9. Classification of mutations

Mutational variability occurs in the event of the appearance of mutations - persistent changes in the genotype (i.e. DNA molecules), which can affect entire chromosomes, their parts or individual genes.
Mutations can be beneficial, harmful, or neutral. According to modern classification mutations are usually divided into the following groups.
1. Genomic mutations associated with a change in the number of chromosomes. Of particular interest is POLYPLOIDY - a multiple increase in the number of chromosomes. The occurrence of polyploidy is associated with a violation of the mechanism of cell division. In particular, nondisjunction of homologous chromosomes during the first division of meiosis leads to the appearance of gametes with a 2n set of chromosomes.
Polyploidy is widespread in plants and much less frequently in animals (roundworm, silkworm, some amphibians). Polyploid organisms tend to be more large size, enhanced synthesis of organic substances, which makes them especially valuable for breeding work.
2. Chromosomal mutations- these are rearrangements of chromosomes, a change in their structure. Separate plots chromosomes can be lost, doubled, change their position.
Like genomic mutations, chromosomal mutations play a role huge role in evolutionary processes.
3. Gene mutations associated with a change in the composition or sequence of DNA nucleotides within a gene. Gene mutations are the most important of all mutation categories.
Protein synthesis is based on the correspondence between the arrangement of nucleotides in a gene and the order of amino acids in a protein molecule. The occurrence of gene mutations (changes in the composition and sequence of nucleotides) changes the composition of the corresponding enzyme proteins and, as a result, leads to phenotypic changes. Mutations can affect all features of the morphology, physiology and biochemistry of organisms. Many hereditary diseases human beings are also caused by gene mutations.
Mutations in natural conditions are rare - one mutation of a particular gene per 1000-100000 cells. But the mutation process goes on constantly, there is a constant accumulation of mutations in genotypes. And if we take into account that the number of genes in the body is large, then we can say that in the genotypes of all living organisms there is a significant number of gene mutations.
Mutations are the largest biological factor that determines the huge hereditary variability of organisms, which provides material for evolution.

1. According to the nature of the change in the phenotype, mutations can be biochemical, physiological, anatomical and morphological.

2. According to the degree of adaptability, mutations are divided into beneficial and harmful. Harmful - can be lethal and cause the death of the organism even in embryonic development.

3. Mutations are direct and reverse. The latter are much less common. Usually, a direct mutation is associated with a defect in the function of the gene. The probability of a secondary mutation in reverse side at the same point is very small, other genes mutate more often.

Mutations are more often recessive, since dominant ones appear immediately and are easily "rejected" by selection.

4. According to the nature of the change in the genotype, mutations are divided into gene, chromosomal and genomic.

Gene, or point, mutations - a change in a nucleotide in one gene in a DNA molecule, leading to the formation of an abnormal gene, and, consequently, an abnormal protein structure and the development of an abnormal trait. gene mutation is the result of a "mistake" in DNA replication.

Chromosomal mutations - changes in the structure of chromosomes, chromosomal rearrangements. The main types of chromosomal mutations can be distinguished:

a) deletion - loss of a chromosome segment;

b) translocation - the transfer of part of the chromosomes to another non-homologous chromosome, as a result - a change in the linkage group of genes;

c) inversion - rotation of a chromosome segment by 180 °;

d) duplication - doubling of genes in a certain region of the chromosome.

Chromosomal mutations lead to a change in the functioning of genes and are important in the evolution of a species.

Genomic mutations - changes in the number of chromosomes in a cell, the appearance of an extra or loss of a chromosome as a result of a violation in meiosis. A multiple increase in the number of chromosomes is called polyploidy. This type of mutation is common in plants. Many cultivated plants are polyploid in relation to their wild ancestors. An increase in chromosomes by one or two in animals leads to anomalies in the development or death of the organism.

Knowing the variability and mutations in one species, one can foresee the possibility of their appearance in related species, which is important in breeding.

10. Phenotype and genotype - their differences

The genotype is the totality of all the genes of an organism, which are its hereditary basis.
Phenotype - the totality of all the signs and properties of an organism that are revealed in the process individual development under these conditions and are the result of the interaction of the genotype with a complex of factors of internal and external environment.
The phenotype in the general case is what can be seen (color of the cat), heard, felt (smell), as well as the behavior of the animal.
In a homozygous animal, the genotype matches the phenotype, but in a heterozygous animal it does not.
Each species has its own unique phenotype. It is formed in accordance with the hereditary information embedded in the genes. However, depending on changes in the external environment, the state of signs varies from organism to organism, resulting in individual differences- variability.
45. Cytogenetic monitoring in animal husbandry.

The organization of cytogenetic control should be based on a number of basic principles. 1. It is necessary to organize a rapid exchange of information between institutions dealing with issues of cytogenetic control, for this purpose it is necessary to create a single data bank that would include information about carriers of chromosomal pathology. 2. inclusion of information about the cytogenetic characteristics of the animal in breeding documents. 3. The purchase of semen and breeding material from abroad should be carried out only in the presence of a cytogenetic certificate.

Cytogenetic examination in the regions is carried out using information on the prevalence of chromosomal abnormalities in breeds and lines:

1) breeds and lines in which cases of chromosomal pathology transmitted by inheritance are registered, as well as descendants of carriers of chromosomal abnormalities in the absence of a cytogenetic passport on them;

2) breeds and lines not previously studied cytogenetically;

3) all cases of mass reproduction disorders or genetic pathology of an unclear nature.

First of all, sires and males intended for herd repair, as well as breeding young animals of the first two categories, are subject to examination. Chromosomal aberrations can be divided into two large classes: 1. constitutional - inherent in all cells, inherited from parents or arising in the process of gamete maturation, and 2. somatic - arising in individual cells during ontogenesis. Taking into account the genetic nature and phenotypic manifestation of chromosomal abnormalities, animals carrying them can be divided into four groups: 1) carriers of inherited anomalies with a predisposition to a decrease in reproductive qualities by an average of 10%. Theoretically, 50% of offspring inherit the pathology. 2) carriers of inherited anomalies, leading to a pronounced decrease in reproduction (30-50%) and congenital pathology. About 50% of offspring inherit the pathology.

