home Botany book Gene mutations are caused by changes in the structure of a gene. Gene mutations and hereditary diseases. Association of mutations with DNA repair

Gene mutations are caused by changes in the structure of a gene. Gene mutations and hereditary diseases. Association of mutations with DNA repair

Gene mutations occur at the molecular level and usually affect one or more nucleotides within a single gene. This type of mutation can be divided into two large groups. The first of them causes a shift in the reading frame. The second group includes gene mutations associated with the replacement of base pairs. The latter make up no more than 20% of spontaneous mutations, the remaining 80% of mutations occur as a result of various deletions and insertions.

Frameshift Mutations are insertions or deletions of one or more base pairs. Depending on the site of the violation, one or another number of codons changes. Accordingly, additional amino acids may appear in the protein or their sequence may change. Most of the mutations of this type are found in DNA molecules consisting of identical bases.

Replacement types vany :

Transitions consist in replacing one purine with a purine base or one pyrimidine with a pyrimidine base

Transversions, in which a purine base changes to a pyrimidine base or vice versa.

The significance of gene mutations for the viability of an organism is not the same. Various changes in the DNA nucleotide sequence manifest themselves differently in the phenotype. Some "silent mutations" do not affect the structure and function of the protein. An example of such a mutation is a nucleotide substitution that does not result in an amino acid substitution.

By functional value identify gene mutations

leading to complete loss of function;

as a result of which quantitative changes in mRNA and primary protein products occur;

dominant-negative, changing the properties of protein molecules in such a way that they have a damaging effect on the vital activity of cells.

The so-called non sense mutations , associated with the appearance of terminator codons that cause a stop in protein synthesis. Moreover, the closer the mutations are to the 5 "end of the gene (to the beginning of transcription), the shorter the protein molecules will be. Deletions or insertions (inserts) that are not multiple of three nucleotides and, therefore, causing a reading frame shift, can also lead to premature termination of protein synthesis or to the formation of a meaningless protein that is rapidly degraded.

Missense mutations associated with the replacement of nucleotides in the coding part of the gene. Phenotypically manifested as an amino acid substitution in the protein. Depending on the nature of the amino acids and the functional significance of the damaged area, there is a complete or partial loss of the functional activity of the protein.

Splicing mutations affect sites at the junction of exons and introns and are accompanied by either excision of the exon and the formation of a delegated protein, or excision of the intron region and translation of a meaningless altered protein. As a rule, such mutations cause a severe course of the disease.

Regulatory mutations associated with a quantitative violation in the regulatory regions of the gene. They do not lead to changes in the structure and function of proteins. The phenotypic manifestation of such mutations is determined by the threshold level of protein concentration at which its function is still preserved.

Dynamic Mutations or Mutations expansion represent a pathological increase in the number of trinucleotide repeats localized in the coding and regulatory parts of the gene. Many trinucleotide sequences are characterized by a high level of population variability. A phenotypic disorder manifests itself when a certain critical level in terms of the number of repetitions is exceeded.

Chromosomal mutations

This type of mutation combines chromosomal disorders associated with changes in the structures of chromosomes (chromosomal aberrations).

Chromosomal aberrations can be classified using various approaches. Depending on at what point in the cell cycle - before or after chromosome replication rearrangements occurred - aberrations are distinguished chromosomal and chromatid types. Aberrations of the chromosomal type occur at the pre-synthetic stage - G 1 phase, when the chromosome is represented by a single-stranded structure. Chromatid-type aberrations occur after chromosome replication in the S and G2 phases and affect the structure of one of the chromatids. As a result, the chromosome at the metaphase stage contains one altered and one normal chromatid.

If the rearrangement occurred after replication and affected both chromatids, a isochromatid aberration. Morphologically, it is indistinguishable from aberrations of the chromosomal type, although by origin they belong to the chromatid type. Among aberrations of chromosomal and chromatid types, there are simple and exchange aberrations. They are based on disorders of one or more chromosomes. Simple aberrations - fragments (deletions) - result from a simple break in the chromosome. In each case, 2 types of fragments are formed - centric and acentric. There are terminal (terminal) and interstitial (middle sections of chromosomes) deletions or fragments.

