TRISOMY: DOWN SYNDROME AND SEX CHROMOSOMES - BIOLOGY - 2025

A trisomy is a chromosomal condition of individuals who carry three chromosomes instead of the normal pair. In diploids, the normal endowment is two chromosomes from each of the chromosomal complement that defines the species.

An alteration in number in only one of the chromosomes is called aneuploidy. If it encompassed changes in the total number of chromosomes it would be a true ploidy, or eupolidy. The human being has 46 chromosomes in each of its somatic cells. If they have a single trisomy they will have 47 chromosomes.

Karyotype showing a trisomy on chromosome 21. US Department of Energy Human Genome Program., via Wikimedia Commons.

Trisomies are statistically frequent and represent great changes for the carrier organism. They can also occur in humans, and are associated with complex diseases or syndromes.

There are trisomies in humans known to all. The most attended, frequent and known of all is the trisomy of chromosome 21, the most common cause of the so-called Down syndrome.

There are other trisomies in humans that represent a great physiological cost for the carrier. Among them we have the trisomy of the X chromosome, which represents a huge challenge for the woman who suffers from it.

Any living eukaryotic organism can have a trisomy. In general, in plants any alteration in the number of chromosomes (aneuploidy) is much more damaging than an increase in the number of the chromosomal complement of the species. In other animals, as a general rule, aneuploidies are also the cause of multiple conditions.

Chromosome 21 trisomy (Down syndrome: 47, +21)

Trisomy (complete) of chromosome 21 in humans determines the presence of 47 chromosomes in diploid somatic cells. Twenty-two pairs provide 44 chromosomes, while the trio on chromosome 21 provides three more - one of which is supernumerary. In other words, it is a chromosome that "is too much."

Description and a bit of history

Chromosome 21 trisomy is the most common aneuploidy in humans. Similarly, this trisomy is also the most common cause of Down syndrome. However, although other somatic trisomies are more common than those on chromosome 21, most tend to be more lethal in embryonic stages.

That is, embryos with trisomies 21 can reach birth, while other trisomic embryos cannot. Furthermore, postnatal survival is much higher in children with trisomy on chromosome 21 due to the low gene frequency of this chromosome.

In other words, few genes will be increased in copy number because chromosome 21 is the smallest autosome of all.

Down syndrome was first described by the English physician John Langdon Down in the period from 1862 to 1866. However, the association of the disease with chromosome 21 was established about a hundred years later. French researchers Marthe Gautier, Raymond Turpin and Jèrôme Lejeune participated in these studies.

Genetic causes of the disease

Chromosome 21 trisomy is caused by the union of two gametes, one of which is a carrier of more than one copy, total or partial, of chromosome 21. There are three ways this can happen.

In the first one, in one of the parents, the nondisjunction of chromosomes 21 during meiosis gives rise to gametes with two chromosomes 21 instead of one. Nondisjunction means "lack of separation or segregation." It is the gamete that can give rise to true trisomy by joining another gamete with a single copy of chromosome 21.

Another less common cause of this trisomy is what is called a Robertsonian translocation. In it, the long arm of chromosome 21 translocates to another chromosome (usually 14). The union of one of these gametes with another normal will give rise to embryos with normal karyotypes.

However, there will be extra copies of the inherited material from chromosome 21, which is sufficient cause of the disease. The syndrome can also be caused by other chromosomal aberrations or mosaicism.

In a mosaic, the individual has cells with normal karyotypes, alternating with cells with aberrant karyotypes (trisomic for chromosome 21).

Meiotic nondisjunction during phenenin gametic meiosis, or oogenesis. Taken from https://commons.wikimedia.org/wiki/File:Trisomy_due_to_nondisjunction_in_maternal_meiosis_1.png. Via Wikimedia Commons.

Manifestation of the disease

The underlying cause of Down syndrome is the increased expression of some enzymes due to the existence of three copies of the genes on chromosome 21, instead of two.

This increased expression leads to alterations in the normal physiology of the individual. Some of the enzymes so affected include superoxide dismutase and cystation beta-synthase. Many others are related to the synthesis of DNA, the primary metabolism and the cognitive capacity of the individual.

The disease manifests itself at different levels. One of the most important, and that determine the life time of those affected by trisomy, are congenital heart defects.

Other conditions afflicting sick individuals include gastrointestinal tract abnormalities, hematologic, endocrinologic, ENT, and musculoskeletal disorders, as well as visual abnormalities, among others.

Neurological disorders are also important, and include mild to moderate learning difficulties. Most adult individuals with Down syndrome develop Alzheimer's disease.