3) Animals with anomalies that occur de novo, leading to congenital pathology (monosomy, trisomy and polysomy in the system of autosomes and sex chromosomes, mosaicism and chimerism). In the vast majority of cases, these animals are sterile. 4) Animals with increased karyotype instability. Reproductive function is reduced, hereditary predisposition is possible.

46. ​​pleiotropy (multiple action of genes)
The pleiotropic action of genes is the dependence of several traits on one gene, that is, the multiple action of one gene.
The pleiotropic effect of a gene can be primary or secondary. In primary pleiotropy, the gene exhibits its multiple effect.
In secondary pleiotropy, there is one primary phenotypic expression of a gene, followed by a stepwise process of secondary changes leading to multiple effects. In pleiotropy, a gene, acting on one main trait, can also change, modify the manifestation of other genes, and therefore the concept of modifier genes has been introduced. The latter enhance or weaken the development of traits encoded by the "main" gene.
Indicators of the dependence of the functioning of hereditary inclinations on the characteristics of the genotype are penetrance and expressivity.
Considering the action of genes, their alleles, it is necessary to take into account the modifying influence of the environment in which the organism develops. Such a fluctuation of classes during splitting depending on environmental conditions is called penetrance - the strength of phenotypic manifestation. So, penetrance is the frequency of gene manifestation, the phenomenon of the appearance or absence of a trait in organisms that are identical in genotype.
Penetrance varies considerably among both dominant and recessive genes. It can be complete, when the gene appears in 100% of cases, or incomplete, when the gene does not appear in all individuals containing it.
Penetrance is measured by the percentage of organisms with a phenotypic trait out of the total number of examined carriers of the corresponding alleles.
If the gene is complete, regardless of environment, determines the phenotypic manifestation, then it has a penetrance of 100 percent. However, some dominant genes appear less regularly.

Multiple or pleiotropic effects of genes are associated with the stage of ontogeny at which the corresponding alleles appear. The earlier the allele appears, the greater the effect of pleiotropy.

Given the pleiotropic effect of many genes, it can be assumed that some genes often act as modifiers for the action of other genes.

47. modern biotechnologies in animal husbandry. The use of selection. - genetic. value (art. axes; transp. Fetus).

Embryo transfer

Development of a method for artificial insemination of farm animals and its practical use provided big success in the field of improving animal genetics. The use of this method, combined with long-term storage of the seed in a frozen state, has opened up the possibility of obtaining tens of thousands of offspring from one producer per year. This technique essentially solves the problem rational use producers in animal husbandry practice.

As for females, traditional methods of breeding animals allow you to get from them only a few offspring in a lifetime. Low level reproduction in females and a long time interval between generations (6-7 years in cattle) limit the genetic process in animal husbandry. Scientists see the solution to this problem in the use of the method of embryo transplantation. The essence of the method is that genetically outstanding females are freed from the need to bear a fetus and feed offspring. In addition, they are stimulated to increase the yield of eggs, which are then removed at the stage of early embryos and transplanted into genetically less valuable recipients.

Embryo transplantation technology includes such basic links as induction of superovulation, artificial insemination of a donor, extraction of embryos (surgical or non-surgical), assessment of their quality, short-term or long-term storage and transplantation.

Stimulation of superovulation. Female mammals are born with a large (several tens and even hundreds of thousands) number of germ cells. Most of them gradually die as a result of follicular atresia. Only a small number of primordial follicles become antral during growth. However, almost all growing follicles respond to gonadotropic stimulation, which leads them to final maturation. Treatment of females with gonadotropins in the follicular phase of the sexual cycle or in the luteal phase of the cycle in combination with the induction of corpus luteum regression by prostaglandin F 2 (PGF 2) or its analogues leads to multiple ovulation or the so-called superovulation.

Cattle. Induction of superovulation in female cattle is carried out by treatment with gonadotropins, follicle-stimulating hormone (FSH) or foal mare blood serum (FFS), starting from the 9-14th day of the sexual cycle. 2-3 days after the start of treatment, animals are injected with prostaglandin F 2a or its analogues to cause regression of the corpus luteum.

Due to the fact that the terms of ovulation in hormonally treated animals increase, the technology of their insemination also changes. Initially, multiple insemination of cows using multiple doses of semen was recommended. Usually, 50 million live spermatozoa are introduced at the beginning of the hunt and insemination is repeated after 12-20 hours.

Extraction of embryos. Bovine embryos arrive from the oviduct into the uterus between the 4th and 5th day after the onset of estrus (between the 3rd and 4th day after ovulation),

Due to the fact that non-surgical extraction is possible only from the horns of the uterus, the embryos are removed no earlier than the 5th day after the start of the hunt.

Despite the fact that excellent results have been achieved with the surgical extraction of embryos from cattle, this method is inefficient - relatively expensive, inconvenient for use in production conditions.

Non-surgical embryo retrieval consists of using a catheter.

The most optimal time for embryo retrieval is 6-8 days after the start of estrus, since early blastocysts of this age are most suitable for deep freezing and can be transplanted non-surgically with high efficiency. The donor cow is used 6-8 times a year, removing 3-6 embryos.

In sheep and pigs, non-surgical embryo retrieval is not possible
due to the difficulty of passing the catheter through the cervix into the uterine horns. One
but surgery in these animal species is relatively simple
and not long.

Embryo transfer. In parallel with the development of the surgical method for embryo retrieval in cattle, significant progress has also been made in non-surgical embryo transfer. They collect fresh nutrient medium(column 1.0-1.3 cm long), then a small air bubble (0.5 cm) and then the main volume of the medium with the embryo (2-3 cm). After that, a little air (0.5 cm) and a nutrient medium (1.0-1.5 cm) are sucked in. The straw with the embryo is placed in the Cass catheter and kept in a thermostat at 37°C until transplantation. By pressing on the catheter rod, the contents of the straw are squeezed out together with the embryo into the uterine horn.

Embryo storage. The application of the method of embryo transplantation required the development effective methods their storage in the period between extraction and transplantation. AT working conditions embryos are usually retrieved in the morning and transferred at the end of the day. Phosphate buffer is used to store the embryos during this time, with some modifications when adding fetal bovine serum and when room temperature or a temperature of 37°C.