Exchange aberrations are very diverse. They are based on the exchange of sections of chromosomes (or chromatids) between different chromosomes (interchromosomal exchange) or within one chromosome (intrachromosomal exchange) during the redistribution of genetic material. There are two types of exchange rearrangements: symmetric and asymmetric. Asymmetric exchanges lead to the formation of polycentric chromosomes and acentric fragments. With symmetrical exchanges, acentric fragments are combined with centric ones, as a result of which the chromosomes involved in the exchange aberration remain monocentric.

Intrachromosomal exchanges can occur both within one (intra-arm exchange) and between both arms of the chromosome (inter-arm exchange). In addition, exchanges can be simple or complex when multiple chromosomes are involved. As a result, unusual and rather complex configurations of chromosomes can form. Any exchange (symmetric and asymmetric, interchromosomal and intrachromosomal) can be complete (reciprocal nym) or incomplete (non-reciprocal nym) . With a complete exchange, all damaged areas are connected, and with an incomplete exchange, some of them may remain with an open damaged area.

Genomic mutations

Genomic mutations change the number of chromosomes. Such changes usually occur when the distribution of chromosomes in daughter cells is disturbed.

There are two main types of genomic mutations:

Polyploidy and monoploidy.

Aneuploidy.

At polyploidy the number of sets of nonhomologous chromosomes in the karyotype differs from two (3n; 4n, etc.). This is the result of disturbances in the mitotic cycle, when doubling of chromosomes occurs without subsequent division of the nucleus and cell. One of the reasons for this phenomenon may be endomitosis, in which the achromatic apparatus in the cell is blocked and the nuclear membrane is preserved throughout the entire mitotic cycle. A variation of endomitosis is endoreduplication - the reduplication of chromosomes that occurs outside of cell division. With endoreduplication, two successive S periods of the mitotic cycle are repeated, as it were. As a result of this, a double (tetraploid) set of chromosomes will be observed in subsequent mitosis. Such mutations most often lead to the death of the fetus during embryogenesis. Triploidy is found in 4% and tetraploidy in approximately 1% of all miscarriages. Individuals with such karyotypes are characterized by numerous malformations, including asymmetrical physique, dementia, and hermaphroditism. Tetraploid embryos die in the early stages of pregnancy, while embryos with triploid cells occasionally survive, but only if they contain cells with a normal karyotype simultaneously with triploid ones. Triploidy syndrome (69, XXY) was first discovered in humans in the 1960s. 20th century About 60 cases of triploidy in children have been described in the literature. The maximum duration of their life was 7 days.

Aneuploidy - non-fold haploid decrease or increase in the number of chromosomes (2n + 1; 2n + 2; 2n-1, etc.) - occurs as a result of abnormal behavior of homologous chromosomes in meiosis or sister chromatids in mitosis.

If chromosomes do not diverge, at one of the stages of gametogenesis, extra chromosomes may appear in germ cells. As a result, upon subsequent fusion with normal haploid gametes, zygotes 2n +1 - or trisomy on any of the chromosomes. If there is one less chromosome in the gamete, then during subsequent fertilization a zygote 2 n - 1 is formed, or monosomic one of the chromosomes. Nondisjunction can affect not one, but several pairs of chromosomes, leading to trisomy or monosomy for several chromosomes. Often, extra chromosomes cause developmental depression or death of the individual carrying them.

T E M A No. 6 Types of inheritance in humans

Mendelian signs

All eukaryotic organisms are characterized by the general patterns of inheritance of traits discovered by G. Mendel. To study them, it is necessary to recall the basic terms and concepts used in genetics. Mendel's main postulate, which he proved in his famous experiments on garden peas, is that each trait is determined by a pair of hereditary inclinations, later called allelic genes. With the development of the chromosome theory of heredity, it became clear that allelic genes are located in the same loci of homologous chromosomes and encode the same trait. A pair of allelic genes can be the same (AA) or (aa), then the individual is said to be homozygous for that trait. If the allelic genes in a pair are different (Aa), then the individual is heterozygous for this trait. The totality of the genes of an organism is called the genotype. True, often a genotype is understood as one or more pairs of allelic genes that are responsible for the same trait. The totality of the characteristics of a given organism is called the phenotype, the phenotype is formed as a result of the interaction of the genotype with the external environment.

