, such as humans, this number is called 2n.

When an organism or cell contains 2n, n chromosomes (or some other multiple of n), it is said to be euploid, which means that it contains chromosomes correctly arranged in complete sets (eu- = good).

If a cell is missing one or more chromosomes, it is said to be aneuploid (an- = no, “not good”).

For example, human somatic cells with chromosome numbers of (2n-1) = 45 (2n-1) = 45, 45 or (2n + 1) = 47 (2n +1) = 47, 47 are aneuploid.

Similarly, a normal human sperm or sperm has only one set of chromosomes (n = 23n = 23n, equals 23).

An egg or sperm with (n-1) = 22 (n-1) = 22, 22 or (n + 1) = 24 (n + 1) = 24, 24 chromosomes is considered aneuploid.

Two common types of aneuploidy have their own special names:

  • Monosomy is when an organism has only one copy of a chromosome that must be present in two copies (2n-1) (2n-1).
  • Trisomy is when an organism has a third copy of a chromosome that must be present in two copies (2n + 1) (2n + 1).

Aneuploidy also includes cases where a cell has a greater number of extra or missing chromosomes, such as in (2n – 2), (2n + 3) (2n-2), (2n + 3), etc.

However, if there is an extra or missing set of chromosomes (eg, 3n), this is not formally considered aneuploidy, although it can still be bad for the cell or the organism.

Organisms with more than two complete sets of chromosomes are said to be polyploid.

Nondisjunction of chromosomes

Chromosome number disorders are due to nondisjunction, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis I or II (or during mitosis).

Meiosis I

Nondisjunction can occur during meiosis I if the homologues do not separate, and how this can lead to the production of aneuploid gametes (eggs or sperm).

A pair of homologous chromosomes do not separate during meiosis I, leading to two abnormal cells as products of meiosis I, one cell with an extra chromosome and one with a missing chromosome.

Meiosis II

In meiosis II, the chromatid of the chromosomes separates normally. This leads to the production of two gametes with an extra chromosome (n + 1 gametes) and two gametes with a missing chromosome (n-1 gametes).

Nondisjunction can also occur in meiosis II, and sister chromatids (rather than homologous chromosomes) do not separate.

Again, some gametes contain extra or missing chromosomes. Homologous chromosomes are normally separated during meiosis I.

However, the sister chromatids of a chromosome do not separate during meiosis II, but instead move to the same pole of the cell and secrete into the same gamete.

In this case, the products of meiosis are two normal euploid gametes (n), a gamete with an extra chromosome (n + 1), and a gamete with a missing chromosome (n-1).

Mitosis

Nondisjunction can also occur during mitosis.

In humans, chromosomal changes due to non-disjunction during mitosis in the cells of the body will not be passed on to children (because these cells do not produce sperm and eggs).

But mitotic nondisjunction can cause other problems – cancer cells often have abnormal numbers of chromosomes.

A pair of sister chromatids do not separate normally and instead move to the same pole of the dividing cell and segregate into the same daughter cell.

This error results in a daughter cell with an extra chromosome (2n + 1) and a daughter cell with a missing chromosome (2n-1).

When an aneuploid sperm combines with a normal sperm or egg in fertilization, it produces a zygote and this is also aneuploid

For example, if a sperm with an extra chromosome (n + 1n + 1n) combines with a normal egg (n), the resulting zygote or single-celled embryo will have a chromosome number of 2n + 12n + 12.

The zygote formed by fertilization is aneuploid (2n +1).

Genetic disorders caused by aneuploidy

Human embryos that lack a copy of any autosome (non-sex chromosome) do not develop until birth.

In other words, human autosomal monosomies are always lethal.

This is because embryos have too low a ‘dosage’ of proteins and other gene products encoded by genes on the missing chromosome.

Most autosomal trisomies also prevent an embryo from developing until birth.

However, an extra copy of some of the smaller chromosomes (13, 15, 18, 21 or 22) can allow the affected person to live for a short period after birth or for many years.

