Chromosomal mutations
There are two main types of chromosome mutations: numerical chromosomal mutations and structural chromosomal mutations. In turn, numerical mutations are divided into aneuploidy, when mutations are expressed in the loss or appearance of additional one or more chromosomes, and polyploidy, when the number of haploid sets of chromosomes increases. The loss of one of the chromosomes is called monosomy, and the emergence of an additional chromosome in any pair of chromosomes - trisomy. Structural chromosomal mutations are represented by translocations, deletions, insertions, inversions, rings and isochromosomes. Numerical chromosomal mutations
Trisomy. Trisomy is the appearance in the karyotype of an additional chromosome. The most famous example of trisomy is Down's disease, which is often called trisomy on chromosome 21. The result of trisomy on chromosome 13 is the Patau syndrome, and on chromosome 18 - Edwards syndrome. All these trisomies are autosomal. Other trisomy on autosomes are not viable, die in utero and, apparently, are lost in the form of spontaneous abortions. Viable are individuals with additional sex chromosomes. Moreover, the clinical manifestations of additional chromosomes X or Y can be quite insignificant.
Typically, trisomy occurs due to a violation of the discrepancy between homologous chromosomes in the anaphase of meiosis I. As a result, both homologous chromosomes fall into one daughter cell, and none of the bivalent chromosomes enter the second daughter cell. Sometimes, however, trisomy can be the result of a disruption of the sister chromatid divergence in meiosis II.In this case, two absolutely identical chromosomes fall into one gamete, which in the case of its fertilization with normal sperm will give a trisomic zygote. This type of chromosomal mutations leading to trisomy are called non-divergence of chromosomes. Autosomal trisomies arise from the non-divergence of chromosomes, which is observed predominantly in oogenesis, but also in spermatogenesis, non-dissociation of autosomes can also be. Nondisjunction of chromosomes can also occur in the early stages of crushing of a fertilized egg. In this case, there is a clone of mutant cells in the body that can capture more or less of the organs and tissues and sometimes give clinical manifestations similar to those observed in ordinary trisomy.
The reasons for the nondisjunction of chromosomes remain unclear. The well-known fact of the connection between non-dissociation of chromosomes( especially chromosome 21) and the mother's age still has no unambiguous interpretation.
Monosomy .The absence of any autosome is in most cases incompatible with normal development and leads to early spontaneous abortions. A very rare exception is monosomy on chromosome 21. Monosomy can be the result of chromosome nondisjunction or loss of the chromosome during its movement to the cell pole in anaphase.
Aneuploidy on the sex chromosomes. Monosomy by sex chromosomes leads to the formation of an organism with a karyotype of CW, the clinical manifestation of which is Turner's syndrome. In 80% of cases, X chromosome monosomy is the result of meiosis in the father( non-separation of chromosomes X and Y).Most XO-zygotes die in utero.
Trisomy on the sex chromosomes can be of three types - with karyotype 47, XXY, 47, XXX and 47, XYY.Trisomy 47, XXY is known as Klinefelter's syndrome. In about 50% of cases, the cause of the syndrome is the non-dissociation of X chromosomes in oogenesis, the other 50% of cases are attributed to the non-divergence of X and Y chromosomes of spermatogenesis. About 50% of embryos with such a karyotype are aborted. Trisomy 47, XXX is in the vast majority of cases the result of non-discrepancy of chromosomes in the gametogenesis of the mother. In contrast, Trimosia 47, XYY occurs as a result of meiosis disturbance in the gametogenesis of the father. This disorder can only occur in meiosis II due to the non-divergence of chromosomes Y. Trisomy 47, XXX and 47, XYY occur at a frequency of 1: 1000 in women and men respectively, they show relatively small phenotypic changes and are usually found in the form of random findings.
Polyploidy of .Polyploid cells contain a triple or quadruple haploid set of chromosomes. In humans, triploidy is sometimes found in spontaneous abortions, several cases of live births are also known, but the patients died within the first month of life. Triploidy can be caused by a violation of the meiotic divergence of the entire set of chromosomes in the meiosis of female or male sex cells. As a result, either the ovum or the sperm are diploid. As a mechanism of triploidy, the possibility of fertilization of eggs with two spermatozoa is also considered. In the case when triploidy is due to the fatherly diploid set of chromosomes, a placental degeneration of the placenta occurs, the so-called bladder drift.
Structural chromosomal mutations
Structural mutations of chromosomes can arise only as a result of chromosome rupture with subsequent reunion, accompanied by a violation of the initial configuration of chromosomes. Such mutations can be balanced or unbalanced. With balanced chromosomal mutations, there is no loss or excess of genetic material, so they do not have phenotypic manifestations, except in cases when as a result of chromosome rupture a functionally important gene appears at the site of the rupture. At the same time gametes unbalanced by the chromosome set can be formed in carriers of balanced chromosomal mutations, and as a consequence, in the fetus, resulting from fertilization with such a gamete, the chromosome set will also be unbalanced. With an unbalanced chromosome set, the fetus develops severe clinical manifestations of pathology, usually in the form of a complex of congenital malformations.