Observations show that bovine embryos can be cultured in vitro for up to 24 hours without a noticeable decrease in their subsequent engraftment.

The transplantation of pig embryos cultivated for 24 hours is accompanied by normal engraftment.

The survival of embryos can be increased to a certain extent by cooling them below body temperature. The sensitivity of embryos to cooling depends on the type of animal.

Pig embryos are especially sensitive to cold. So far, it has not been possible to maintain the viability of pig embryos in the early stages of development after cooling them below 10-15°C.

Embryos of cattle in the early stages of development are also very sensitive to cooling to 0°C.

Experiments recent years made it possible to determine the optimal ratio between the rate of cooling and thawing of cattle embryos. It has been found that if embryos are cooled slowly (1°C/min) to very low temperatures (below -50°C) and then transferred to liquid nitrogen, they also require slow thawing (25°C/min or slower). Rapid thawing of such embryos can cause osmotic rehydration and destruction. If the embryos are frozen slowly (1°C/min) only to -25 and 40°C and then transferred to liquid nitrogen, they can be thawed very quickly (300°C/min). In this case, the residual water, when transferred to liquid nitrogen, is transformed into a glassy state.

The identification of these factors has led to a simplification of the procedure for freezing and thawing of cattle embryos. In particular, embryos, like sperm, are thawed in warm water at 35°C for 20 s immediately before transplantation without the use of special equipment with a given rate of temperature increase.

Fertilization of eggs outside the body of an animal

The development of a system for fertilization and ensuring the early stages of development of mammalian embryos outside the animal body (in vitro) is of great importance in solving a number of scientific problems and practical issues aimed at improving the efficiency of animal breeding.

For these purposes, embryos in the early stages of development are needed, which can only be removed by surgical methods from the oviducts, which is laborious and does not provide a sufficient number of embryos for this work.

Fertilization of mammalian eggs in vitro includes the following main stages: maturation of oocytes, capacitation of spermatozoa, fertilization and provision of early stages of development.

Oocyte maturation in vitro. Big number germ cells in the ovaries of mammals, in particular in cattle, sheep and pigs with high genetic potential, represents a source of enormous potential for the reproductive ability of these animals in accelerating genetic progress compared to using the possibilities of normal ovulation. In these animal species, as in other mammals, the number of oocytes that ovulate spontaneously during heat is only a small fraction of the thousands of oocytes present in the ovary at birth. The rest of the oocytes regenerate inside the ovary or are commonly said to undergo atresia. Naturally, the question arose whether it was possible to isolate oocytes from the ovaries by appropriate processing and carry out their further fertilization outside the body of the animal. Currently, no methods have been developed for using the entire stock of oocytes in the ovaries of animals, but a significant number of oocytes can be obtained from cavitary follicles for their further maturation and fertilization outside the body.

At present, only in vitro maturation of bovine oocytes has found application in practice. Oocytes are obtained from the ovaries of cows after the slaughter of animals and by intravital extraction, 1-2 times a week. In the first case, the ovaries are taken from animals after slaughter, delivered to the laboratory in a thermostated container for 1.5-2.0 hours. In the laboratory, the ovaries are washed twice with fresh phosphate buffer. Oocytes are extracted from follicles with a diameter of 2-6 mm by suction or cutting the ovary into plates. Oocytes are collected in TCM 199 medium with the addition of 10% blood serum from a cow in heat, then they are washed twice and only oocytes with compact cumulus and homogeneous cytoplasm are selected for further maturation in vitro.

AT recent times developed a method for intravital extraction of oocytes from the ovaries of cows using ultrasonic device or laparoscope. In this case, oocytes are aspirated from follicles with a diameter of at least 2 mm, 1-2 times a week from the same animal. On average, 5-6 oocytes per animal are obtained once. Less than 50% of oocytes are suitable for in vitro maturation.

A positive value - despite the low yield of oocytes, with each extraction the possibility of repeated use of the animal.

Sperm capacitation. An important milestone in the development of the method of fertilization in mammals was the discovery of the phenomenon of capacitation of spermatozoa. In 1951 M.K. Chang and at the same time G.R. Austin found that fertilization in mammals occurs only if the sperm is in the animal's oviduct for several hours before ovulation. Based on observations on the penetration of rat spermatozoa at various times after mating, Austin introduced the term capacitation. It means that some physiological changes before the spermatozoon acquires the ability to fertilize.

Several methods have been developed to capacitate ejaculated sperm from domestic animals. A medium with high ionic strength was used to remove proteins from the surface of spermatozoa that appear to inhibit spermatocapacitation.

However, the method of capacitation of spermatozoa using heparin has received the greatest recognition (J. Parrish et al., 1985). Straws with frozen bull semen are thawed in a water bath at 39°C for 30–40 s. Approximately 250 µl of thawed semen is layered under 1 ml of capacitation medium. The capacitation medium consists of a modified Tyroid medium, without calcium ions. After incubation for one hour, the upper layer of the medium with a volume of 0.5-0.8 ml, containing the majority of motile spermatozoa, is removed from the tube and washed twice by centrifugation at 500 g for 7-10 minutes. After 15 minutes of incubation with heparin (200 µg/ml), the suspension is diluted to a concentration of 50 million spermatozoa per ml.

Fertilization in vitro and provision of early stages of embryo development. Fertilization of eggs in mammals takes place in the oviducts. This makes it difficult for the researcher to study the environmental conditions in which the process of fertilization takes place. Therefore, an in vitro fertilization system would be a valuable analytical tool for studying the biochemical and physiological factors involved in the successful mating of gametes.

Apply the following scheme of in vitro fertilization and cultivation of early embryos of cattle. Fertilization in vitro is carried out in a drop of modified Thyroid medium. After in vitro maturation, the oocytes are partially cleared of the surrounding expanded cumulus cells and transferred in a microdroplet of five oocytes each. A sperm suspension of 2-5 µl is added to the medium with oocytes to achieve a sperm drop concentration of 1-1.5 million/ml. 44-48 hours after insemination, the presence of oocyte crushing is determined. The embryos are then placed on a monolayer of epithelial cells for further development within 5 days.