G. Mendel introduced the concepts of dominant and recessive genes. The allele that determines the phenotype of the heterozygote, he called dominant. For example, gene A in heterozygote Aa . The other allele, which does not manifest itself in the heterozygous state, is called recessive by him. In our case, this is gene a.

The main patterns of inheritance of traits according to Mendel (the law of uniformity of hybrids of the first generation, splitting into phenotypic classes of hybrids of the second generation and independent combination of genes) are realized due to the existence of the law of purity of gametes. The essence of the latter is that a pair of allelic genes that determines one or other sign: a) never mixes; b) in the process of gametogenesis, it diverges into different gametes, that is, one gene from an allelic pair enters each of them. Cytologically, this is provided by meiosis: allelic genes lie in homologous chromosomes, which in the anaphase of meiosis diverge to different poles and enter different gametes.

Human genetics is based on general principles derived initially from research on plants and animals. Like them, a person has Mendelians, i.e. signs inherited according to the laws established by G. Mendel. For humans, as well as for other eukaryotes, all types of inheritance are characteristic: autosomal dominant, autosomal recessive, inheritance of traits linked to sex chromosomes, and due to the interaction of non-allelic genes. G. Mendel also developed the main method of genetics - hybridological. It is based on crossing individuals of the same species with alternative traits and quantitative analysis of the resulting phenotypic classes. Naturally, this method cannot be used in human genetics.

First Description autosomal dominant inheritance of anomalies in humans was given in 1905 by Farabi. The pedigree was compiled for a family with short fingers (brachydactyly). In patients, the phalanges of the fingers and toes are shortened and partially reduced, in addition, as a result of shortening of the limbs, they are characterized by short stature. The trait is transmitted from one of the parents to about half of the children, regardless of gender. An analysis of the pedigrees of other families indicates that brachydactyly is absent among the offspring of parents who are not carriers of this gene. Since a trait cannot exist in a latent form, therefore, it is dominant. And its manifestations, regardless of gender, allow us to conclude that it is not sex-linked. Based on the foregoing, we can conclude that brachydactyly is determined by a gene located in autosomes and is a dominant pathology.

The use of the genealogical method made it possible to identify dominant, non-sex-linked traits in humans. These are dark eye color, curly hair, a hump bridge, a straight nose (the tip of the nose looks straight), a dimple on the chin, early baldness in men, right-handedness, the ability to roll the tongue into a tube, a white curl above the forehead, the "Habsburg lip" - the lower the jaw is narrow, protruding forward, the lower lip is pendulous and the mouth is half open. According to the autosomal dominant type, some pathological signs of a person are also inherited: polydactyly or polydactylism (when there are from 6 to 9 fingers on the hand or foot), syndactyly (fusion of soft or bone tissues of the phalanges of two or more fingers), brachydactyly (underdevelopment of the distal phalanges of the fingers, leading to short fingers), arachnodactyly (very elongated "spider" fingers, one of the symptoms of Marfan's syndrome), some forms of myopia. Most carriers of an autosomal dominant anomaly are heterozygotes. It sometimes happens that two carriers of the same dominant anomaly marry and have children. Then a quarter of them will be homozygous for the mutant dominant allele (AA) . Many cases from medical practice indicate that homozygotes for dominant anomalies are more severely affected than heterozygotes. For example, in a marriage between two carriers of brachydactyly, a child was born who not only lacked fingers and toes, but also had multiple skeletal deformities. He died at the age of one. Another child in this family was heterozygous and had the usual symptoms of brachydactyly.

