How chromosomes are involved in embryo development. Chromosomal diseases. Phenotypic manifestations of some lethal chromosomal aberrations

A man was born! From this day the countdown will begin for months, years, decades of his life. But after all, before the birth of a future man, for nine whole months he lives and develops in the mother’s womb! And the health of the unborn child, its physical and mental abilities, largely depend on how the intrauterine period proceeds.

A person’s life begins at the moment when two reproductive cells merge together in the mother’s body: a female - an egg and a male -. At the same time, 23 paternal and 23 maternal chromosomes are found in the nucleus of the formed new cell - zygotes. These material carriers of hereditary information form the genetic apparatus of a new person who will henceforth control the individual development of his body. Chromosomes also determine the gender of the unborn child. Or rather, it is determined by the 23rd sex chromosome of the father.

As you know, in women, sex chromosomes are the same (XX), so the egg always carries the X chromosome. But options are possible. Indeed, in men in the genetic apparatus, cells in the 23rd pair can contain both XX and XU chromosomes. Therefore, approximately half of the mature ones carry the X chromosome, and the other half carry the U chromosome. And if the carrier of the X chromosome merges with the egg, the girl will develop, and when the carrier of the U chromosome is involved in fertilization, then it’s a boy. Thus, the gender of the unborn child, as they say, depends on the man.

So, the sex cells of the parents merged together. Then for some time - from 15 minutes to several hours - nothing happens and the future person remains a unicellular organism, such as an amoeba. Finally, 2 are formed from one cell, then 4, 5, 7, 8 ... 16 ... The rate of division increases, but the cells divide asynchronously, that is, not all at once, forming either an even or an odd number.

In this period, when the sufficiently large first cells are in close contact with each other, the embryo is most similar to a mulberry. It is called - morula (from the Latin morus - mulberry). This “berry”, continuing to divide, slowly moves along the oviduct to the place where it is destined to settle for a long nine months - to the uterus. The whole first week takes this path. Towards its end, the morula ceases to be a berry and turns into a bubble: a dense cell mass is divided into an embryonic nodule and the surface layer of cells surrounding this nodule.

In this form, the fetus enters the uterus. Since by this time he manages to almost completely use up that small supply of nutrients that was stored for him in the egg, the embryo hurries to attach itself to the wall of the uterus in order to receive oxygen and nutrition from the mother’s body. He does this with the help of his outer cells. Part of them forms the shell of the fetus, protecting it from various adverse effects. And other external cells grow, like plants with roots, into the uterine mucosa. There they grow rapidly and branch strongly. Inside the branches, small blood vessels pass through the umbilical cord to the fetus. This forms the placenta, or child's place, - the organ of communication of the fetus and mother.

The placenta provides the fetus with oxygen and nutrients. Through the placenta, unnecessary, waste substances are eliminated from the body. It serves as a barrier, prevents the passage of chemically harmful substances into the bloodstream of the embryo. It is the placenta that protects the fetus from the penetration of pathogenic microbes if the mother becomes ill. Its role is so important and diverse that experts even say that violations of the placenta can make ordinary Einstein an ordinary mediocrity, despite all the hereditary inclinations. Damage to the placenta, its detachment most often threatens the fetus with death.

Simultaneously with the child's place, the umbilical cord arises and gradually increases. Through her blood vessels, the blood of the fetus flows to a child's place. There, saturated with oxygen and nutrients and cleansed of unnecessary, waste products of vital activity, blood returns again to the embryo.
   Amniotic fluid is located between the embryo and the surrounding thin membrane. Absorbed and formed again, they contribute to the metabolism of the embryo. And besides, they protect him from the uneven pressure of the walls of the uterus, which could disrupt the shape of the developing organs.
But what happens at this time with the embryo itself? Its development does not stop even for a second: it is necessary to hurry, because in a matter of weeks he will have to follow the path of evolutionary development, which nature, creating man, has gone for millions of years.

During the second week after fertilization, the cells of the germinal nodule are split into two layers, and then in the third week a third layer appears between them. These are the so-called embryonic leaves: strictly defined organs and tissues will subsequently develop from each leaf. At the same time as the middle leaf, a chord-skeletal cord is laid along the midline from the side of the embryo's back. Over time, a spine forms at the site of the chord.

In the middle of the third week, the first blood vessels appear in the embryo. And about three days after their appearance, the heart will begin to form. Surprisingly, in a 23-day-old embryo, it has the shape of a tube, but is already shrinking! The heart works and simultaneously creates itself - its cavities, intra-cardiac septa, valves are formed.

At this time, the arterial and venous system of blood vessels is already functioning. But the path of blood flow in the embryo is different than in the newborn. After all, until the moment of birth, the lungs do not work, and oxygen is delivered along with the blood through the umbilical cord. Only after birth, when the umbilical cord is cut, the direction of blood flow changes and the pulmonary circulation begins to function. Then the vessels directing blood to the umbilical cord and back will die. True, this is not soon, because only the first month has passed.

Only a month, but the heart is already contracting and blood is flowing through the blood vessels, already in three germ layers the prototypes of future organs are lurking ... But future diseases often also have their roots in these first days, because it is during this period that the embryo is extremely sensitive to any kind of adverse effects, damaging factors. And such a "damaging factor" for him can be any trifle, in your opinion - a little dry wine, one - three cigarettes, a sleeping pill ... Think about it and try to exclude from your very first day everything that could harm your unborn baby!