Interspecies embryo transfers and production of chimeric animals

It is generally accepted that a successful embryo transfer can only be carried out between females of the same species. The transplantation of embryos, for example, from sheep to goats and vice versa, is accompanied by their engraftment, but does not end with the birth of offspring. In all interspecies pregnancies direct cause abortion is a violation of the function of the placenta, apparently due to the immunological reaction of the maternal organism to foreign antigens of the fetus. This incompatibility can be overcome by obtaining chimeric embryos using microsurgery.

First, chimeric animals were obtained by combining blastomeres from embryos of the same species. For this purpose, complex chimeric sheep embryos were obtained by combining 2-, 4-, 8-cell embryos from 2-8 parents.

Embryos were introduced into agar and transferred into ligated sheep oviducts to develop to the early blastocyst stage. Normally developing blastocysts were transplanted into recipients and live lambs were obtained, most of which turned out to be chimeric according to blood analysis and external signs.

Chimeras have also been obtained in cattle (G. Brem et al., 1985) by combining halves of 5-6.5-day-old embryos. Five of the seven calves obtained after non-surgical transfer of aggregated embryos showed no signs of chimerism.

Animal cloning

The number of offspring from one individual, as a rule, is small in higher animals, and the specific complex of genes that determines high productivity rarely occurs and undergoes significant changes in subsequent generations.

Getting identical twins is of great importance for animal husbandry. On the one hand, the yield of calves from one donor increases, and on the other hand, genetically identical twins appear.

The possibility of microsurgical division of mammalian embryos at early stages of development into two or more parts, so that each subsequently develops into individual organism, was expressed several decades ago.

Based on these studies, it can be assumed that a sharp decrease in the number of embryonic cells is the main factor that reduces the ability of these embryos to develop into viable blastocysts, although the stage of development at which separation occurs is of little importance.

Currently, a simple technique is used to divide embryos at various stages of development (from the late morula to the hatched blastocyst) into two equal parts.

A simple separation technique has also been developed for 6-day-old porcine embryos. In this case, the inner cell mass of the embryo is cut with a glass needle.

Most of the information about chromosomal rearrangements that cause phenotypic or bodily changes and abnormalities was obtained as a result of genotype studies (location of genes on chromosomes salivary glands) of the common fruit fly. Despite the fact that many human diseases are hereditary in nature, only a small part of them are reliably known to be caused by chromosomal abnormalities. Only from observations of phenotypic manifestations can we conclude that certain changes in genes and chromosomes have occurred.

Chromosomes are deoxyribonucleic acid (DNA) molecules arranged in a double helix, forming chemical basis heredity. Experts believe that chromosomal disorders occur as a result of a rearrangement of the order or number of genes on chromosomes. Genes are groups of atoms that make up DNA molecules. As is known, DNA molecules determine the nature of ribonucleic acid (RNA) molecules, which act as "deliverers" of genetic information that determines the structure and function of organic tissues.

The primary genetic substance, DNA, acts through the cytoplasm, which acts as a catalyst in changing the properties of cells, forming skin and muscles, nerves and blood vessels, bones and connective tissue, as well as other specialized cells, but without allowing changes in the genes themselves during this process. At almost all stages of the construction of an organism, many genes are involved, and therefore it is not at all necessary that each physical trait is the result of the action of a single gene.

Chromosomal disorder

A variety of chromosomal abnormalities can result from the following structural and quantitative violations:

Breakage of chromosomes. Chromosomal rearrangements can be caused by exposure to x-rays, ionizing radiation, possibly cosmic rays, as well as many other, yet unknown to us, biochemical or environmental factors.

X-rays. Can cause chromosome breakage; during the rearrangement, a segment or segments detached from one chromosome may be lost, resulting in a mutation or phenotypic change. It becomes possible to express a recessive gene that causes a certain defect or anomaly, since the normal allele (paired gene on the homologous chromosome) is lost and, as a result, cannot neutralize the effect of the defective gene.

Crossover. Pairs of homologous chromosomes are twisted into a spiral like earthworms during mating and can break at any homologous points (i.e., at the same level forming a pair of chromosomes). During meiosis, each pair of chromosomes separates so that only one chromosome from each pair enters the resulting egg or sperm. When a break occurs, the end of one chromosome can be joined to the broken end of the other chromosome, and the two remaining pieces of chromosomes are tied together. As a result, two completely new and different chromosomes are formed. This process is called crossing over.

Duplication/lack of genes. During duplication, a section of one chromosome breaks off and attaches to a homologous chromosome, doubling the group of genes already existing in it. The acquisition of an additional group of genes by a chromosome usually causes less harm than the loss of genes by another chromosome. In addition, with a favorable outcome, duplications lead to the formation of a new hereditary combination. Chromosomes with a lost terminal region (and a lack of genes localized in it) can lead to mutations or phenotypic changes.

Translocation. Segments of one chromosome are transferred to another, non-homologous chromosome, causing the sterility of the individual. In this case, any negative phenotypic manifestation cannot be passed on to subsequent generations.

Inversion. The chromosome breaks in two or more places, and its segments are inverted (turned 180°) before joining in the same order to form the whole reconstructed chromosome. This is the most common and most important way of rearranging genes in the evolution of species. However, the new hybrid can become an isolant because it is sterile when crossed with the original form.

position effect. In cases of a change in the position of a gene on the same chromosome, phenotypic changes can be detected in organisms.

Polyploidy. Failures in the process of meiosis (chromosomal reduction division in preparation for reproduction), which are then found in the germ cell, can double the normal number of chromosomes in gametes (sperms or eggs).

Polyploid cells are present in our liver and some other organs, usually without causing any noticeable harm. When polyploidy is manifested in the presence of a single "extra" chromosome, the appearance of the latter in the genotype can lead to serious phenotypic changes. These include down syndrome, in which each cell contains an additional 21st chromosome.

Among patients with diabetes there is a small percentage of births with complications in which this extra autosome (non-sex chromosome) causes insufficient weight and growth of the newborn and delays subsequent physical and mental development. People with Down syndrome have 47 chromosomes. Moreover, the additional 47th chromosome causes in them an excessive synthesis of an enzyme that destroys the essential amino acid tryptophan, which is found in milk and is necessary for the normal functioning of brain cells and the regulation of sleep. Only in a small percentage of those born with the syndrome, this disease is definitely hereditary.