When an extra chromosome is present, it can cause developmental problems due to an imbalance between the gene products of the duplicated chromosome and those of other chromosomes.

The most common trisomy among embryos that survive to birth is Down syndrome or trisomy 21.

People with this inherited disorder have short height and digits, facial distinctions that include a wide skull and large tongue, and developmental delays.

A person with Down syndrome shows all three characteristic copies of chromosome 21. Most of the autosomal pairs and the XY sex chromosome pair are normal.

However, chromosome 21 is present in three copies.

About 1 in 800 newborns are born with Down syndrome.

However, the probability that a pregnancy will lead to an embryo with Down syndrome increases with the age of the woman, particularly above 40 years.

This is probably due to the more frequent non-disjunction in the developing eggs of older women.

Human genetic disorders can also be caused by aneuploidies that involve sex chromosomes.

These aneuploidies are better tolerated than autosomal ones because human cells have the ability to shut down extra X chromosomes in a process called X inactivation.

Chromosomal rearrangements

In another class of large-scale mutations, large pieces of chromosomes (but not entire chromosomes) are affected.

Such changes are called chromosomal rearrangements. They include:

  • A duplication, where part of a chromosome is copied.
  • A deletion, where the t part of a chromosome is deleted.
  • An inversion, where the chromosomal region is turned over so that it points in the opposite direction.

Suppression

A region of the original chromosome is removed, leading to a shorter chromosome missing a section.

Duplication

A region of the original chromosome is duplicated, giving rise to a longer chromosome with an additional copy of a particular section.

Investment

A region of the original chromosome is separated from the rest of the chromosome and replaced in its original place, but in the opposite orientation,

Translocation

Where a piece of a chromosome joins another chromosome.

A reciprocal translocation involves two chromosomes exchanging segments; a non-reciprocal translocation means that a piece of one chromosome moves to another.

Reciprocal translocation

Two non-homologous chromosomes exchange fragments.

No genetic material is lost, but the resulting chromosomes are hybrids, each containing segments that are normally found on a different chromosome.

Non-reciprocal translocation

A fragment is taken from a donor chromosome and inserted into a recipient chromosome.

The donor chromosome loses a region, while the recipient chromosome gains a region not normally found on that chromosome.

In some cases, a chromosome rearrangement causes symptoms similar to the loss or gain of an entire chromosome.

For example, Down syndrome is usually caused by a third copy of chromosome 21.

But it can also occur when a large portion of chromosome 21 moves to another chromosome (and is passed on to offspring along with a regular chromosome 21).

In other cases, the rearrangements cause unique disorders, which are not associated with aneuploidy.

Aneuploidía meiótica

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

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

While Turner syndrome is relatively rare in people (approximately one in 2,500 live births) studies reveal that approximately 10% of spontaneously aborted fetuses have this disorder.

This indicates that most victims of Turner syndrome do not survive fetal life. In general, the lack of one or more chromosomes is usually fatal.

In general, the absence of one of the autosomal chromosomal chromosomes leads to embryonic death, that is, spontaneous abortion.

Extra copies of autosomal chromosomes also often cause death. An extra copy is called a “trisomy.”

Trisomy of three of the smallest chromosomes (numbers 13, 18, 21) usually does not result in fetal death, but instead causes severe birth defects and, in most cases, death in early childhood .

As noted above, people with extra copies of chromosomes 21 develop Down syndrome. They can survive into adulthood, but have significant health problems and developmental delays, and are almost always mentally retarded.

The 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 chromosomes (which geneticists call 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.

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

As the discussion above reveals, much is known about the effects of aneuploidy. Much less is understood about the biological mechanisms that cause it.

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

People inherit one copy of each chromosome from their parents and therefore have what are called “homologous pairs” of chromosomes in each cell.

Before meiosis, each chromosome has made a copy of itself through DNA replication. Therefore, at the beginning of meiosis, each cell begins with two copies of each pair.

In the early phase of meiosis, chromosomes normally line up with their homologous pair within the nucleus in a characteristic pattern, perpendicular to the “microtubule axis apparatus.”