Autosomal recessive Mendelian traits in humans are determined by genes localized in autosomes and can appear in offspring in marriages of two heterozygotes, two recessive homozygotes, or a heterozygote and a recessive homozygote. Research shows that most marriages with recessive offspring occur between phenotypically normal heterozygotes (Aa x Aa) . In the offspring of such a marriage, the genotypes AA, Aa and aa will be presented in a ratio of 1:2:1, and the probability that the child will be affected will be 25%. According to the autosomal recessive type, soft straight hair, a snub nose, light eyes, thin skin and Rh-negative first blood group, many metabolic diseases are inherited: phenylketonuria, galactosemia, histidinemia, etc., as well as xeroderma pigmentosa.

Xeroderma pigmentosa, one of the recessive diseases, has attracted the attention of molecular biologists relatively recently. This pathology is due to the inability of the patient's skin cells to repair DNA damage caused by ultraviolet radiation. As a result, inflammation of the skin develops, especially on the face, followed by atrophy. Finally, skin cancer develops, leading to death if left untreated. In patients with a rare recessive disease, the degree of consanguinity between parents is usually significantly higher than the average level in the population. Typically, parents inherit this gene from common ancestor and are heterozygotes. The vast majority of patients with autosomal recessive diseases are children of two heterozygotes.

In addition to autosomal dominant and autosomal recessive types of inheritance in humans, incomplete dominance is also detected. , coding and overdominance.

incomplete dominance associated with an intermediate manifestation of the trait in the heterozygous state of alleles (Aa) . For example, a large nose is determined by two AA alleles, small nose - aa alleles, normal nose of medium size - Aa . According to the type of incomplete dominance in humans, the bulge of the lips and the size of the mouth and eyes, the distance between the eyes are inherited.

Codominance- this is such an interaction of allelic genes, in which two dominant genes are in a heterozygous state and work together at the same time, that is, each allele determines its own trait. It is most convenient to consider codominance using the example of inheritance of blood groups.

The blood groups of the AB0 system are determined by three alleles: A, B and 0. Moreover, the A and B alleles are dominant, and the 0 allele is recessive. The pairwise combination of these three alleles in the genotype gives four blood groups. Allelic genes that determine blood groups are located in the ninth pair of human chromosomes and are designated respectively: I A, I in and I °. The first blood group is determined by the presence of two recessive alleles I° I° in the genotype. Phenotypically, this is manifested by the presence of alpha and beta antibodies in the blood serum. The second blood group can be determined by two dominant alleles I A I A if a person is homozygous, or by alleles I A I ° if he is heterozygous. Phenotypically, the second blood group is manifested by the presence of group A antigens on the surface of erythrocytes and the presence of beta antibodies in the blood serum. The third group is determined by the functioning of the B allele. And in this case, the genotype can be heterozygous (I in I °) or homozygous (I in I c). Phenotypically, in people with the third blood group, B antigens are detected on the surface of erythrocytes, and blood protein fractions contain alpha antibodies. People with the fourth blood group combine two dominant AB alleles (I A I c) in the genotype, and both of them function: the surface of erythrocytes carries both antigens (A and B), and the blood serum does not contain the corresponding serum proteins alpha and beta to avoid agglutination. Thus, people with the fourth blood group are examples of codominance, since they have two dominant allelic genes working simultaneously.

Phenomenon overdominance due to the fact that in some cases dominant genes in the heterozygous state are more pronounced than in the homozygous state. This concept correlates with the effect of heterosis and is associated with such complex traits as viability, total life expectancy, etc.

Thus, in humans, as in other eukaryotes, all types of interaction of allelic genes and a large number of Mendelian traits determined by these interactions are known. Using the Mendelian laws of inheritance, it is possible to calculate the probability of having children with certain modeling traits.

most convenient methodical approach to the analysis of the inheritance of traits in several generations is a genealogical method based on the construction of pedigrees.

Gene Interaction

So far, we have considered only traits controlled monogenously. However, the phenotypic expression of one gene is usually influenced by other genes. Often, traits are formed with the participation of several genes, the interaction between which is reflected in the phenotype.