Diagnosis of chromosomal disorders

Congenital malformations are persistent structural or morphological defects of an organ or part thereof that occur in utero and disrupt the functions of the affected organ. There may be major defects that lead to significant medical, social or cosmetic problems (spinal hernia, cleft lip and palate) and small ones, which are small deviations in the structure of the organ that are not accompanied by a violation of its function (epicantus, short frenulum of the tongue, deformity of the auricle, accessory lobe of the unpaired vein).

Chromosomal disorders are divided into:

Severe (require urgent medical intervention);

moderately severe (require treatment, but do not threaten the patient's life).

Congenital malformations are a large and very diverse group of conditions, the most common and representing greater value of them, these are:

anencephaly (absence of a large brain, partial or complete absence bones of the cranial vault);

craniocerebral hernia (protrusion of the brain through a defect in the bones of the skull);

spinal cord herniation (protrusion spinal cord through a defect in the spine);

congenital hydrocephalus (excessive accumulation of fluid inside the ventricular system of the brain);

cleft lip with or without cleft palate;

anophthalmia / microphthalmia (absence or underdevelopment of the eye);

transposition of the great vessels;

malformations of the heart;

esophageal atresia/stenosis (lack of continuity or narrowing of the esophagus);

anus atresia (lack of continuity of the anorectal canal);

kidney hypoplasia;

bladder exstrophy;

diaphragmatic hernia (protrusion of the abdominal organs into the chest through a defect in the diaphragm);

reduction malformations of the limbs (total or partial limbs).

Characteristic signs of congenital anomalies are:

Congenital character (symptoms and signs that were from birth);

uniformity of clinical manifestations in several family members;
long-term persistence of symptoms;

the presence of unusual symptoms (multiple fractures, subluxation of the lens, and others);

multiplicity of lesions of organs and systems of the body;

resistance to treatment.

Various methods are used to diagnose congenital malformations. Recognition of external malformations (cleft lip, palate) is based on clinical examination of the patient, which is the main one here, and usually does not cause difficulties.

Malformations internal organs(heart, lungs, kidneys and others) require additional methods studies, since there are no specific symptoms for them, complaints can be exactly the same as with ordinary diseases of these systems and organs.

These methods include all the usual methods that are also used to diagnose neurological pathology:

beam methods (radiography, computed tomography, magnetic resonance imaging, magnetic resonance imaging, ultrasound diagnostics);

endoscopic (bronchoscopy, fibrogastroduodenoscopy, colonoscopy).

Used to diagnose defects genetic methods research: cytogenetic, molecular-genetic, biochemical.

Currently, congenital malformations can be detected not only after birth, but also during pregnancy. The main thing is the ultrasound examination of the fetus, with the help of which both external defects and defects of the internal organs are diagnosed. Of the other methods for diagnosing defects during pregnancy, chorionic villus biopsy, amniocentesis, cordocentesis are used, the resulting material is subjected to cytogenetic and biochemical studies.

Chromosomal disorders are classified according to the principles of a linear sequence of genes and are in the form of deletion (lack), duplication (doubling), inversion (reversal), insertion (insertion) and translocation (movement) of chromosomes. It is now known that almost all chromosomal disorders are accompanied by developmental delay (psychomotor, mental, physical), in addition, they may be accompanied by the presence of congenital malformations.

These changes are typical for anomalies of autosomes (1 - 22 pairs of chromosomes), less often for gonosomes (sex chromosomes, 23 pairs). In the first year of a child's life, many of them can be diagnosed. The main ones are cat's cry syndrome, Wolff-Hirshhorn syndrome, Patau syndrome, Edwards syndrome, Down syndrome, cat's eye syndrome, Shereshevsky-Turner syndrome, Klinefelter's syndrome.

Previously, the diagnosis of chromosomal diseases was based on the use of traditional methods cytogenetic analysis, this type of diagnosis made it possible to judge the karyotype - the number and structure of human chromosomes. In this study, some chromosomal abnormalities remained unrecognized. Currently, fundamentally new methods for diagnosing chromosomal disorders have been developed. These include: chromosome-specific DNA probes, a modified hybridization method.

Prevention of chromosomal disorders

Currently, the prevention of these diseases is a system of measures at various levels, which are aimed at reducing the frequency of birth of children with this pathology.

Available three preventive levels, namely:

Primary level: are carried out before the conception of a child and are aimed at eliminating the causes that can cause birth defects or chromosomal abnormalities, or risk factors. The activities of this level include a set of measures aimed at protecting a person from the action of harmful factors, improving the state of the environment, testing for mutagenicity and teratogenicity of food products, food additives, medicines, labor protection for women in hazardous industries, and the like. After the relationship between the development of some malformations and a deficiency of folic acid in a woman's body was revealed, it was proposed to use it as a prophylactic for all women of reproductive age 2 months before conception and within 2-3 months after conception. Also preventive measures include vaccination of women against rubella.

Secondary prevention: is aimed at identifying the affected fetus, followed by termination of pregnancy or, if possible, treatment of the fetus. Secondary prevention can be mass (ultrasound examination of pregnant women) and individual (medical genetic counseling of families at risk of having a sick child, which establishes an accurate diagnosis of a hereditary disease, determines the type of inheritance of the disease in the family, calculates the risk of a recurrence of the disease in the family, determines the most effective method of family prevention).

Tertiary level of prevention: implies the implementation of therapeutic measures aimed at eliminating the consequences of a malformation and its complications. Patients with serious congenital anomalies are forced to see a doctor for life.

5.2. Chromosomal mutations

Chromosomal mutations are divided into two categories: 1) mutations associated with changes in the number of chromosomes in the karyotype (sometimes they are also called numerical aberrations or genomic mutations); 2) mutations consisting in changes in the structure of individual chromosomes (structural aberrations).