The sex of the fetus is determined by fertilization; however, structural differentiation of the sexes occurs only at the seventh week of fetal development. It is possible that for some time the gonads have the potency of both sexes. At some point, the presence or absence of a full-fledged Υ-chromosome is apparently of critical importance. In the presence of the хром chromosome, the gonads develop into the testes. Otherwise, ovaries form. Having arisen in the embryo, the testes begin to secrete hormones, the action of which causes the development of the remaining signs of the male sex. A. Jost was able to find out that male characters develop in the embryos of rabbits only after the formation of testes. For the occurrence of female sexual characteristics, the ovaries are not required and may even be completely absent.

It seems that the function of human sex chromosomes is reduced to directing the development of the embryo along the path of formation of either the female or male organism. Further differentiation occurs already under the influence of hormones. In the event of a malfunction of the guide mechanism, disturbances in the synthesis of hormones and abnormalities in the sexual characteristics of the developing embryo occur.

The discovered relationship between deviations in sexual development and chromosomal abnormalities provides a key to understanding the mechanism for determining sex. Many deviations appear as a result of random disturbances in the normal course of the formation of an egg or sperm, taking part in the creation of a new organism. As a rule, two sex chromosomes of each pair are separated even before the appearance of the germ cell. In the vast majority of cases, this divergence of chromosomes proceeds unhindered. However, sometimes chromosomes do not diverge. It is possible that the cause of Klinefelter and Turner syndromes is the non-divergence of chromosomes in the germ cells of one of the parents (Figs. 8 and 9). If such a discrepancy occurred in the maternal organism, then a female organism with three X chromosomes may appear (see Fig. 9). Theoretically, even the formation of a fertilized egg without the X chromosomes, with the Υ chromosome alone, is possible, but such a case has never been detected. Obviously, for the normal functioning of cells, at least one X chromosome is required, without which the embryos die. Finally, an egg or sperm that does not contain sex chromosomes at all can appear if, during cell division, the X- or двиг-chromosome moved too slowly and did not manage to get into one of the daughter cells. A similar loss of the chromosome can also be the cause of Turner syndrome.

Deviations occur not only during the formation of germ cells, but also during the development of the embryo. In the early stages of embryo development, their cells actively divide: each daughter cell usually receives one half from each longitudinally doubling chromosome. However, it may happen that a cell receives both halves at once or, conversely, does not receive either: such a cell can then give rise to a whole line of cells in which this chromosome will be present in an excess or insufficient number. In an organism developed from such an embryo, the cells will have a heterogeneous chromosome set. Similar "mosaic" organisms are really found among patients with impaired sexual function. Some patients with Klinefelter syndrome have cells with a chromosome set of XX and ΧΧΥ, while others have ΧΥ and ΧΧΥ. Similarly, some women with Turner syndrome contain cells XX and X, and others XXX and X. The number of possible combinations is large, and researchers are finding more and more new combinations.

Studies of human sex differences at the cell level are developing rapidly. The successes achieved so recently have already brought the first fruits in medicine, helping to establish the physical cause of a number of diseases that remained previously inexplicable. Further achievements will shed light on the nature of the most insignificant deviations from the norm. The next step will be the cure or prevention of such disorders, which will undoubtedly come, although not tomorrow. There is a special appeal in these new data on the relationship between the cellular structures that are visible under the microscope and the characteristics of the two sexes, unless, of course, you agree with Hamlet, who is “not interested in men, and women, too.”

TBegin -\u003e
TEnd -\u003e

Fig. 8. Nondisjunction, that is, the inability of homologous chromosomes to disperse in the process of cell division, can cause sexual dysfunctions. The diagram shows the possible consequences of such a discrepancy in the formation of spermatozoa: a fertilized egg will receive either two X chromosomes and one Υ chromosome, or only one X chromosome. In both cases, there will be known manifestations of intersexuality.

TBegin -\u003e
TEnd -\u003e

Fig. 9. Non-divergence of the chromosomes of the mother’s body will lead to the formation of eggs with either two X chromosomes, or without them at all. Depending on which sperm they are fertilized, such eggs can give rise to the body with any of the four possible chromosome sets.

Ministry of Education of the Russian Federation

Cheboksary City Department of Education

MOU "Cadet School"

Abstract on the topic:

Human embryo development

Completed: cadet 9 "A" class

Ivanov K.

Checked: Nardina S.A.

Cheboksary 2004

What does a child look like at the very beginning of his life - in his mother’s stomach?

This is an egg, in other words, a cell. It consists, like all cells of the human body, of a droplet of matter - protoplasm with a core in the middle. This is a very large cell almost visible to the naked eye, the size of one tenth of a millimeter.

This occurs as a result of the connection of two cells: the male cell, or sperm, and the female, the egg. The egg is a large round-shaped cell. As for the sperm, it is 30 or 40 times smaller - however, without taking into account its long oscillating tail, due to which the sperm moves. Upon contact with the egg, the sperm loses its tail. And its core penetrates the egg. Both nuclei merge, fertilization of the egg occurs; henceforth, it becomes an egg. Each of the cells that make up the egg carries the signs of one of the parents. The carriers of these signs are small, stick-like formations contained in the nuclei of all cells and called chromosomes. The nucleus of each cell in the human body contains 46 chromosomes: 23 from the father and 23 from the mother. The same chromosomes of the father and mother form a pair. Each of us in any cell of the body has 23 pairs of chromosomes that are inherent only to him and determine his individual characteristics; this is why certain traits of our appearance, mind, or character make us look like father and mother, grandparents, or other relatives.

