Chromosome mutation

chromosomal mutations, non-point mutations or chromosomopathies are alterations in the number of genes or in the order of genes within chromosomes. They are due to errors during gametogenesis (formation of gametes by meiosis) or the first divisions of the zygote. In the first case, the anomaly will be present in all cell lines of the individual, while when the anomaly occurs in the zygote it can give rise to mosaicism, thus coexisting populations of normal cells with others that present chromosomal mutations.

Human female cell cyariotype in metaphase state.

These alterations can be observed during the metaphase of the cell cycle and originate from breaks (clastogenic processes) of unrepaired or poorly repaired DNA strands, among other factors.

At present there is a wide knowledge of the human karyotype and chromosomal abnormalities. Since these alterations are genetic abnormalities, they can be transmitted to offspring if they affect germ cells. It is estimated that about 60% of abortions that occur in the first trimester of pregnancy are due to chromosomal abnormalities and 0.5% of newborns have aneuploidies. For this reason, the study of these mutations by means of a karyotype or FISH is very useful to detect any anomaly in advance.

Numerical anomalies

These abnormalities are also called genomic mutations, since the number of chromosomes in the genome varies. They can be aneuploidy or polyploidy. The most common case is aneuploidy, which occurs when an individual accidentally has an extra chromosome (trisomy, 2n+1) or less (monosomy, 2n-1) in relation to their normal condition (diploid).

Polyploidies occur when you have three or more complete sets of chromosomes (Triploidy,3n; Tetraploidy, 4n). In humans, triploidies usually end in abortion and if it comes to birth, it ends up suffering a premature death. Tetraploidy is lethal.

Autosomal Aneuploidies

chromosomal alteration in chromosome 21, causative trisomy of Down Syndrome.

They are alterations in the number of copies of one of the non-sex chromosomes. In humans, not all numerical aneuploidies are viable, and those that are viable produce alterations in the phenotype. Among the most frequent are:

• Chromosome 21 Trisomy best known as Down Syndrome (it is the cause of 95% of cases).
• Trisomy of chromosome 18 best known as Edwards Syndrome.
• Trisomy of chromosome 13 best known as Patau Syndrome.
• Trisomy of chromosome 22 (letal, cases of mosaicism have been described).
• Monosomy of chromosome 21 (letal, cases of mosaicism have been described).

Numerical variations in key chromosomes in the early development of the embryo are not viable even at the embryonic level, so they are not detected as frequent causes of spontaneous abortions caused by chromosomal aneuploidies (this is the case of chromosome 1, for example).

Sexual Aneuploidies

They are alterations in the number of copies of one of the two human sex chromosomes. Aneuploidies in this case are usually viable. Among the most frequent are:

• Klinefelter syndrome (sex chromosomes: 47, XXY).
• Turner Syndrome (sexual chromosomes monomia: 45, X). It's the only viable monosomy.
• Double Y syndrome (sometimes called supermacho syndrome: 47, XYY).
• Triple X syndrome (sometimes called superhero syndrome: 47, XXX).

Structural chromosomal abnormalities

Types of structural chromosomal mutations.

These abnormalities affect the structure of the chromosome in terms of the linear arrangement of genes. One or more chromosomes change their own structure by the addition or loss of genetic material, by alteration of their shape or banding pattern. These changes are called rearrangements and are always associated with chromosome breakage. These include the following anomalies:

• Deletions: consists of the loss of a fragment of chromosome, which causes an imbalance (the carrier of a deletion is monosomal compared to the ice affected by deletion). It can be produced at the end of a chromosome (final deletion) or along its short or long arms (interstitial deletion). One of the causes of Prader-Willi syndrome is a partial deletion of the long arm of chromosome 15.
• Duplications: Consiste in the presence of an extra copy of a segment of a chromosome. Duplications are sometimes known as partial trisomnia. It may occur that a person possesses two extra copies of a fragment of a chromosome and then it is said that his genome has a trillion or partial tetrasomy. Some duplications are so small that they cannot be detected by the optical microscope and then are called microduplications. Fragile X syndrome is due to a partial duplication of the end of the long arm of chromosome X.

• Investments: a segment of the chromosome changes its orientation within it. They are caused by two breakages in the same chromosome and the genetic material between the two breakpoints rotates 180o and rests in the gap that has left in the chromosome. There are two types of investments: Pericéntricawhen the centromer is part of the invested segment. In these cases a break point is found in the short arm and the other in the long arm. On investment paracentric It is not enveloped in centromer and both stitches are found in the same arm. They have a very low frequency and do not usually cause major disorders in their carriers (unless investment causes disruption of important genes). However, investments can cause problems in the offspring of carrier individuals, especially in the case of pericentric investments, as they generate gametes that often carry duplications and deletions of genetic material.

• Chromosome in ring: it occurs when both arms of a chromosome merge forming a ring. They usually form when the short and long arm of the same chromosome have a terminal deletion, this causes them to remain "small" ends in both arms that often merge originating the chromosome in the ring. Deletioned genetic material is usually insignificant. Although rare, they are also involved in diseases. For example, one of the causes of Turner syndrome is the formation of a ring in chromosome X.

• Translocations: take place when a portion of one chromosome is transferred to another. When a segment is exchanged between two non-homologist chromosomes takes place reciprocal translocation. A reordering of genetic material occurs, but there is no loss or gain of genetic information as in the case of deletions and duplication. Robertsonian translocation is a special case of translocation ("almost balanced") in which two non-homologist chromosomes lose their short arms while the lengths are joined by the centromer of one of the chromosomes, forming a unique chromosome. This type of translocation affects acrocentric chromosomes with a very small p arm (in humans, chromosomes 13, 14, 15, 21 and 22). 4% of the cases of Down syndrome are due to a 21/21 or 14/21 translocation.

• Isochromosome: it is a chromosome that has lost one arm and the other has doubled, so there is a partial monosomy due to the lost arm, and a partial trisomy, due to the duplicate arm. It occurs when the centromer division occurs according to the transverse plane instead of vertical.

• Chrome marker or sSMC: It is a small extra chromosome made from parts of one or more chromosomes, therefore the genetic material that forms it will be duplicated or triplicated. The origin of this extra chromosome is often unknown. It is called chromosome marker or sSMC ("small supernumerary marker chromosome").

• Uniparental (UPD): This alteration consists of both chromosomes of one of the 23 pairs of homologous chromosomes present in humans coming from the same parent, instead of belonging one to the mother and the other to the father. The result is that the chromosome of one parent is duplicated and the chromosome of the other parent is absent. However, the net number of chromosomes is 46. When both chromosomes come from the mother it is called a maternal uniparental dysomy (mUPD). If they came from the father, he disliked a single parent (pUPD). Uniparental dysomy may be associated with certain pathologies, depending on the duplicate chromosome and the parent from which it comes. For example, the Prader-Willi Syndrome is associated with a maternal uniparent dysomy of chromosome 15 and the Angelman Syndrome with an uniparent paternal dysomy of the same chromosome.

Derivative chromosomes will always be named according to the centromere they carry.