ISOCHROMOSOME: DEFINITION, ORIGIN, ASSOCIATED PATHOLOGIES - BIOLOGY - 2025

An isochromosome is an abnormal metacentric chromosome that is caused by the loss of one of the arms of the parental chromosome and the consequent duplication of the arm that is preserved.

There are two mechanisms that have been proposed to explain the generation of this type of genetic abnormality. The most accepted of the two proposes that isochromosomes originate during the process of cell division, as a product of a transversal division of the centromere rather than longitudinal.

Formation of an Isochromosome. By Miguelferig, from Wikimedia Commons.

Since, the result consists of an alteration of the genetic information contained in the parental chromosome, numerous genetic disorders can originate. Turner syndrome, which occurs due to the duplication of the long arm of the X chromosome and the loss of the short arm, has been the most studied of these disorders.

Additionally, many types of cancer are also associated with these types of abnormalities. Therefore, the study of isochromosomes has become an attractive and important field of research.

Isochromosome: a structural chromosomal abnormality

An isochromosome is a structural chromosomal abnormality that results in an aberrant metacentric chromosome. This is caused by the loss of one of the arms of a chromatid and the subsequent duplication of the undeleted arm.

In other words, on this chromosome both arms of a chromatid are morphologically and genetically identical. This duplication results in partial monosomy or partial trisomy.

Monosomy is a term used to refer to the fact that the genetic information contained in a locus is found in a single copy. A situation that is abnormal in diploid cells, where two copies are always present. Now, it is said that it is partial when the lost information is found on the other chromosome of the pair.

On the other hand, the trisomy caused by this type of structural disruption is partial, because the genetic information contained in an arm is present in three copies.

However, two of these copies are the same, product of the duplication event of one of the arms in one of the chromosomes of the pair.

Origin

The mechanisms by which isochromosomes are generated still remain to be fully elucidated. However, two explanations made to date are supported.

The first of them, the most accepted, states that during cell division the centromere is formed by transversal and not longitudinal division, as it usually occurs under normal conditions. This leads to the loss of one of the arms of the parental chromosome and the subsequent duplication of the arm that remains intact.

The second of the mechanisms involves the detachment of one of the arms and its consequent fusion of the daughter chromatids just above the centromere, giving rise to a chromosome with two centromeres (dcentric chromosome). In turn, one of these two centromeres experiences a total loss of functionality, which makes it possible for chromosomal segregation during cell division to occur normally.

Associated pathologies

The formation of isochromosomes results in an imbalance in the amount of genetic information held by the parental chromosomes. These imbalances often lead to the appearance of genetic disorders, which are translated into specific pathologies.

Among the many syndromes that have been associated with this type of structural abnormality, we find Turner syndrome. This condition is the best known, in fact it is related to the first report of an isochromosome in humans. The latter comes from the formation of an X isochromosome, in which the short arm of the original chromosome has been lost and the long arm has been duplicated.

Numerous investigations have shown that the presence of isochromosomes is the trigger for the development of numerous types of cancer, among which the chronic myeloid leukemia associated with isochromosome i (17q) stand out. These findings make isochromosomes a highly relevant focus for researchers.

What is a chromosome?

In all living cells, DNA is packaged in highly organized structures called chromosomes.

This packaging in eukaryotic cells takes place thanks to the interaction of DNA with proteins called histones, which in a group of eight units (octamer) form a nucleosome.

The nucleosome (basic unit of organization of chromatin) consists of a histone octamer composed of histone dimers H2A, H2B, H3 and H4. The octamer's structure resembles a spool of thread through which the large DNA molecule is wound.

The coiling of the DNA molecule, through a vast number of nucleosomes linked together by spacer regions associated with another type of histone (H1) called linkers, finally gives rise to chromosomes. The latter can be seen under the microscope as well-defined bodies during the processes of cell division (mitosis and meiosis).

Each diploid species has a well-defined number of chromosome pairs. Each pair is distinctive in size and shape for easy identification.

Structure of chromosomes

Chromosomes have a fairly simple structure, made up of two parallel arms (chromatids) that are united through the centromere, a densely packed DNA structure.

The centromere sections each chromatid into two arms, a short one called the "P arm" and a longer one called the "Q arm". In each of the arms of each chromatid the genes are arranged in identical locations.

Formation of an Isochromosome. By Miguelferig, from Wikimedia Commons

The position of the centromere along each chromatid gives rise to different structural types of chromosomes:

- Acrocentric: those in which the centromere occupies a position very close to one of the ends, originating a very long arm with respect to the other.

- Metacentric: in this type of chromosomes, the centromere occupies a middle location, giving rise to arms of equal length.

- Submetacentric: these are, the centromere is only slightly displaced from the center, yielding arms that diverge very little in length.

Chromosomal abnormalities

Each of the chromosomes that make up the karyotype of an individual harbors millions of genes, which encode an endless number of proteins that fulfill different functions, as well as regulatory sequences.

Any event that introduces variations in the structure, number or size of chromosomes, can lead to alterations in the quantity, quality and location of the genetic information contained in them. These alterations can lead to catastrophic conditions, both in development and in the functioning of individuals.

These abnormalities are generally generated during gametogenesis or during the early stages of embryonic development and, although they tend to be extremely varied, they have been simplified into two categories: structural chromosomal abnormalities and numerical chromosomal abnormalities.

The former involve variations in the standard number of chromosomes, that is, they allude to the loss or gain of chromosomes, while the latter refer to the loss, duplication or inversion of a part of the chromosome

References

1. Alberts B, Johnson AD, Lewis J, Morgan D, Raff M, Roberts K, Walter P. (2014) Molecular Biology of the Cell (6th Edition). WW Norton & Company, New York, NY, USA.
2. Annunziato A. DNA Packaging: Nucleosomes and chromatin. Nature Education. 2008; 1:26.
3. Caspersson T, Lindsten J, Zech L. The nature of structural X chromosome aberrations in Turner's syndrome as revealed by quinacrine mustard fluorescence analysis. Hereditas. 1970; 66: 287-292.
4. de la Chapelle A. How do human isochromosome arise? Cancer Genet Cytogenet. 1982; 5: 173-179.
5. Fraccaro M, Ikkos D, Lindsten J, Luft R, Kaijser K. A new type of chromosomal abnormality in gonadal dysgenesis. Lancet. 1960; 2: 1144.
6. First International Workshop on Chromosomes in Leukaemia. Chromosomes in Phi-positive chronic granulocytic leukaemia. Br J Haematol. 1978; 39: 305-309.
7. Mitelman F, Levan G. Clustering of aberrations to specific chromosomes in human neoplasms. Hereditas. 1978; 89: 207-232.
8. Simpson JL. Disorders of Sexual Differentiation. 1970. Academic Press, New York, San Francisco, London.
9. Vinuesa M, Slavutsky I, Larripa I. Presence of isochromosomes in hematologic diseases. Cancer Genet Cytogenet. 1987; 25: 47-54.