The gender of the child is the result of random selection of chromosomes. First, pay attention to the appearance of chromosomes: their size and shape are different, but in every normal cell there are at least 44 chromosomes, each of which has a similar shape. Grouped in two, they form 22 pairs. They are classified by size: the largest is number 1, and the smallest is number 22. 23 - I pair stands apart. In a woman, she, like everyone else, is formed by two similar chromosomes indicated by the letter X (X). And in men in the 23rd pair there is only one X-chromosome, together with a smaller one indicated by the letter igra (Y).

In the body of parents, an egg or sperm are cells containing only half of the chromosomes, that is, 23 each. Thus, all eggs are of the same type: they all have an X chromosome. Sperm cells are of two types: some of them have the X chromosome under number 23, the others have the Y chromosome. If, by chance, an egg is connected to a sperm carrying the X chromosome, the egg will develop into a girl, and if the case results in the fertilization of the egg with a sperm containing the Y chromosome, then the egg develops into a boy. Thus, sex determination occurs during fertilization.

Theoretically, it would be possible to find out the sex of the child from that moment, if we had the technical means to watch the egg without risking damage to it. Perhaps the day will come when chance will give way to science and parents will choose the sex of their child, in any case, this will happen only if the semen contains X- and Y-sperm. Once formed, the egg begins to divide into two, four, eight, sixteen, etc. cells. After several days, the cells functionally specialize: some on the formation of the senses, others on the intestines, others on the genitals, etc. It is the Y chromosome that tells the sex cells that they have to develop according to the male type. External signs of sex become noticeable at the beginning of the fourth month of pregnancy. But at the chromosomal level, which determines its external manifestations, gender has existed since fertilization. That is why in some cases it is possible to find out the sex of the baby already at the beginning of pregnancy (in the second or third month), due to chromosomal studies of some egg cells (the so-called trophoblast puncture and amniocentesis), or thanks to a kind of radar, which using ultrasound allows you to see a small penis fetus in the maternal uterus.

A fertilized egg moves along the fallopian tube, simultaneously divides and turns into a multicellular embryo, which after 4-5 days enters the uterine cavity. Within 2 days, the embryo remains free in the uterus, then immerses in its mucous membrane and attaches to it. The embryonic period of fetal development begins. Shells form from part of the cells. The outer shell has villi with capillaries. Through the villi, the embryo is nourished and breathed. Inside the villous membrane there is another, thin and transparent, like cellophane. It forms a bubble. An embryo floats in the fluid of the bubble. This shell protects the fetus from shock and noise.

By the end of the 2nd month of intrauterine development, the villi remain only on the side of the germinal membrane that faces the uterus. These villi grow and branch, plunging into the uterine mucosa, abundantly equipped with blood vessels. A placenta develops in the form of a disk firmly fixed in the uterine mucosa. From this moment begins the fetal period of fetal development.

Through the wall of blood capillaries and villi of the placenta, there is an exchange of gases and nutrients between the mother and child. The blood of the mother and the fetus never mixes. From the 4th month of pregnancy, the placenta, performing the role of the endocrine gland, secretes a hormone. Thanks to him, during pregnancy, the uterine mucosa does not exfoliate, menstrual cycles do not occur, and the fetus remains in the uterus throughout pregnancy.

During ovulation and fertilization of two or more eggs, two or more fruits are formed. These are the future twins. They are not very similar to each other. Sometimes two fruits develop from the same egg, often they have one placenta. Such twins are always the same sex and very similar to each other.

The embryo in the uterus develops rapidly. By the end of the first month of fetal development, the embryo’s head is 1/3 of the body length, eye contours appear, fingers can be distinguished at the 7th week. After 2 months, the embryo becomes similar to a person, although its length at this time is 3 cm.

By 3 months of fetal development, almost all organs are formed. By this time, you can determine the gender of the unborn child. By 4.5 months, fetal heart contractions are heard, the frequency of which is 2 times greater than that of the mother. During this period, the fetus grows rapidly and by 5 months weighs about 500 g, and by the time of birth 3-3.5 kg.

LIST OF REFERENCES:

1.Encyclopedia of Blinov I.I. and Karzova S.V. p. 367-369

2. Biology textbook for grade 9, auth. Tsuzmer A.M., Petrishina O.L. pg. 167-172

The composition of the human embryo in the first days of existence

Fertilization of an egg - page 3

The formation of the placenta - page 3

Embryo Development - page 4

References - page 5

Agents from the placenta to the embryo extravascularly and thus performs a protective function. Based on the foregoing, the main features of the early stages of the development of the human embryo can be noted: 1) asynchronous type of complete fragmentation and the formation of “light” and “dark” blastomeres; 2) early isolation and the formation of extra-germ organs; 3) early formation of an amniotic vesicle and ...

The period of the embryo is a two-layer scutellum, consisting of two leaves: the external germinal (ectoderm), and the internal germinal (endoderm). Fig. 2. The position of the embryo and embryonic membranes at different stages of human development: A - 2-3 weeks; B - 4 weeks: 1 - amnion cavity; 2 - the body of the embryo; 3 - yolk sac; 4 - tropholast; B - 6 weeks; G - fetus 4-5 months: 1 - the body of the embryo ...

The problem was discovered by Engels in his work The Role of Labor in the Transformation of a Monkey into a Man, published in 1896, although it was written shortly after the publication of Darwin's Origin of Man. At that time, science had relatively scarce data on the fossil ancestors of man. Later, numerous finds of the remains of bones and tools of fossil people brilliantly confirmed ...

Five cerebral vesicles (cavities with fluid); there are also bulging eyes with lenses and a pigmented retina. In the period from the fifth to the eighth week, the actual embryonic period of intrauterine development ends. During this time, the embryo grows from 5 mm to about 30 mm and begins to resemble a person. Its appearance changes as follows: 1) the bend decreases ...

