3. Cytogenetics. Chromosome mutations
3.2. Numerical chromosome aberrations
The numerical anomalies, when one or more chromosomes are in excess or missing, ultimately modify the entire genome size, so they can be considered genome mutations as well.
There are three types of numerical chromosome aberrations:
1/ euploid 2/ aneuploid
3/ mixoploid mutations
3.2.1. Euploid chromosome mutations
In the case of euploidy each chromosome is present in the same number, i.e. in a haploid cell everything is present only once, twice in diploids, three times in triploids and so on.
The haploid chromosome number - i.e. typical of the gametes - is n, its exact multiples, that is, 2n, 3n, etc. found in the euploid somatic cells. Polyploidy means, if we find a multiple of n, either in gametes or in somatic cells. However, mutations only have arisen if the individuals or just the cell have chromosomes in a number different from the species specific (haploid or diploid) set. The multiplication of the chromosome set occurs in the M phase of the cell cycle due to the defects of microtubules and / or the abnormal organization of mitotic spindle.
In plants, polyploidy is compatible with normal life moreover it is economically quite advantageous, since the multiplication of chromosomes leads not only to the multiplication of genes, but also to the multiplication of their products. Thus the protein content and the crop yield grow, such as banana, wheat etc. In plant cells, the polyploidy found is either the result of that species’ evolution or the result of conscious plant breeding work. For the induction of polyploidy spindle poisons - Colcemid, Colchicine, Vincristine, Vinblastine - alkaloids inhibiting the polymerization of spindle microtubules can also be used. In this case autopolyploidy is created, since every chromosome is of the same species. In contrast, hybrids (e.g. wheat) established by crossing of species or related species are allopolyploids.
Unlike plants polyploidy in animals or in humans is lethal, leads to death in utero.
With the exception of certain cells/tissues, for example bone marrow megakaryocytes and a part of the regenerating liver cells which are also polyploids. In these cases it is fixed during the millions of years of evolution what type of cell has the multiplication of chromosome number during ontogeny.
In 10% of the spontaneously aborted fetuses triploidy occurs. Interestingly, 90% of them is of paternal origin, derived either from fertilization by a diploid sperm or from double fertilization. Only a minority comes from fertilization of a diploid egg.
3.2.2. Aneuploid chromosomal aberrations
Aneuploidy is a chromosomal abnormality when only a certain chromosome is in excess or missing. If there is only one chromosome instead of the normal two homologues we are talking about monosomy, if there are three copies trisomy occurs. If a particular chromosome is not found at all in a cell / organism nullisomy is present. The latter is lethal both in humans and animals, but in plants is not. Generally speaking, in humans / animals the excess of chromosomes is tolerated better than the chromosomal deficiency.
48 Genetics and genomics
Several somatic and especially sex chromosome aneuploidies - trisomies - occur in born, but only one - the X chromosomal monosomy (Turner syndrome) occurs in live-born. The aneupolid mutations are due to mitotic or meiotic non-disjunctions, when the sister chromatids or the chromosomes do not separate in the anaphase – because of the abnormality of the kinetochore, the centromere or both. Less frequently (uniparental disomy) a chromatid / chromosome lagging behind the others in the anaphase - anaphase lag - does not get to the right pole, and therefore not to the daughter cell.
Due to this one of the daughter cells is with an extra chromosome, while there is a deficiency in the other. Of course, from medical point of view meiotic non-disjunctions are more important as these lead to defective gametes, and finally to affected offspring.
In the case of mitotic non-disjunction, it is crucial, when and in which cell type’s division occurs. The early non-disjunction, eventually involving many cells / tissues leads to severe consequences (mosaicism).
The meiotic non-disjunctions are grouped according to when they occur – in the first or in the second meiotic division. In the first meiotic non-disjunction, some pairs of homologous chromosomes are not segregated, whereas in the second meiotic non-disjunction - as in mitotic non-non-disjunctions the sister chromatids are not separated.