Changes in the number of chromosomes. They can be expressed in addition to the initial diploid set of chromosomes (2n) of one or more haploid sets (n), which leads to the emergence of polyploidy (triploidy, 3n, tetraploidy, 4n, etc.). It is also possible to add or lose one or more chromosomes, resulting in aneuploidy (heteroploidy). If aneuploidy is associated with the loss of one chromosome (formula 2n-1), then it is customary to speak of monosomy; loss of a pair of homologous chromosomes (2n-2) leads to nullisomy; when one chromosome (2n + 1) is added to the diploid set, trisomy occurs. In cases where there is an increase in the set by two and more chromosomes (but less than the haploid number), the term "polysemy" is used.

Polyploidy is very common in some plant groups. Obtaining polyploid varieties of cultivated plants is an important task of breeding practice, since with an increase in ploidy, the economic value of such plants increases (leaves, stems, seeds, fruits become larger). On the other hand, polyploidy is quite rare in dioecious animals, since in this case the balance between sex chromosomes and autosomes is often disturbed, which leads to infertility of individuals or to lethality (death of the organism). In mammals and humans, the resulting polyploids, as a rule, die at the early stages of ontogeny.

Aneuploidy is observed in many species of organisms, especially in plants. Trisomies of some agricultural plants also have a certain practical value, while monosomies and nullisomy often lead to the non-viability of the individual. Human aneuploidies are the cause of severe chromosomal pathology, which manifests itself in serious violations development of the individual, his disability, often ending in the early death of the organism at a particular stage of ontogenesis (lethal outcome). Human chromosomal diseases will be considered in more detail in subsection. 7.2.

The causes of polyploidy and aneuploidy are associated with violations of the divergence of the diploid complex of chromosomes (or chromosomes of individual pairs) of parental cells in daughter cells during meiosis or mitosis. So, for example, if a person during oogenesis has a nondisjunction of one pair of autosomes of the mother cell with a normal karyotype (46, XX), then the formation of eggs with mutant karyotypes 24 ,X and 22 X. Therefore, when such eggs are fertilized by normal spermatozoa (23,X or 23,X), zygotes (individuals) with trisomy may appear. (47,XX either 47 ,XY) and with monosomy (45,XX or 45,XY) for the corresponding autosome. On fig. 5.1 is given general scheme possible violations oogenesis at the stage of reproduction of primary diploid cells (during the mitotic division of oogonia) or during the maturation of gametes (during the division of meiosis), leading to the emergence of triploid zygotes (see Fig. 3.4). Similar effects will be observed with appropriate disorders of spermatogenesis.

If the above disorders affect mitotically dividing cells at the early stages of embryonic development (embryogenesis), then individuals appear with signs of mosaicism (mosaic), i.e. having both normal (diploid) cells and aneuploid (or polyploid) cells.

Currently, various agents are known, for example, high or low temperatures, some chemicals called "mitotic poisons" (colchicine, heteroauxin, acenaphthol, etc.), which disrupt normal work cell division apparatus in plants and animals, preventing

normal completion of the process of chromosome segregation in anaphase and telophase. With these agents, experimental conditions receive polyploid and aneuploid cells of different eukaryotes.

Changes in the structure of chromosomes (structural aberrations). Structural aberrations are intrachromosomal or interchromosomal rearrangements that occur when chromosomes break under the influence of environmental mutagens or as a result of violations in the crossing over mechanism, leading to an incorrect (unequal) genetic exchange between homologous chromosomes after enzymatic "cutting" of their conjugating regions.

Intrachromosomal rearrangements include deletions (deficiencies), i.e. losses individual sections chromosomes, duplications (duplications) associated with the doubling of certain sections, as well as inversions and non-reciprocal translocations (transpositions) that change the order of genes in the chromosome (in the linkage group). An example of interchromosomal rearrangements are reciprocal translocations (Fig. 5.2).

Deletions and duplications can change the number of individual genes in the genotype of an individual, which leads to an imbalance in their regulatory relationships and corresponding phenotypic manifestations. Large deletions are usually lethal in the homozygous state, while very small deletions are most often not the direct cause of homozygous death.

Inversion occurs as a result of a complete rupture of the two edges of the chromosome region, followed by a turn of this region by 180° and the reunion of the broken ends. Depending on whether the centromere is included or not included in the inverted region of the chromosome, inversions are divided into pericentric and paracentric (see Fig. 5.2). The resulting permutations in the location of the genes of an individual chromosome (rearrangements of the linkage group) can also be accompanied by impaired expression of the corresponding genes.

Rearrangements that change the order and (or) content of gene loci in linkage groups also occur in the case of translocations. The most common are reciprocal translocations, in which there is a mutual exchange of previously broken sections between two non-homologous chromosomes. In the case of non-reciprocal translocation, the damaged area moves (transposition) within the same chromosome or into the chromosome of another pair, but without mutual (reciprocal) exchange (see Fig. 5.2).

explanation of the mechanism of such mutations. These rearrangements consist in the centric fusion of two nonhomologous chromosomes into one or in the division of one chromosome into two as a result of its break in the centromere region. Therefore, such rearrangements can lead to a change in the number of chromosomes in the karyotype without affecting the total amount of genetic material in the cell. It is believed that Robertsonian translocations are one of the factors in the evolution of karyotypes in different types eukaryotic organisms.

As noted earlier, in addition to errors in the recombination system, structural aberrations are usually caused by chromosome breaks that occur under the action of ionizing radiation, some chemical substances, viruses and other agents.

The results of an experimental study of chemical mutagens indicate that heterochromatic regions of chromosomes are the most sensitive to their effects (most often breaks occur in the centromere region). In the case of ionizing radiation, this regularity is not observed.

Basic terms and concepts: aberration; aneuploidy (heteroploidy); deletion (lack); duplication (duplication); mortality; "mitotic poisons"; monosomy; non-reciprocal translocation; nullisomy; paracentric inversion; pericentric inversion; polyploidy; polysemy; reciprocal translocation; Robertsonian translocation; transposition; trisomy; chromosomal mutation.

Chromosomal mutations (otherwise they are called aberrations, rearrangements) are unpredictable changes in the structure of chromosomes. Most often they are caused by problems that occur during cell division. Exposure to initiating environmental factors is another possible cause of chromosomal mutations. Let's see what the manifestations of such changes in the structure of chromosomes can be and what consequences they have for the cell and the whole organism.