The human body is a complex system, the activity of which is regulated at various levels. Moreover, certain substances must participate in specific biochemical processes, so that all cells, organs and entire systems can function correctly. And for this, it is necessary to lay the right foundation. Just as a multi-storey building cannot stand without an appropriately prepared foundation, the “building” of the human body requires the correct transmission of hereditary material. It is the genetic code embedded in it that controls the development of the embryo, allows all interactions to form, and determines the normal existence of a person.

However, in some cases errors appear in the hereditary information. They can arise at the level of individual genes or concern their large associations. Such changes are called gene mutations. In some situations, the problem relates to entire chromosomes, that is, to the structural units of the cell. Accordingly, they are called chromosomal mutations. Hereditary diseases that develop as a result of chromosomal abnormalities or chromosome structure are called chromosomal.

Normally, each cell in the body contains the same number of chromosomes paired with the same genes. In humans, the complete set consists of 23 pairs, and only in germ cells instead of 46 chromosomes is half the number. This is necessary so that in the process of fertilization during the fusion of the sperm and egg, a full combination with all the necessary genes is obtained. Genes are distributed on the chromosomes not by chance, but in a strictly defined order. In this case, the linear sequence remains the same for all people.

However, various “mistakes” can occur during the formation of germ cells. As a result of mutations, the number of chromosomes or their structure changes. For this reason, after fertilization in the egg, there may be an excess or, conversely, an insufficient amount of chromosomal material. Due to the imbalance, the process of embryo development is disrupted, which can lead to spontaneous abortion, the birth of a dead child, or the development of a hereditary chromosomal disease.

Etiology of chromosomal diseases

The etiological factors of chromosomal pathologies include all varieties of chromosomal mutations. In addition, some genomic mutations are also capable of exerting a similar effect.

In humans, deletions, duplications, translocations and inversions occur, that is, all types of mutations. When deletion and duplication of genetic information is in insufficient and excessive quantities, respectively. Since modern methods can detect the absence of even a small part of the genetic material (at the gene level), it is almost impossible to draw a clear line between gene and chromosomal diseases.

Translocations are the exchange of genetic material that occurs between individual chromosomes. In other words, a portion of the genetic sequence is moved to a non-homologous chromosome. Among translocations, two important groups are distinguished - reciprocal and Robertson.

Reciprocal translocations without loss of involved sites are called balanced. They, like inversions, do not cause loss of gene information, and therefore do not lead to pathological effects. Nevertheless, with the further participation of such chromosomes in the process of crossing over and reduction, gametes with unbalanced sets with an insufficient set of genes can form. Their participation in the process of fertilization leads to the fact that the offspring develop certain hereditary syndromes.

Robertson translocations are characterized by the participation of two acrocentric chromosomes. During the process, short shoulders are lost, and long ones are preserved. Of the 2 initial chromosomes, one whole, metacentric, is formed. Despite the loss of part of the genetic material, the development of pathologies in this case usually does not occur, since the functions of the lost sites are compensated by similar genes in the remaining 8 acrocentric chromosomes.

With terminal deletions (that is, with their loss), an annular chromosome can form. At its carrier, which received such gene material from one of the parents, a partial monosomy at the terminal sections is noted. Upon rupture through the centromere, an isochromosome can be formed that has shoulders that are identical in the set of genes (they differ in the ordinary chromosome).

In some cases, homogenous dysomy may develop. It occurs if trisomy occurs during non-divergence of chromosomes and fertilization, and then one of the three chromosomes is deleted. The mechanism of this phenomenon has not yet been studied. However, as a result, two copies of the chromosome of one parent will appear in the chromosome set, while some of the gene information from the second parent will be lost.

The variety of chromosome distortion variants causes various forms of disease.

There are three basic principles that allow you to accurately classify the resulting chromosomal pathology. Their observance provides an unambiguous indication of the deviation form.

According to the first principle, it is necessary to determine the characteristics of the mutation, gene or chromosome, and it is also required to clearly indicate the specific chromosome. For example, it can be a simple trisomy on the 21st chromosome or triploidy. The combination of an individual chromosome and the type of mutation determines the forms of chromosomal pathology. Due to the observance of this principle, it is possible to precisely determine in which structural unit there are changes, as well as to find out whether an excess or deficiency of chromosome material is recorded. This approach is more effective than classification by clinical features, since many deviations cause similar disorders in the development of the body.

According to the second principle, it is necessary to determine the type of cells in which the mutation occurred - zygote or gamete. Mutations in gametes lead to the appearance of complete forms of a chromosomal disease. Each cell of the body will contain a copy of the genetic material with a chromosomal abnormality. If the violation occurs later, at the zygote stage or during crushing, the mutation is classified as somatic. In this case, part of the cells receives the original genetic material, and part - with an altered chromosome set. At the same time, two or more types of sets may be present in the body. Their combination resembles a mosaic, therefore this form of the disease is called mosaic. If more than 10% of cells with a modified chromosome set are present in the body, the clinical picture repeats the full form.

According to the third principle, the generation in which the mutation appeared for the first time is revealed. If a change was noted in the gametes of healthy parents, then they speak of a sporadic case. If it already existed in the maternal or paternal organism, then we are talking about the heritable form. A significant part of inherited chromosomal diseases is caused by Robertson translocations, inversions, and balanced reciprocal translocations. In the process of meiosis, they can lead to the formation of a pathological combination.

A complete accurate diagnosis implies that the type of mutation, the affected chromosome is established, the full or mosaic nature of the disease is clarified, and inheritance transmission or sporadic occurrence is established. The necessary data can be obtained during genetic diagnostics using samples of the patient, and in some cases, his relatives.