These have different consequences accordingly.
Following the first meiotic non-disjunction all four progeny cells - in spermatogenesis the four sperms - will have an abnormal chromosome set – will be aneuploid. Two is with an additional chromosome (n+1); two is without one (n-1).
In the second meiotic non-disjunction only the half of the daughter cells are affected.
They will also be with an extra or an absent chromosome.
The fusion of such abnormal gamete with a normal one results in trisomic or monosomic zygote.
In the case of trisomies there is difference in the origin of the three homologues depending on in which meiotic division the mutation took place. Trisomies derived from the first meiotic division all three homologues are of different origin (e.g. one is from the maternal grandmother, the other is from the maternal grandfather, and the third is inherited from the father). However, in trisomies from the second meiotic non- disjunction two homologues are identical (e.g. either from the maternal grandmother or from the maternal grandfather) and only the third comes from the other parent, from the father. 70% of the human aneuploid chromosome mutations are derived from the first and 30% from of the second meiotic non-disjunction.
So most of the meiotic non-disjunctions occur during the first meiotic division and are of maternal origin. The frequency of maternal non-disjunctions and the aneuploid offspring (like Down syndrome) - increases with maternal age (Figure 3.7).
The reason of this lies in the characteristics of female gametogenesis: probably the aging of the synaptonemal complex, which reduces the chance of co-segregation of homologues leads to the formation of gametes with abnormal chromosome number.
This is why above a certain maternal age (35-40) prenatal tests are recommended or required, to determine whether a fetus carries a numerical chromosome aberration or not.
Figure 3.7.. Rate of meiotic non-disjunctions in function of maternal age.
Source: http://9e.devbio.com/article.php?id=189; 29/07/2013.
3.2.3. The most common numerical chromosomal abnormalities
All chromosome trisomies except the one of the largest human chromosome (chromosome 1) were found in spontaneously aborted fetuses, among live born three autosomal trisomies and some involving sex chromosomes occur (Figure 3.8). Two things are suggested by this: first, the fate of trisomies is strongly dependent on the number and type and function of genes present in the chromosome, on the other hand there is a strong intrauterine selection, so the most severely affected fetuses die in utero.
These are confirmed by the fact that in spontaneously aborted fetuses the most common abnormalitiy is the trisomy 16, which although affects a relatively small chromosome, is never found in live born! All the monosomies, with the exception of the X chromosomal monosomy are incompatible with life.
Figure 3.8. Autosomal numerical chromosome aberrations.
Source: https://www.landesbioscience.com/curie/images/chapters/Levy_1.jpg;
29/07/2013.
50 Genetics and genomics
3.2.3.1. Trisomy 21
Trisomy 21 is the cause of Down syndrome. Although the non-disjunction of chromosome 21 is not the only cause of Down syndrome - a smaller proportion of the cases is due to either centric fusion or translocation - it is the most common type.
Despite the fact that trisomy 21 fetuses die in utero the average population frequency of Down syndrome is 1:650, but this value increases dramatically with maternal age, at 45 years of age it is more than 1:100!
Although today live-born trisomy 21 patients have more or less the same life expectancy than healthy individuals, but the leukemia and some other disease prevalence is higher among them than in the general population. In recent decades, there is a significant change in the social status of Down syndromic individuals, whereas before they were excommunicated, teaching them was thought to be impossible, now increasing efforts have been made to facilitate their social integration (e.g. special kindergartens, in many countries they are taught together with healthy children in public school classes, sporting events etc.).
3.2.3.2. Trisomy 13
Trisomy 13 is the Patau syndrome. Similar to Down syndrome it is most commonly derived from maternal non-disjunction. 65% of such non-disjunctions derived from the first meiotic division. Frequency of birth is 1:12 500 - 1:21 700. Only <5% of these infants survive the first year of life.
3.2.3.3. Trisomy 18
Trisomy 18 is the Edwards syndrome. It is primarily due to maternal non-disjunction.