Homologous pairs separate from each other and migrate along the spindle apparatus to opposite ends of the cell. A cleft then forms that separates the two poles and completes cell division. In this first phase of meiosis, daughter cells end up with two copies of each chromosome.

This is because before the onset of meiosis, each chromosome duplicated in a process called DNA replication.

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

In women, the meiosis process takes place in two stages. The cells that will become the woman’s ovules actually start meiosis during fetal life, but the process stops during what scientists call the “first prophase,” the leftmost 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.

A careful study of the chromosomal arrangements in human eggs prior to fertilization has revealed a high frequency of chromosome misalignment relative to the spindle, called congress failure, in women 35 years of age and older.

The risk of aneuploidy increases rapidly as women reach the age of 35 and over.

Congressional failure is believed to be an early sign of aneuploidy, because chromosomes that are not properly arranged in the microtubule axis apparatus are unlikely to migrate correctly towards the poles.

Mistakes in migration could put chromosomes in the wrong daughter cell, ending with one cell that has an extra copy and the other has no copy.

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 develops normally.

This interpretation suggests that variations in hormonal conditions, either due to intrinsic changes related to aging in women, or contamination by hormonally active compounds such as bisphenol A, can lead to congressional failure and therefore , to aneuploidy.

The demonstration that bisphenol A causes a congressional failure is consistent with this interpretation.

Aneuploidy test

What is PGD for aneuploidy?

Examination for aneuploidy reduces the chance that a transferred embryo will have a chromosomal abnormality. Learn more about chromosomes and genes.

The most common chromosomal abnormalities in miscarriages include: trisomy (three copies of a chromosome) or monosomy (one copy of a chromosome) for chromosomes 13, 15, 16, 18, 21, or 22; triploidy (three copies of all chromosomes); and sex chromosome abnormalities.

About three out of four (75%) embryos created by IVF will not be able to produce a live-born child. Some will not be able to implant in the uterus, while others will implant but will not be able to carry out early embryonic development.

Finally, as in natural pregnancy, approximately 15% -20% of conceptions will be lost as a clinical miscarriage.

While there are many reasons for the failure of an embryo to have a baby, the most important factor is the abnormality of the chromosomes.

Similarly, for most couples, a significant number of embryos created by IVF will have chromosomal abnormalities.

The exact percentage of chromosomally abnormal embryos each pair produces is related to many factors, including maternal age, the number of failed IVF cycles, and the type of sperm used.

When does PGD occur in the IVF cycle?

After the embryos are created in the laboratory, they grow for three days. On day three, the DPG biopsy is performed and one or two cells are removed from the embryo. The genetic material within these cells is tested for abnormalities.

On day five, the woman returns to discuss the results of her DPG test. Decisions regarding the selection of embryos for transfer to the uterus are made with the advice of the medical team.

Is the DPG safe?

Yes. Data from many years of PGD in animals and approximately thousands of live births in humans indicate that PGD does not lead to an increase in birth defects or chromosomal disorders. PGD ​​is done before the embryo’s genetic material becomes “active.”

Because it is done so early, the cells within the embryo remain identical and each cell can become part of a baby. Removing some of the cells from the early embryo does not alter that embryo’s ability to develop into a full and normal pregnancy.

How do you get the cells from the embryo?

Embryos created in an IVF cycle are cultured in the laboratory for three days. At this time, they contain approximately eight cells. Each embryo at this point is called a blastomere.

Normally developing embryos on day three will have one or two cells removed for testing in a procedure called a biopsy. The embryos are placed under a powerful microscope and a laser is used to create a small opening in the zona pellucida, a tough outer membrane that supports the embryo.

One or two cells are removed. The opening is then closed and no cells can accidentally “fall out”.

To obtain the results of the biopsy, the one or two cells removed must contain a nucleus, since the nucleus contains the genetic information necessary for the test. If the killed cell does not have a nucleus or if the nucleus ruptures while it is being prepared, the test cannot be performed on that cell.