General issues

The intensive development of genetics over the past decades has allowed the development of a separate area of \u200b\u200bchromosomal pathology, which is gradually becoming increasingly important. This area includes not only chromosomal diseases, but also various disorders during fetal development (for example, miscarriages). Currently, the anomaly count is already at 1000. Over a hundred forms are characterized by a clinically defined picture and are called syndromes.

There are several groups of diseases. Triploidy is a case in which there is an extra copy of the genome in the cells of the body. If a duplicate of only one chromosome appears, then such a disease is called trisomy. Also, the causes of the abnormal development of the body can be deletions (remote areas of the genetic code), duplications (respectively, extra copies of genes or their groups) and other defects. The English doctor L. Down in 1866 described one of the most famous diseases of this kind. The syndrome, which received his name, develops in the presence of an extra copy of chromosome 21 (trisomy-21). Trisomies on other chromosomes, as a rule, end in miscarriages or lead to death in childhood due to serious developmental disorders.

Later, cases of monosomy on the X chromosome were discovered. In 1925, Shereshevsky N.A. and in 1938 Turner G. described his symptoms. Trisomy-XXY, which occurs in men, was described by Klinefelter in 1942.

These cases of disease were the first objects of research in this area. After the etiology of the three listed syndromes was deciphered, the direction of chromosomal diseases actually appeared. During the 60s, further cytogenetic studies led to the formation of clinical cytogenetics. Scientists have proven the relationship between pathological abnormalities and chromosomal mutations, and also received statistics on the frequency of mutations in newborns and in cases of spontaneous abortion.

Types of chromosomal abnormalities

Chromosomal abnormalities can be both relatively large and small. Research methods vary depending on their size. For example, for point mutations, deletions, and duplications involving sites of a hundred nucleotides long, detection with a microscope is not possible. Determining a chromosomal disorder using the differential staining method is possible only if the value of the affected area is calculated in millions of nucleotides. Small mutations can be detected only by establishing the nucleotide sequence. As a rule, large violations (for example, visible through a microscope) lead to a more pronounced effect on the functioning of the body. In addition, the anomaly can affect not only the gene, but also the site of hereditary material, the functions of which are not currently studied.

Monosomy is an abnormality expressed in the absence of one of the chromosomes. The opposite is trisomy — adding an extra copy of the chromosome to a standard set of 23 pairs. Accordingly, the number of copies of genes, which are normally present in two copies, also changes. With monosomy, a lack of gene is noted, with trisomy, there is an excess of it. If a chromosomal abnormality leads to a change in the number of individual sites, then they speak of partial trisomy or monosomy (for example, along the shoulder 13q).

Cases of homogeneous disomy are also known. In this case, a pair of homologous chromosomes (or one and a part homologous to it) enters the body from one of the parents. The reason is the unexplored mechanism, presumably consisting of two phases - the formation of trisomy and the removal of one of the three chromosomes. The impact of homogenous disomy can be both minor and noticeable there. The fact is that if in the same chromosomes there is a recessive mutant allele, then it automatically appears. At the same time, the parent from whom the chromosome with the mutation was obtained, due to heterozygosity for the gene, may not have health problems.

Due to the high importance of genetic material for all stages of the development of an organism, even small anomalies can cause serious changes in the coordinated activity of genes. After all, their joint work has been polished over millions of years of evolution. It is not surprising that the consequences of the occurrence of such a mutation, most likely, begin to manifest themselves already at the level of gametes. They especially affect men, since the embryo at some point must go from the female path to the male. If the activity of the corresponding genes is insufficient, various deviations arise, up to hermaphroditism.

The first studies of the effects of chromosomal abnormalities began to be carried out in the 60s, after the chromosome nature of some diseases was established. We can conditionally distinguish two large groups of related effects: congenital malformations and changes that cause fatal outcomes. Modern science has information that chromosomal abnormalities begin to appear already at the zygote stage. In this case, lethal effects are one of the main causes of fetal death in the womb (this indicator in humans is quite high).

Chromosomal aberration is a change in the structure of the chromosomal material. They can either occur sporadically or be inherited. The exact reason why they appear has not been established. Scientists believe that for some part of such mutations, various environmental factors (for example, chemically active substances) that affect the embryo or even the zygote are responsible. An interesting fact is that most of the chromosomal aberrations are usually associated with the chromosomes that the fetus receives from the father.

A significant part of chromosomal aberrations is very rare and was detected once. At the same time, some others are quite common, even among people who are not connected by family ties. For example, translocation of centromeric or close to them regions of 13 and 14 chromosomes is widespread. The loss of inactive chromatin of short shoulders practically does not affect the state of health. With similar Robertsonian translocations, 45 chromosomes fall into the karyotype.

About two-thirds of all chromosomal abnormalities found in newborns are compensated by other copies of the genes. For this reason, they do not pose a serious threat to the normal development of the child. If compensation for the violation is not possible, malformations arise. Often, such an unbalanced anomaly is detected in patients with mental retardation and other congenital malformations, as well as in the fetus after spontaneous abortions.

Compensated anomalies are known that can be inherited from generation to generation without the occurrence of diseases. In some cases, such an anomaly can go into an unbalanced form. So, if there is a translocation affecting the 21 chromosome, the risk of trisomy along it increases. According to statistics, such translocations are available in every 20 children who have trisomy-21, and in every fifth case, one of the parents has a similar violation. Since the majority of children with translocation-induced trisomy-21 are born in young (less than 30 years old) mothers, in case of detection of this disease in a child, a diagnostic examination of young parents is necessary.

