46 is the norm?
Counting chromosomes: how much does a person need for happiness
Polina Loseva, "The Attic"
Unlike teeth, a person is supposed to have a strictly defined number of chromosomes – 46 pieces. However, upon closer examination, it turns out that each of us may be a carrier of extra chromosomes. Where do they come from, where do they hide and what harm (or maybe benefit?) – let's deal with the participation of modern scientific literature
Subsistence optimum
First, let's agree on the terminology. Finally, human chromosomes were counted a little more than half a century ago – in 1956. Since then, we know that in somatic, that is, not germ cells, there are usually 46 pieces – 23 pairs.
Chromosomes in a pair (one received from the father, the other from the mother) are called homologous. They contain genes that perform the same functions, but often differ in structure. The exception is the sex chromosomes – X and Y, the gene composition of which does not completely coincide. All other chromosomes, except sex chromosomes, are called autosomes.
The number of sets of homologous chromosomes – ploidy – in germ cells is one, and in somatic cells, as a rule, two.
Interestingly, not all mammalian species have a constant number of chromosomes. For example, some representatives of rodents, dogs and deer were found to have so-called B-chromosomes. These are small additional chromosomes in which there are practically no sites encoding proteins, but they are divided and inherited together with the main set and, as a rule, do not affect the functioning of the body. It is believed that B chromosomes are simply doubled DNA fragments "parasitizing" on the main genome.
No B chromosomes have been detected in humans so far. But sometimes there is an additional set of chromosomes in the cells – then they talk about polyploidy, and if their number is not a multiple of 23 – about aneuploidy. Polyploidy occurs in certain types of cells and contributes to their enhanced work, while aneuploidy usually indicates violations in the work of the cell and often leads to its death.
We must share honestly
Most often, the wrong number of chromosomes is a consequence of unsuccessful cell division. In somatic cells, after DNA doubling, the maternal chromosome and its copy are linked together by cohesin proteins. Then kinetochore protein complexes sit on their central parts, to which microtubules are later attached. When dividing by microtubules, the kinetochores disperse to different poles of the cell and pull the chromosomes with them. If the crosslinking between copies of the chromosome collapses ahead of time, then microtubules from the same pole can attach to them, and then one of the daughter cells will receive an extra chromosome, and the second will remain deprived.
Division during the formation of germ cells (meiosis) is more complicated. After DNA doubling, each chromosome and its copy, as usual, are cross-linked by cohesins. Then homologous chromosomes (obtained from the father and mother), or rather their pairs, also interlock with each other, and the so-called tetrad, or four, is obtained. And then the cell will have to share twice. During the first division, homologous chromosomes diverge, that is, daughter cells contain pairs of identical chromosomes. And in the second division, these pairs diverge, and as a result, the germ cells carry a single set of chromosomes.
Meiosis also often passes with errors. The problem is that the construction of two pairs of homologous chromosomes linked together can twist in space or separate in the wrong places. The result will again be an uneven distribution of chromosomes. Sometimes the germ cell manages to track this so as not to pass on the defect by inheritance. Extra chromosomes are often incorrectly stacked or torn, which triggers a death program. For example, among spermatozoa, there is such a selection by quality. But the eggs were less lucky. All of them are formed in a person before birth, are preparing for division, and then freeze. Chromosomes have already been doubled, tetrads have been formed, and division has been postponed. In this form, they live until the reproductive period. Then the eggs mature in turn, divide for the first time and freeze again. The second division occurs immediately after fertilization. And at this stage, it is already difficult to control the quality of the division. And the risks are greater, because the four chromosomes in the egg remain stitched for decades. During this time, breakdowns accumulate in cohesins, and chromosomes can spontaneously separate. Therefore, the older a woman is, the more likely it is that the chromosomes in the egg are incorrectly diverged.