95%! of the cases are due to non-disjunction in the first meiotic division. The frequency is 1:6000 -1:10 000 live-born but the frequency at the time of conception can be much higher, since approx. 95% of the fetuses die within the womb. 30% of the Edwards syndromic abnormal newborns die within one month, > 95% of them die within a year.
3.2.4. Numerical sex chromosome aberrations
3.2.4.1. Turner syndrome
The Turner syndrome is characterized by 45,X0 karyotype. This is the only viable monosomy. The explanation for this lies in the fact that while both homologues of the autosomes are necessary to the normal phenotype - so their monosomy is lethal – by contrast in females only one X chromosome is active (see the dose compensation in X inactivation), so a functional monosomy and Barr body negativity can be maintained.
However, for the normal development of female sex characteristics both X chromosome is needed, as indicated by the symptoms of Turner syndrome.
Although the frequency is 1:5000 in newborn female infants, the conception rate is much higher, but 99% of them spontaneously abort. This is in good agreement with the concepts of the viability of monosomies. 80% of these cases are due to paternal meiotic non-disjunctions, therefore in these patients only one maternal X chromosome is present.
While it is easy to understand the sexual development related characteristics of the syndrome, the low height is still not fully explained. It is assumed that a gene coding a protein of the small ribosome subunit (RPS4X) may also play a role. Because this gene has a Y chromosomal counterpart (RPS4Y) as well, both in normal females and males double dose of this ribosomal protein is produced. In Turner syndromic individuals less than sufficient amount is produced, and if the ribosome number is less than normal it
will largely influence the production of other proteins, and thus indirectly the body height, too.
Although Turner syndrome is often characterized by normal intelligence there is a difference in verbal skills, social integration between patients inherited their X chromosome from father or the mother. Maternal X carriers, according to surveys are weaker in these features than the patients inherited paternal X. The phenomenon is explained by the different methylation of the two types X chromosomes and the genomic imprinting.
3.2.4.2. Klinefelter syndrome
Klinefelter syndrome is characterised by 47,XXY karyotype and male phenotype. The frequency is 1:1000. Nearly it is derived with the same probability from maternal (56%) and paternal (44%) non-disjunction. 36% of the maternal non-disjunctions take place in the first meiotic division. Since there are two X chromosomes, thus they are Barr body positive. Their sterility can also be attributed to presence of 2 X chromosomes, since certain X chromosomal gene products are in a higher dose than in normal fertile males.
3.2.4.3. Triple X syndrome
Feminine phenotype and 47, XXX karyotype are present. 89% is of maternal, 8% is of paternal origin, and the remaining 3% is due to post-fertilization mitotic non-disjunction. Neonatal frequency is 1:1000. Two Barr bodies are typical.
3.2.4.4. Double-Y syndrome, "superman" or Jacobs syndrome
In this case normal, slightly taller than the average males have 47,XYY karyotype.
The birth rate is 1:1000. They derived only from paternal second meiotic non-disjunction. In contrast to all meiotic non-disjunctions, the formation is not affected by age, as paternal gametogenesis is continuous from puberty, there are no aged sperms.
They are also featured by poorly tolerated frustration and stronger aggressivity;
perhaps that is why this chromosome abnormality is found in greater numbers amongst imprisoned men. The aggressiveness and the possible criminal tendency are strongly debated, and it would only be 100% decided if the entire male population would be karyotyped and comparative data about their aggressivity would have been available as well. Today many different aggressiveness associated genes and gene mutations are known, that is why the role of the Y chromosome in aggressiveness is questioned.
Knowing the characteristics of meiotic division we could ask that the two aneuploidies (47,XXX and 47,XYY) with normal fertility are characterized by greater prevalence of similar disorders among offspring or not. For example, in the case of double Y syndrome the following karyotypes offspring are expected in the offspring: 2 XXY, 2 XY, 1 XX and 1 XYY. In contrast, birth of only normal offspring was reported so far, however its exact explanation is still not known.