The risk of disturbances that are not compensated is highly dependent on translocation; therefore, theoretical calculations are difficult. Nevertheless, it is possible to approximately determine the likelihood of an appropriate pathology based on statistical data. Such information is collected for common translocations. In particular, Robertson translocation between the 14th and 21st chromosomes in the mother with a 2 percent probability leads to trisomy-21 in the child. The same translocation in the father is inherited with a probability of 10%.

The prevalence of chromosomal abnormalities

Research results show that at least a tenth of the eggs after fertilization and about 5-6 percent of the fetuses have various chromosomal abnormalities. As a rule, at 8-11 weeks in this case, spontaneous abortion occurs. In some cases, they cause later miscarriages or lead to the birth of a dead child.

In newborns (according to a survey of more than 65 thousand children), a change in the number of chromosomes or significant chromosomal aberrations occur in about 0.5% of the total. At least every 700th has a trisomy of 13, 18 or 21 chromosomes; about 1 out of 350 boys have an extended set of chromosomes up to 47 units (karyotypes 47, XYY and 47, XXY). Monosomy on the X chromosome is less common - isolated cases of several thousand. About 0.2% have compensated chromosomal aberrations.

In adults, sometimes inherited abnormalities (usually compensated) are also detected, sometimes with trisomy on the sex chromosomes. Studies also show that approximately 10-15 percent of the total number of cases of mental retardation can be explained by the presence of a chromosomal abnormality. This indicator increases significantly if, together with impaired mental development, anatomical defects are observed. Infertility is also often caused by an extra sex chromosome (in men) and monosomy / aberration on the X chromosome (in women).

The relationship of chromosomal abnormalities and malignant tumors

As a rule, the study of cells of malignant neoplasms leads to the detection of chromosomal abnormalities visible in the microscope. Similar results are given by checking for leukemia, lymphoma and a number of other diseases.

In particular, for lymphomas, a frequent case is the detection of translocation, accompanied by a gap inside or near the locus of the immunoglobulin heavy chain (chromosome 14). In this case, the MYC gene moves from chromosome 8 to 14.

For myeloid leukemia in most cases (over 95%), a translocation between 22 and 9 chromosomes is fixed, causing the appearance of a characteristic “Philadelphia” chromosome.

Blast crisis in the process of development is accompanied by the appearance of consecutive chromosomal abnormalities in the karyotype.

By means of differential staining followed by observation under a microscope, as well as using molecular genetic testing methods, chromosomal abnormalities in various leukemia can be detected in a timely manner. This information helps to make a development forecast, it clarifies the diagnosis and adjusts therapy.

For common solid tumors, such as colon cancer, breast cancer, etc. conventional cytogenetic methods are applicable with some limitations. However, their characteristic chromosomal abnormalities have also been identified. Abnormalities in tumors are often associated with genes responsible for normal cell growth. Due to amplification (the formation of multiple copies) of the gene, the formation of small mini-chromosomes in neoplasm cells is sometimes observed.

In some cases, the appearance of a malignant formation causes the loss of a gene, which should provide suppression of proliferation. There may be several reasons: deletions and rupture in the process of translocation are the most frequent. Mutations of this kind are considered recessive, since the presence of even one normal allele usually provides sufficient control over growth. Violations may appear or be inherited. If in the genome there is no normal copy of the gene, then proliferation ceases to depend on regulatory factors.

Thus, the most significant chromosomal abnormalities that affect the onset and growth of malignant neoplasms are the following types:

Translocation, since they can lead to disruption of the normal functioning of the genes responsible for proliferation (or cause their increased work);

Deletions, which, along with other recessive mutations, cause changes in the regulation of cell growth;

Recessive mutations, due to recombination, become homozygous and therefore fully manifest;

Amplifications that stimulate the proliferation of tumor cells.

Identification of these mutations during genetic diagnosis may indicate an increased risk of developing malignant neoplasms.

Known diseases of a chromosome nature

One of the most famous diseases that occur due to the presence of abnormalities in the genetic material is Down syndrome. It is caused by trisomy on the 21st chromosome. A characteristic sign of this disease is a developmental delay. Children experience serious problems while studying at school, often they need an alternative methodology for teaching material. At the same time, physical development disorders are noted - a flat face, enlarged eyes, clinodactyly and others. If such people make significant efforts, they can socialize quite well, even the case of a successful higher education by a man with Down syndrome is known. Patients have an increased risk of developing dementia. This and a number of other reasons leads to a short life expectancy.

Pratau syndrome also belongs to trisomy, only in this case there are three copies of the 13th chromosome. The disease is characterized by multiple malformations, often with polydactyly. In most cases, there is a violation of the central nervous system or its underdevelopment. Often (approximately 80 percent) patients have heart defects. Severe violations lead to high mortality - in the first year of life, up to 95% of children with this diagnosis die. The disease is not amenable to treatment or correction, as a rule, it is only possible to provide a fairly constant control of the human condition.

Another form of trisomy with which children are born refers to the 18th chromosome. The disease in this case is called Edwards syndrome and is characterized by multiple disorders. Bones are deformed, an altered shape of the skull is often observed. The cardiovascular system is usually with malformations, also problems are noted with the respiratory system. As a result, about 60% of children do not live up to 3 months; by 1 year, up to 95% of children with this diagnosis die.

Trisomy on other chromosomes in newborns practically does not occur, since it almost always leads to premature termination of pregnancy. In some cases, a dead child is born.