Scheme of meiosis
Aneuploidy in the germ cells inevitably leads to aneuploidy of the embryo. When a healthy egg with 23 chromosomes is fertilized by a sperm with an extra or missing chromosome (or vice versa), the number of chromosomes in the zygote will obviously be different from 46. But even if the germ cells are healthy, this does not guarantee healthy development. In the first days after fertilization, the cells of the embryo actively divide in order to quickly gain cell mass. Apparently, during rapid divisions there is no time to check the correctness of the chromosome divergence, so aneuploid cells may occur. And if an error occurs, then the further fate of the embryo depends on the division in which it happened. If the balance is disturbed already in the first division of the zygote, then the whole organism will grow aneuploid. If the problem occurred later, the outcome is determined by the ratio of healthy and abnormal cells.
Some of the latter may continue to die, and we will never know about their existence. Or it can take part in the development of the organism, and then it will turn out to be mosaic – different cells will carry different genetic material. Mosaicism causes a lot of trouble to prenatal diagnosticians. For example, at the risk of having a child with Down syndrome, one or more embryo cells are sometimes extracted (at a stage when it should not be dangerous) and chromosomes are counted in them. But if the embryo is mosaic, then this method becomes not particularly effective.
The third extra
All cases of aneuploidy logically fall into two groups: lack and excess of chromosomes. The problems that arise with a shortage are quite expected: minus one chromosome means minus hundreds of genes.
If the homologous chromosome is working normally, then the cell can only get off with an insufficient number of proteins encoded there. But if some genes do not work among the genes remaining on the homologous chromosome, then the corresponding proteins will not appear at all in the cell.
In the case of an excess of chromosomes, everything is not so obvious. There are more genes, but here – alas – more does not mean better.
Firstly, excess genetic material increases the load on the nucleus: an additional strand of DNA needs to be placed in the nucleus and serviced by information reading systems.
The location of chromosomes in the nucleus of a human cell (chromosomal territories).
Image: Bolzer et al., 2005 / Wikimedia Commons / CC BY 2.5
Scientists have found that in people with Down syndrome, whose cells carry an additional 21st chromosome, the work of genes located on other chromosomes is mainly disrupted. Apparently, the excess of DNA in the nucleus leads to the fact that there are not enough proteins that support the work of chromosomes at all.
Secondly, the balance in the number of cellular proteins is disturbed. For example, if activator proteins and inhibitor proteins are responsible for some process in a cell and their ratio usually depends on external signals, then an additional dose of one or the other will cause the cell to stop responding adequately to an external signal. And finally, aneuploid cells have an increasing chance of dying. When DNA is doubled before division, errors inevitably occur, and the cellular proteins of the repair system recognize them, repair them and start doubling again. If there are too many chromosomes, then there are not enough proteins, errors accumulate and apoptosis is triggered – programmed cell death. But even if the cell does not die and divides, then the result of such division is also likely to be aneuploids.
Will you live
If even within a single cell aneuploidy is fraught with malfunctions and death, it is not surprising that it is not easy for an entire aneuploid organism to survive. At the moment, only three autosomes are known – the 13th, 18th and 21st, the trisomy for which (that is, the extra, third chromosome in cells) is somehow compatible with life. This is probably due to the fact that they are the smallest and carry the least genes. At the same time, children with trisomy on the 13th (Patau syndrome) and 18th (Edwards syndrome) chromosomes live up to 10 years at best, and more often live less than a year. And only a trisomy on the smallest in the genome, the 21st chromosome, known as Down syndrome, allows you to live up to 60 years.
It is very rare to meet people with general polyploidy. Normally, polyploid cells (carrying not two, but from four to 128 sets of chromosomes) can be found in the human body, for example, in the liver or red bone marrow. These are usually large cells with enhanced protein synthesis that do not require active division.
An additional set of chromosomes complicates the task of distributing them to daughter cells, so polyploid embryos, as a rule, do not survive. Nevertheless, about 10 cases have been described when children with 92 chromosomes (tetraploids) were born and lived from several hours to several years. However, as in the case of other chromosomal abnormalities, they lagged behind in development, including mental. However, mosaicism comes to the aid of many people with genetic abnormalities. If the anomaly has already developed during the crushing of the embryo, then a certain number of cells may remain healthy. In such cases, the severity of symptoms decreases, and life expectancy increases.