Also, since embryos are actively growing and dividing, sometimes the removed cell contains two nuclei. This could mean that the cell is abnormal or is caught up in the division process. Tests for these cells can be difficult to interpret.

How exactly is the PGD test done?

The PGD test is different from most genetic tests in that it is performed on only one or two embryonic cells and is completed within 48 hours of fresh embryo transfer by day five.

Since the standard chromosome analysis takes several days, a different method called fluorescent in situ hybridization (FISH) is performed.

Each chromosome has unique areas of DNA present only on that chromosome. A small DNA probe is used to recognize these unique patterns and fluoresce or light up when attached to the chromosome. Each probe illuminates the light in a different color, allowing multiple chromosomes to be tested at the same time.

This technique is called FISH. FISH is used for chromosomes 13, 15, 16, 18, 21, 22, X, and Y because these are the chromosomes that are most often abnormal.

A normal cell should show two FISH signals (or lights) for each of the numbered chromosomes, and two X signals for a female or one X and one Y for a male. Only five different colors can be used, so most tests are done in two parts.

The first five chromosomes are tested, those probes are washed, and then the remaining chromosomes are tested. The washing process can affect the integrity of each chromosome, therefore a maximum of two cycles of FISH is used per cell. For this reason, every chromosome cannot be tested.

When does PGD occur in the IVF cycle?

After the embryos are created in the laboratory, they grow for three days. On day three, the DPG biopsy is performed and one or two cells are removed from the embryo. The genetic material within these cells is tested for abnormalities.

On day five, the woman returns to discuss the results of her DPG test. Decisions regarding the selection of embryos for transfer to the uterus are made with the advice of the medical team.

Is the DPG safe?

Yes. Data from many years of PGD in animals and approximately thousands of live births in humans indicate that PGD does not lead to an increase in birth defects or chromosomal disorders. PGD ​​is done before the embryo’s genetic material becomes “active.”

Because it is done so early, the cells within the embryo remain identical and each cell can become part of a baby. Removing some of the cells from the early embryo does not alter that embryo’s ability to develop into a full and normal pregnancy.

How do you get the cells from the embryo?

Embryos created in an IVF cycle are cultured in the laboratory for three days. At this time, they contain approximately eight cells. Each embryo at this point is called a blastomere.

Normally developing embryos on day three will have one or two cells removed for testing in a procedure called a biopsy. The embryos are placed under a powerful microscope and a laser is used to create a small opening in the zona pellucida, a tough outer membrane that supports the embryo.

One or two cells are removed. The opening is then closed and no cells can accidentally “fall out”.

To obtain the results of the biopsy, the one or two cells removed must contain a nucleus, since the nucleus contains the genetic information necessary for the test. If the killed cell does not have a nucleus or if the nucleus ruptures while it is being prepared, the test cannot be performed on that cell.

Also, since embryos are actively growing and dividing, sometimes the removed cell contains two nuclei. This could mean that the cell is abnormal or is caught up in the division process. Tests for these cells can be difficult to interpret.

How exactly is the PGD test done?

The PGD test is different from most genetic tests in that it is performed on only one or two embryonic cells and is completed within 48 hours of fresh embryo transfer by day five.

Since the standard chromosome analysis takes several days, a different method called fluorescent in situ hybridization (FISH) is performed.

Each chromosome has unique areas of DNA present only on that chromosome. A small DNA probe is used to recognize these unique patterns and fluoresce or light up when attached to the chromosome. Each probe illuminates the light in a different color, allowing multiple chromosomes to be tested at the same time.

This technique is called FISH. FISH is used for chromosomes 13, 15, 16, 18, 21, 22, X, and Y because these are the chromosomes that are most often abnormal.

A normal cell should show two FISH signals (or lights) for each of the numbered chromosomes, and two X signals for a female or one X and one Y for a male. Only five different colors can be used, so most tests are done in two parts.

The first five chromosomes are tested, those probes are washed, and then the remaining chromosomes are tested. The washing process can affect the integrity of each chromosome, therefore a maximum of two cycles of FISH is used per cell. For this reason, every chromosome cannot be tested.