With violations of the number of sex chromosomes, Shereshevsky-Turner syndrome is associated. Due to abnormalities in the process of chromosome separation, the X chromosome in the female body is lost. As a result, the body does not receive the proper amount of hormones, therefore its development is disrupted. First of all, this applies to the genitals, which develop only partially. Almost always for a woman, this means the impossibility of having children.

In men, a polysomy on the Y or X chromosome leads to the development of Klinefelter syndrome. This disease is characterized by a weak severity of male signs. Often accompanied by gynecomastia, developmental delay is possible. In most cases, early problems with potency and infertility are observed. In this case, as well as for Shereshevsky-Turner syndrome, in vitro fertilization can be a way out.

Thanks to the methods of prenatal diagnosis, it became possible to identify these and other diseases in the fetus during pregnancy. Couples may decide to terminate their pregnancy to try to conceive another baby. If they decide to bear and give birth to a baby, then knowing the features of their genetic material allows you to prepare in advance for certain methods of prevention or treatment.

A karyotype is a systematic set of chromosomes of the nucleus of a cell with its quantitative and qualitative characteristics.

Normal Female Karyotype - 46, XX Normal Male Karyotype - 46, XY

The study of the karyotype is a procedure designed to identify deviations in the structure of the structure and the number of chromosomes.

Indications for karyotyping:

• Multiple congenital malformations accompanied by a clinically abnormal phenotype or dysmorphism
• Mental retardation or developmental retardation
• Violation of sexual differentiation or anomalies of sexual development
• Primary or secondary amenorrhea
• Spermogram abnormalities - azoospermia or severe oligospermia
• Infertility of unknown etiology
• Habitual miscarriage
• Parents of a patient with structural chromosomal abnormalities
• Rebirth of children with chromosomal abnormalities

Unfortunately, with the help of the study of the karyotype, only large structural rearrangements can be determined. In most cases, anomalies in the structure of chromosomes are microdeletions and microduplications invisible under a microscope. However, such changes are well identified by modern molecular cytogenetic methods - fluorescence hybridization (FISH) and chromosome microarray analysis.

The abbreviation FISH stands for fluorescent in situ hybridization - in situ fluorescence hybridization. This is a cytogenetic method that is used to identify and determine the position of a specific DNA sequence on chromosomes. For this, special probes are used - nucleosides connected to fluorophores or some other labels. The visualization of the bound DNA probes is carried out using a fluorescence microscope.

The FISH method allows the study of small chromosomal rearrangements that are not identifiable in a standard karyotype study. However, it has one significant drawback. The probes are specific to only one part of the genome and, as a result, with one study, you can determine the presence or number of copies of only this site (or several using multicolor probes). Therefore, the correct clinical premise is important, and a FISH analysis can only confirm or not confirm the diagnosis.

An alternative to this method is chromosome microarray analysis, which, with the same accuracy, sensitivity and specificity, determines the amount of genetic material in hundreds of thousands (or even millions) of genome points, which makes it possible to diagnose almost all known microdeletion and micro duplication syndromes.

Chromosomal microarray analysis is a molecular cytogenetic method for detecting variations in the number of DNA copies compared to a control sample. When performing this analysis, all clinically significant parts of the genome are examined, which allows the chromosome pathology of the subject to be excluded with maximum accuracy. Thus, pathogenic deletions (disappearance of chromosome sites), duplications (the appearance of additional copies of genetic material), areas with heterozygosity loss, which are important in imprinting diseases, closely related marriages, and autosomal recessive diseases, can be detected.

When chromosome microarray analysis is needed

• As a first-line test for the diagnosis of patients with dysmorphia, congenital malformations, mental retardation / developmental delay, multiple congenital malformations, autism, seizures, or any suspected genomic imbalance.
• As a substitute for karyotype, FISH, and comparative genomic hybridization if microdeletion / microduplication syndrome is suspected.
• As a study to detect unbalanced chromosomal aberrations.
• As an additional diagnostic study for monogenic diseases associated with functional loss of one allele (haplo-deficiency), especially if pathogen mutation cannot be detected during sequencing, and deletion of the entire gene may be the cause.
• To determine the origin of genetic material in case of homogeneous disomy, duplication, deletion.

1 test - 400 syndromes (list)

Introduction to chromosome microarray analysis.

Information for doctors

Choice of material for chromosome microarray analysis

Question 1.
Zygote   (from Greek   Zygotos   - joined together) - a fertilized egg. A diploid cell resulting from the fusion of gametes (sperm and egg) is the initial unicellular stage of embryo development.
Zygote   - unicellular stage of development of a new organism.

Question 2.
In the process of crushing, the cells divide by mitosis. Mitotic division during crushing differs significantly from the reproduction of cells of an adult organism: the mitotic cycle is very short, the cells do not differentiate - they do not use hereditary information. In addition, when crushing, the cytoplasm of the cells does not mix and does not move; no cell growth.