Deletions. Deletion means loss of the chromosome region. Terminal deletions occur when, as a result of a single break in the chromosome, the chromosome itself is shortened, and the fragment is usually lost the next time the cell divides. The remaining deletions, which are called interstitial, arise as a result of two discontinuities in the chromosome. Deletion of the chromosome region causes monosomy over this site, which, as a rule, is lethal. It is believed that the deletion of more than 2% of the chromosomal material from the haploid set will be lethal. At the same time, some deletion syndromes are compatible with life. These include Wolf-Hirschhorn syndrome and cat-scream syndrome.
Duplications of .Duplication is a doubling of the DNA portion, and duplication of a part of the chromosomal material involved in translocation may also occur. Microduplications can also be the result of unequal crossing-over in homologous chromosomes. Usually, duplications do not lead to the appearance of such pronounced developmental anomalies as deletions.
Translocations. Translocation refers to the transfer of genetic material from one chromosome to another. If discontinuities occur simultaneously in two chromosomes and the latter are exchanged by the formed free segments, then such translocations are called reciprocal translocations. In this case, the karyotype remains represented by 46 chromosomes, and translocation can be detected only by a detailed analysis of the chromosomes. Reciprocal translocations are usually not accompanied by phenotypic manifestations. Reciprocal translocations lead to the formation of unbalanced gametes when they undergo meiosis. Usually, the following two possibilities are realized: two normal ones fall into one gamete, and the other two translocated( this type of discrepancy is called an alternative one) of the chromosome, and in both gametes one normal and one translocated chromosome enter. In the second case, two combinations of normal and translocated chromosomes are possible. Theoretically, all 4 types of discrepancy should be realized with equal probability.
A special type of reciprocal translocations are the so-called Robertson translocations. In this case, the discontinuities in the two acrocentric chromosomes are localized in the region of the centromere or in the immediate vicinity of them. The long shoulders of the chromosomes merge, and the short ones are lost. Since short shoulders of acrocentric chromosomes contain rRNA genes, their loss does not appear, since multiple copies of these genes are also contained in other acrocentric chromosomes. Therefore, the Robertsonian translocation is functionally balanced. In the karyotype, the number of chromosomes decreases to 45. As with reciprocal translocations, the risk of formation of unbalanced gametes is related to the way meiosis occurs in carriers of Robertsonian translocation.
6 types of gametes are possible as a result of the different chromosome divergence methods involved in the Robertson translocation:
1) gametes with normal chromosomes;
2) complementary gametes with Robertson translocation( both types of gametes are balanced);
3) gametes carrying one normal and translocated chromosome;
4) gametes carrying the second normal and translocated chromosome;
5) gametes carrying only one normal chromosome;
6) gametes carrying only the second normal chromosome.
In the case where the Robertsonian translocation is the result of the fusion of long arms of chromosomes 21, all gametes will be unbalanced. In a family in which one of the parents is the bearer of such a translocation, all children will have Down's disease.
Insertions. When a segment of one chromosome is transferred and inserted into another chromosome, such a rearrangement is called an insertion. In order for an insertion to occur, at least 3 chromosome breaks are necessary. Since the insertion does not lose or add new genetic material, such a restructuring is considered balanced. However, in carriers of such an insertion, 50% gametes will be unbalanced, since they will carry the chromosome either with deletion or with insertion. As a result, zygotes with partial monosomy or partial trisomy will be formed.
Inversion. An inversion is called a chromosomal mutation, when after two breaks in one chromosome the segment of the chromosome located between the breaks rotates 180 ° and takes an inverted position. If a centromere enters the inverted segment, then this inversion is called pericentric, and if the inversion of the chromosome segment occurs within one arm, the paracentric one. With inversion, there is no loss of genetic material, except when the chromosome rupture can affect a functionally important gene. Therefore, carriers of both types of inversions do not, as a rule, have any pathological symptoms. Moreover, some inversions, such as pericentric inversion in chromosome 9, occur as a normal symptom with a fairly high frequency in some ethnic groups. As with other balanced rearrangements, inversions in meiosis can lead to the formation of unbalanced gametes.
Isochromosomes. Isochromosomes arise when the centromere is not divided longitudinally but transversely. As a result, one of the shoulders is lost, and the second is doubled. Most often, an isochromosome composed of long arms of chromosome X is detected. In this case, the individuals carrying such an isochromosome X exhibit manifestations of the Shereshevsky-Turner syndrome.
Ring chromosomes. This type of chromosomal mutation occurs when ruptures are observed in both shoulders of a chromosome. The acentric fragments are lost, and the central part of the chromosome closes into the ring. If such a ring chromosome is formed from an autosome, then because of the lack of a significant proportion of the genetic material of this chromosome, the gamete and the zygote are unbalanced, which should lead to an early loss of the embryo with the ring chromosome. If the embryo is formed, then the ring chromosome tends to be lost during the mitotic division of the cells. As a consequence, there is a mosaicism due to the presence in the cells of the ring chromosome.