Mutations. General provisions

In biology, a mutation is defined as a permanent change in the structure of the genetic material. What does "persistent" mean? It is inherited by the descendants of an organism that has mutant DNA. It happens in the following way. One cell receives the wrong DNA. It divides, and two daughters copy its structure completely, that is, they also contain altered genetic material. Further, there are more and more such cells, and if the organism proceeds to reproduction, its descendants receive a similar mutant genotype.

Mutations usually do not go unnoticed. Some of them change the body so much that the result of these changes is a fatal outcome. Some of them make the body function in a new way, reducing its ability to adapt and leading to serious pathologies. And a very small number of mutations benefits the body, thereby increasing its ability to adapt to environmental conditions.

Allocate mutations gene, chromosomal and genomic. Such a classification is based on the differences that occur in different structures of the genetic material. Chromosomal mutations thus affect the structure of chromosomes, gene mutations - the sequence of nucleotides in genes, and genomic mutations make changes to the genome of the whole organism, adding or taking away a whole set of chromosomes.

Let's talk about chromosomal mutations in more detail.

What are chromosomal rearrangements?

Depending on how the changes occurring are localized, the following types of chromosomal mutations are distinguished.

1. Intrachromosomal - transformation of genetic material within one chromosome.
2. Interchromosomal - rearrangements, as a result of which two non-homologous chromosomes exchange their sections. Non-homologous chromosomes contain different genes and do not occur during meiosis.

Each of these types of aberrations correspond to certain types of chromosomal mutations.

Deletions

A deletion is a separation or loss of a portion of a chromosome. It is easy to guess that this type of mutation is intrachromosomal.

If the extreme part of the chromosome is separated, then the deletion is called terminal. If there is a loss of genetic material closer to the center of the chromosome, such a deletion is called interstitial.

This type of mutation can affect the viability of the organism. For example, the loss of a portion of the chromosome encoding a certain gene provides a person with immunity to the immunodeficiency virus. This adaptive mutation arose about 2000 years ago, and some people with AIDS managed to survive only because they were lucky to have chromosomes with an altered structure.

Duplications

Another type of intrachromosomal mutations is duplications. This is a copying of a section of the chromosome, which occurs due to an error in the so-called crossover, or crossing over in the process of cell division.

The region copied in this way can maintain its position, rotate 180°, or even repeat several times, and then such a mutation is called amplification.

In plants, the amount of genetic material can increase precisely through multiple duplications. In this case, the ability of the whole species to adapt usually changes, which means that such mutations are of great evolutionary importance.

Inversions

Also refer to intrachromosomal mutations. Inversion is a rotation of a certain section of the chromosome by 180 °.

The part of the chromosome inverted as a result of inversion can be located on one side of the centromere (paracentric inversion) or on opposite sides of it (pericentric). The centromere is the so-called region of the primary constriction of the chromosome.

Usually, inversions do not affect the external signs of the body and do not lead to pathologies. There is, however, an assumption that in women with an inversion of a certain part of the ninth chromosome, the probability of miscarriage during pregnancy increases by 30%.

Translocations

Translocation is the movement of a section of one chromosome to another. These mutations are of the interchromosomal type. There are two types of translocations.

1. Reciprocal - this is the exchange of two chromosomes in certain areas.
2. Robertsonian - the fusion of two chromosomes with a short arm (acrocentric). In the process of Robertsonian translocation, short sections of both chromosomes are lost.

Reciprocal translocations lead to fertility problems in humans. Sometimes such mutations cause miscarriage or lead to the birth of children with congenital developmental pathologies.

Robertsonian translocations are quite common in humans. In particular, if the translocation occurs with the participation of chromosome 21, the fetus develops Down syndrome, one of the most frequently recorded congenital pathologies.

isochromosomes

Isochromosomes are chromosomes that have lost one arm, but at the same time replaced it with exact copy your other shoulder. That is, in fact, such a process can be considered a deletion and inversion in one vial. In very rare cases such chromosomes have two centromeres.

Isochromosomes are present in the genotype of women suffering from Shereshevsky-Turner syndrome.

All the types of chromosomal mutations described above are inherent in various living organisms, including humans. How do they manifest themselves?

Chromosomal mutations. Examples

Mutations can occur in the sex chromosomes and in autosomes (all other paired chromosomes of the cell). If mutagenesis affects the sex chromosomes, the consequences for the organism, as a rule, are severe. There are congenital pathologies that affect mental development individual and are usually expressed in terms of phenotype changes. That is, outwardly mutant organisms differ from normal ones.

Genomic and chromosomal mutations are more common in plants. However, they are found in both animals and humans. Chromosomal mutations, examples of which we will consider below, are manifested in the occurrence of severe hereditary pathologies. These are Wolff-Hirschhorn syndrome, "cat's cry" syndrome, partial trisomy disease along the short arm of chromosome 9, and some others.

Syndrome "cat's cry"

This disease was discovered in 1963. It arises due to partial monosomy on the short arm of chromosome 5, due to a deletion. One in 45,000 babies is born with this syndrome.

Why is this disease so named? Children suffering from this disease have a characteristic cry that resembles a cat's meow.

With the deletion of the short arm of the fifth chromosome, its different parts may be lost. The clinical manifestations of the disease directly depend on which genes were lost during this mutation.

The structure of the larynx changes in all patients, which means that the “cat's cry” is characteristic of everyone without exception. Most of those suffering from this syndrome have a change in the structure of the skull: a decrease in the brain region, a moon-shaped face. The auricles in the syndrome of "cat's cry" are usually located low. Sometimes patients have congenital pathologies of the heart or other organs. It also becomes a characteristic mental retardation.

Usually patients with this syndrome die in early childhood, only 10% of them survive to the age of ten. However, cases of longevity with the "cat's cry" syndrome have also been recorded - up to 50 years.

Wolff-Hirshhorn Syndrome

This syndrome is much less common - 1 case per 100,000 births. It is caused by a deletion of one of the segments of the short arm of the fourth chromosome.

The manifestations of this disease are varied: physical and mental developmental delay, microcephaly, a characteristic beak-shaped nose, strabismus, cleft palate or upper lip, small mouth, defects of internal organs.