Question 3.
Splitting up   - This is the mitotic division of the zygote. There is no interphase between divisions, and DNA doubling begins in the telophase of the previous division. Also, the growth of the embryo does not occur, that is, the volume of the embryo does not change and is equal to the zygote. Cells formed during crushing are called blastomeres, and the nucleus is called a blastomere. The nature of crushing is determined by the type of egg (Fig. 2.).
The simplest and phylogenetically most ancient type of crushing is the complete uniform crushing of isolecital eggs. The blastula resulting from complete fragmentation is called a coblastula. This is a single-layer blastula with a cavity in the center.
The blastula resulting from complete but uneven crushing has a multilayer blastoderm with a cavity closer to the animal pole and is called an amphiblastula.
Incomplete discoidal fragmentation results in the formation of a blastula, in which the blastomeres are located only at the animal pole, while the vegetative pole consists of an undivided yolk mass. Under the blastoderm layer in the form of a gap is a blastocele. This type of blastula is called a discoblastula.
A particular type of crushing is the incomplete surface crushing of arthropods. Their development begins with repeated fragmentation of the nucleus located in the center of the egg among the vitelline mass. The nuclei formed in this process move to the periphery, where the yolk-poor cytoplasm is located. The latter breaks up into blastomeres, which with their base pass into an undivided central mass. Further crushing leads to the formation of a blastula with one layer of blastomeres on the surface and the yolk inside. Such a blastula is called a periblastula.
In mammalian eggs, there is little yolk. These are alecital or oligolecitic eggs by the number of yolks, and by the distribution of the yolk according to the egg cell, these are homolecytal eggs. Their crushing is complete, but uneven, already in the early stages of crushing, there is a difference in blastomeres in their size and color: light are located on the periphery, dark in the center. The trophoblast surrounding the embryo is formed from light cells, the cells of which perform an auxiliary function and do not directly participate in the formation of the embryo body. Trophoblast cells dissolve tissue, due to which the embryo penetrates the uterine wall. Further, the trophoblast cells exfoliate from the embryo, forming a hollow vesicle. The trophoblast cavity is filled with fluid diffusing into it from the uterine tissue. The embryo at this time has the form of a nodule located on the inner wall of the trophoblast. The mammalian blastula has a small centrally located blastocele and is called a sterroblastula. As a result of further crushing, the embryo has the form of a disk spread on the inner surface of the trophoblast.
Thus, the fragmentation of the embryos of various multicellular animals, although it is very different, ultimately ends up in the fact that the fertilized egg (unicellular developmental stage), as a result of crushing, turns into a multicellular blastula. The outer layer of the blastula is called the blastoderm, and the inner cavity is called the blastocele or primary cavity, where the products of cell vital activity accumulate.

Fig. 2. Types of eggs and their corresponding types of crushing

Regardless of the characteristics of the fragmentation of fertilized eggs in different animals, due to differences in the number and nature of the distribution of yolk in the cytoplasm, the following general features are characteristic of this period of embryonic development.
1. As a result of crushing, a multicellular embryo, a blastula, is formed and cellular material is accumulated for further development.
2. All cells in the blastula have a diploid set of chromosomes, are identical in structure and differ from each other mainly in the number of yolk, that is, the blastula cells are not differentiated.
3. A characteristic feature of crushing is a very short mitotic cycle compared with its duration in adult animals.
4. During the crushing period, DNA and proteins are intensively synthesized and RNA synthesis is absent. Genetic information contained in blastomere nuclei is not used.
5. During crushing, the cytoplasm does not move.
Question 4.
Germ leaves - These are separate layers of cells that occupy a certain position in the embryo and give rise to the corresponding tissues and organs. They are homologous in all animals, i.e., regardless of the systematic position of the animal, they develop to the same organs and tissues. The homology of the germ layers of the vast majority of animals is one of the proofs of the unity of the animal world. Germ layers are formed as a result of the differentiation of similar to each other relatively homogeneous blastula cells.

Question 5.
Cell differentiation is the process by which a cell becomes specialized, that is, acquires chemical, morphological and functional features. An example is the differentiation of human skin epidermis cells, in which, in cells moving from the basal to the prickly and then to other, more superficial layers, keratogialin accumulates, which turns into a shiny layer in the cells of the shiny layer and then into keratin in the stratum corneum. In this case, the shape of the cells, the structure of the cell membranes and the set of organelles change. Not one cell is differentiated, but a group of similar cells. In the human body, there are about 100 different types of cells. Fibroblasts synthesize collagen, myoblasts synthesize myosin, digestive tract epithelial cells pepsin and trypsin, etc.
The first chemical and morphological differences between cells are found during gastrulation. The process, as a result of which individual tissues acquire a characteristic appearance during differentiation, is called histogenesis. Cell differentiation, histogenesis, and organogenesis are performed together, and in certain areas of the embryo and at a certain time. This is very important because it indicates the coordination and integration of embryonic development. The question arises how cells with the same genotype differentiate and participate in histo- and organogenesis in the necessary places and at certain times according to the integral “image” of a given kind of organism. Currently, the generally accepted point of view is the point of view of T. Morgan, who, based on the chromosome theory of heredity, suggested that the differentiation of cells during ontogenesis is the result of successive reciprocal (mutual) effects of the cytoplasm and the changing products of the activity of nuclear genes. The idea was expressed of differential gene expression as the main mechanism of cytodifferentiation.
At present, much evidence has been gathered that in most cases, somatic cells of organisms carry a complete diploid set of chromosomes, and the genetic potencies of the nuclei of somatic cells are also fully preserved, i.e. genes do not lose potential functional activity. Studies of the karyotypes of various somatic cells carried out by the cytogenetic method showed their almost complete identity. Using a cytophotometric method, it was found that the amount of DNA in them does not decrease, and it was shown by molecular hybridization that cells of different tissues are identical in nucleotide sequences.
The hereditary material of somatic cells is able to remain complete not only quantitatively, but also functionally. Therefore, cytodifferentiation is not a consequence of the insufficiency of hereditary material. The main idea is the selective manifestation of genes in the trait, i.e. in differential gene expression.
Gene expression into a trait is a complex step-by-step process, which is studied mainly by the products of gene activity, using an electron microscope or by the results of an individual's development.

Question 6.
In different species of animals, the same germ layers give the same organs and tissues. This means that the germ layers are homologous. The homology of the germ layers of the vast majority of animals is one of the proofs of the unity of the animal world.