Gender injustices
However, there are also such chromosomes, the increase in the number of which is compatible with human life or even goes unnoticed. And these, surprisingly enough, are sex chromosomes. The reason for this is gender injustice: about half of the people in our population (girls) have twice as many X chromosomes as others (boys). At the same time, X chromosomes serve not only to determine sex, but also carry more than 800 genes (that is, twice as many as the extra 21st chromosome, which causes a lot of trouble to the body). But the girls come to the aid of a natural mechanism for eliminating inequality: one of the X chromosomes is inactivated, twisted and turns into a Barr body. In most cases, the choice is random, and as a result, the maternal X chromosome is active in some cells, and the paternal one in others. Thus, all the girls turn out to be mosaic, because different copies of genes work in different cells. A classic example of this mosaic is tortoiseshell cats: on their X chromosome there is a gene responsible for melanin (a pigment that determines, among other things, the color of the coat). Different copies work in different cells, so the coloration turns out to be spotty and is not inherited, since inactivation occurs randomly.
A tortoiseshell cat.
Photo: Lisa Ann Yount / Flickr / Public domain
As a result of inactivation, only one X chromosome always works in human cells. This mechanism allows you to avoid serious troubles with X-trisomy (girls XXX) and Shereshevsky –Turner syndromes (girls XO) or Kleinfelter (boys XU). About one in 400 children is born this way, but vital functions in these cases are usually not significantly impaired, and even infertility does not always occur. It is more difficult for those who have more than three chromosomes. This usually means that the chromosomes did not diverge twice during the formation of germ cells. Cases of tetrasomy (XXXX, XXUU, XXXX, XYYY) and pentasomy (XXXXX, XXXXY, XXXYY, XXYYY, XYYYY) are rare, some of them have been described only a few times in the history of medicine. All these options are compatible with life, and people often live to old age, while deviations manifest themselves in abnormal skeletal development, genital defects and a decrease in mental abilities. Tellingly, the additional Y chromosome itself does not affect the body's work much. Many men with the XYY genotype do not even know about their peculiarity. This is due to the fact that the Y chromosome is much smaller than X and almost does not carry genes that affect viability.
Sex chromosomes have another interesting feature. Many mutations of genes located on autosomes lead to abnormalities in the work of many tissues and organs. At the same time, most mutations of genes on the sex chromosomes are manifested only in a violation of mental activity. It turns out that to a significant extent, sex chromosomes control the development of the brain. Based on this, some scientists hypothesize that they are responsible for the differences (however, not fully confirmed) between the mental abilities of men and women.
Who benefits from being wrong
Despite the fact that medicine has been familiar with chromosomal abnormalities for a long time, recently aneuploidy continues to attract the attention of scientists. It turned out that more than 80% of tumor cells contain an unusual number of chromosomes. On the one hand, the reason for this may be the fact that proteins that control the quality of division are able to slow it down. In tumor cells, these same control proteins often mutate, so restrictions on division are removed and chromosome verification does not work. On the other hand, scientists believe that this may serve as a factor in the selection of tumors for survival. According to this model, tumor cells first become polyploid, and then, as a result of division errors, they lose different chromosomes or parts of them. It turns out a whole population of cells with a wide variety of chromosomal abnormalities. Most of them are not viable, but some may accidentally be successful, for example, if they accidentally receive additional copies of genes that trigger division, or lose genes that suppress it. However, if you additionally stimulate the accumulation of errors during division, the cells will not survive. The action of taxol, a common cancer drug, is based on this principle: it causes a systemic non–divergence of chromosomes in tumor cells, which should trigger their programmed death.
It turns out that each of us can be a carrier of extra chromosomes, at least in individual cells. However, modern science continues to develop strategies to combat these unwanted passengers. One of them suggests using proteins responsible for the X chromosome and inciting, for example, people with Down syndrome to the extra 21st chromosome. It is reported that this mechanism has been activated in cell cultures. So, perhaps, in the foreseeable future, dangerous extra chromosomes will be tamed and neutralized.
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