Like many other human chromosomal mutations, Wolff-Hirschhorn disease is classified as semi-lethal. This means that the viability of the organism with such a disease is significantly reduced. Children diagnosed with Wolff-Hirschhorn syndrome usually do not live to be 1 year old, but one case has been recorded when the patient lived for 26 years.

Syndrome of partial trisomy on the short arm of chromosome 9

This disease occurs due to unbalanced duplications in the ninth chromosome, as a result of which there is more genetic material in this chromosome. In total, more than 200 cases of such mutations in humans are known.

The clinical picture is described by a delay physical development, mild mental retardation, characteristic facial expression. Heart defects are found in a quarter of all patients.

With the syndrome of partial trisomy of the short arm of chromosome 9, the prognosis is still relatively favorable: most of patients live to old age.

Other syndromes

Sometimes, even in very small sections of DNA, chromosomal mutations occur. Diseases in such cases are usually due to duplications or deletions, and they are called microduplication or microdeletion, respectively.

The most common such syndrome is Prader-Willi disease. It occurs due to a microdeletion of a section of chromosome 15. Interestingly, this chromosome must be obtained by the body from the father. As a result of a microdeletion, 12 genes are affected. Patients with this syndrome are mentally retarded, obese, and usually have small feet and hands.

Another example of such chromosomal diseases is Sotos syndrome. A microdeletion occurs in the long arm of chromosome 5. The clinical picture of this hereditary disease is characterized by rapid growth, an increase in the size of the hands and feet, the presence prominent forehead, some delay mental development. The frequency of occurrence of this syndrome has not been established.

Chromosomal mutations, more precisely, microdeletions in regions of chromosomes 13 and 15, cause Wilms' tumor and retinblastoma, respectively. Wilms' tumor is a kidney cancer that occurs predominantly in children. Retinoblastoma is a malignant tumor of the retina that also occurs in children. These diseases are treated if they are diagnosed in the early stages. In some cases, doctors resort to operative intervention.

Modern medicine eliminates many diseases, but it is not yet possible to cure or at least prevent chromosomal mutations. They can only be detected at the beginning of intrauterine development of the fetus. However Genetic Engineering does not stand still. Perhaps soon a way to prevent diseases caused by chromosomal mutations, will be found.

Introduction

Chromosomal abnormalities usually cause a whole range of disorders in structure and function. various bodies as well as behavioral and mental disorders. Among the latter, a number of typical features are often found, such as mental retardation of one degree or another, autistic features, underdevelopment of skills social interaction leading asociality and antisociality.

Reasons for changing the number of chromosomes

Changes in the number of chromosomes occur as a result of a violation of cell division, which can affect both the spermatozoon and the egg. Sometimes it leads to chromosomal abnormalities

Chromosomes contain genetic information in the form of genes. The nucleus of every human cell, with the exception of the egg and sperm, contains 46 chromosomes, forming 23 pairs. One chromosome in each pair comes from the mother and the other from the father. In both sexes, 22 of the 23 pairs of chromosomes are the same, only the remaining pair of sex chromosomes differs. Women have two X chromosomes (XX), while men have one X and one Y chromosome (XY). Therefore, the normal set of chromosomes (karyotype) of a man is 46, XY, and that of a woman is 46, XX.

If an error occurs during a special kind of cell division, in which eggs and sperm are formed, then abnormal sex cells arise, which leads to the birth of offspring with a chromosomal pathology. Chromosomal imbalance can be both quantitative and structural.

There are four main quantitative chromosomal anomalies, each of which is associated with a specific syndrome:

47, XYY - XYY syndrome;

47, XXY - Klinefelter's syndrome;

45, X - Turner's syndrome;

47, XXX - trisomy.

chromosomal anomaly antisocial characterological

Extra Y chromosome as a cause of antisociality

Karyotype 47,XYY appears only in males. Characteristic features of people with an extra Y chromosome high growth. At the same time, growth acceleration begins at a sufficiently early age and continues for a very long time.

The frequency of this disease is 0.75 - 1 per 1000 people. A cytogenetic examination conducted in 1965 in America revealed that out of 197 mental patients kept as especially dangerous under strict supervision, 7 of them have the XYY chromosome set. According to English data, among criminals above 184 cm, approximately one in four has this particular set of chromosomes.

Most HUU sufferers are not in conflict with the law; however, some of them easily give in to impulses leading to aggression, to homosexuality, pedophilia, theft, arson; any compulsion causes in them outbursts of malicious rage, very weakly controlled by the inhibitory nerves. Due to the double Y chromosome, the X chromosome becomes "fragile" and from the carrier of this set, it turns out, so to speak, a kind of "super-man".

Consider one of the more sensational examples of this phenomenon in the world of crime.

In 1966, the public was disturbed by an incident in Chicago when a man named Richard Speck brutally murdered eight girls, students medical college.On July 14, 1966, he skidded to the outskirts of Chicago, where he knocked on the door of nine medical college students. To the student who opened the door, he promised not to hurt anyone, saying that he just needed money to buy a ticket to New Orleans. Entering the house, he gathered all the students in one room, tying them up. Having learned where the money was, he did not calm down and, having chosen one of the students, took her out of the room. Later he came for another one. At this time, one of the girls, even being tied up, managed to hide under the bed. All the rest were killed. He raped one of the girls. After that, he went to the nearest tavern to “go out” on the proceeds of 50 dollars. A few days later he was caught. During the investigation, he tried to commit suicide. Richard Speck, the killer of eight female students, had an extra Y chromosome - the "crime chromosome" - in a blood test.

The issue of the need for early isolation of chromosomal aberrants with the XYU karyotype, the need for special measures to protect both the general population and criminals with a lower potential for aggressiveness from them has already been widely discussed in foreign genetic and legal literature.

An adult male who has a 47,XYY karyotype for the first time needs psychological support; genetic counseling may be required.

Since the karyological identification of persons with XYY syndrome among tall criminals is a technically time-consuming task, express methods for detecting extra Y chromosome, namely staining of smears of the oral mucosa with acrichiniprite and fluorescent microscopy (YY stands out as two luminous dots).