Diagnosis and studies in other living systems

The prenatal diagnosis of Down can be carried out by several means. This includes ultrasound, as well as chorionic villus sampling and amniocentesis. Both can be used for chromosome counts, but they pose certain risks.

Other more modern assays include FISH chromosomal analysis, other immunohistological techniques, and genetic polymorphism tests based on DNA amplification by PCR.

The study of the trisomy of chromosome 21 in rodent systems has allowed us to analyze the syndrome without experimenting with humans. In this way, genotype / phenotype relationships have been safely and reliably analyzed.

In the same way, it has been possible to proceed to the testing of strategies and therapeutic agents that can then be used in humans. The most successful rodent model for these studies has turned out to be the mouse.

Trisomies of the sex chromosomes in humans

Generally, aneuploidies of the sex chromosomes have fewer medical consequences than those of autosomes in humans. The females of the human species are XX, and the males XY.

The most common sexual trisomies in humans are XXX, XXY and XYY. Obviously, there cannot be YY individuals, much less YYY. XXX individuals are morphologically female, while XXY and XYY are male.

Triple X syndrome (47, XXX)

XXX individuals in humans are females with an extra X chromosome. The phenotype associated with the condition varies with age, but generally adult individuals present a normal phenotype.

Statistically speaking, one in a thousand women is XXX. A common phenotypic trait in XXX women is premature growth and development, and unusually long lower limbs.

At other levels, XXX women often have hearing or language development disorders. At the end of adolescence, they usually overcome problems associated with their social adaptation, and their quality of life improves. However, psychiatric disorders in XXX women are more frequent than in XX women.

In females, one of the X chromosomes is inactivated during the normal development of the individual. Two of them are believed to be inactivated in XXX females. However, it is believed that most of the consequences derived from trisomy are due to genetic imbalances.

This means that such inactivation is not efficient or sufficient to avoid differences in expression of certain (or all) genes. This is one of the most studied aspects of the disease from a molecular point of view.

As in the case of other trisomies, the prenatal detection of triple X trisomy is still supported by the karyotype study.

Kleinefelter syndrome (47, XXY)

These individuals are said to be males of the species with an extra X chromosome. The signs of aneuploidy vary with the individual's age, and usually only when they are adults is the condition diagnosed.

This means that this sexual aneuploidy does not give rise to affectations as great as those caused by trisomies in autosomal chromosomes.

XXY adult males produce little or no sperm, have testicles and a small penis, as well as decreased libido. They are taller than average, but also have less facial and body hair.

They may have enlarged breasts (gynecomastia), decreased muscle mass, and weak bones. The administration of testosterone is usually helpful in the treatment of some endocrinological aspects related to the condition.

XYY syndrome (47, XYY)

This syndrome is experienced by males of the human species (XY) who have an additional Y chromosome. The consequences of the presence of an extra Y chromosome are not as dramatic as those seen in other trisomies.

XYY individuals are phenotypically male, regularly tall, and with slightly elongated limbs. They produce normal amounts of testosterone and have no particular behavioral or learning problems as previously thought.

Many XYY individuals are unaware of their chromosomal status. They are phenotypically normal, and also fertile.

Trisomies in other organisms

The effect of aneuploidies in plants has been analyzed and compared with the effect of the euploidy change. In general, changes in number in one or a few chromosomes are more damaging to the normal functioning of the individual than changes in complete sets of chromosomes.

As in the cases described, the imbalances in expression seem to account for the deleterious effects of the differences.

References

1. Herault, Y., Delabar, JM, Fisher, EMC, Tybulewicz, VLJ, Yu, E., Brault, V. (2017) Rodent models in Down syndrome research: impact and future. The Company of Biologists, 10: 1165-1186. doi: 10.1242 / dmm.029728
2. khtar, F., Bokhari, SRA 2018. Down Syndrome (Trisomy 21). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: ncbi.nlm.nih.gov
3. Otter, M., Schrander-Stumpel, CT, Curfs, LM (2010) Triple X syndrome: a review of the literature. European Journal of Human Genetics, 18: 265-271.
4. Papavassiliou, P., Charalsawadi, C., Rafferty, K., Jackson-Cook, C. (2014) Mosaicism for trisomy 21: a review. American Journsl of Medical Genetica Part A, 167A: 26–39.
5. Santorum, M., Wright, D., Syngelaki, A., Karagioti, N., Nicolaides, KH (2017) Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound in Obstetrics & Gynecology, 49: 714-720.
6. Tartaglia, NR, Howell, S., Sutherland, A., Wilson, R., Wilson, L. (2010) A review of trisomy X (47, XXX). Orphanet Journal of Rare Diseases, 5, ojrd.com