An example of a complex interaction of genes is the patterns of inheritance of the Rh factor system: Rh plus (Rh +) and Rh minus (Rh-). In 1939, when examining the blood serum of a woman who gave birth to a dead fetus and had a history of transfusion of her husband's AB0-compatible blood group, special antibodies were found that were similar to those obtained by immunizing experimental animals with rhesus macaque erythrocytes. The antibodies detected in the patient are called Rh antibodies, and her blood type is Rh-negative. Rh-positive blood type is determined by the presence on the surface of erythrocytes of a special group of antigens encoded by structural genes that carry information about membrane polypeptides. The genes that determine the Rh factor are located in the first pair of human chromosomes. Rh-positive blood type is dominant, Rh-negative - recessive. Rh-positive people can be heterozygous (Rh + /Rh-) or homozygous (Rh + /Rh +). Rh-negative - only homozygous (Rh-/Rh-).

Later it turned out that antigens and antibodies of the Rh factor have a complex structure and consist of three components. Conventionally, Rh factor antigens are denoted by the letters of the Latin alphabet C, D, E. Based on the analysis of genetic data on the inheritance of the Rh factor in families and populations, a hypothesis was formulated that each component of the Rh factor is determined by its own gene, that these genes are linked together into one locus and have a common operator or promoter that regulates their quantitative expression. Since antigens are denoted by the letters C, D, E, then the same lower case denote the genes responsible for the synthesis of the corresponding component.

Genetic studies in families show the possibility of crossing over between three genes at the Rh factor locus in heterozygotes. Population studies have revealed a variety of phenotypes: CDE, CDe, cDE, cDe, CdE, Cde, cdE, cde. The interactions between the genes that determine the Rh factor are complex. Apparently, the main factor determining the Rh antigen is the D antigen. It is much more immunogenic than the C and E antigens. /d. In CDe/Cde and Cde/cDe heterozygotes with a combination of Cde genes in the Rh locus, the expression of factor D changes, resulting in the formation of a D u phenotype with a weak response to the introduction of Rh-positive antigens. Consequently, the work of genes in the Rh locus can be regulated quantitatively, and the phenotypic manifestation of the Rh factor in Rh-positive people is different: greater or less.

Rh factor incompatibility between the fetus and the mother can cause the development of pathology in the fetus or spontaneous miscarriage in the early stages of pregnancy. With the help of special sensitive methods, it was found that during childbirth, about 1 ml of fetal blood can enter the mother's bloodstream. If the mother is Rh-negative and the fetus is Rh-positive, then after the first birth, the mother will be sensitized to Rh-positive antigens. In subsequent pregnancies with a Rh-incompatible fetus, the titer of anti-Rh antibodies in her blood can increase sharply, and under the influence of their destructive action, the fetus develops a characteristic clinical picture of hemolytic pathology, manifested in anemia, jaundice or dropsy.

In classical genetics, the most studied are three types of interaction of non-allelic genes: epistasis, complementarity, and polymerism. They determine many of the inherited traits of a person.

epistasis- this is a type of interaction of non-allelic genes, in which one pair of allelic genes suppresses the action of another pair. There are dominant and recessive epistasis. Dominant epistasis is manifested in the fact that the dominant allele in the homozygous (AA) or heterozygous (Aa) state suppresses the expression of another pair of alleles. In recessive epistasis, the inhibitory gene is in the recessive homozygous state (aa) prevents the epistated gene from being expressed. A suppressing gene is called a suppressor or inhibitor, and a suppressed gene is called hypostatic. This type of interaction is most characteristic of genes involved in the regulation of ontogeny and human immune systems.

An example of recessive epistasis in humans is the "Bombay phenomenon". In India, a family was described in which parents had the second (A0) and first (00) blood groups, and their children had the fourth (AB) and first (00). In order for a child in such a family to have an AB blood group, the mother must have a B blood group, but not 0. Later it was found that there are recessive modifier genes in the AB0 blood group system, which in the homozygous state suppress the expression of antigens on the surface of erythrocytes. For example, a person with a third blood group should have a group B antigen on the surface of erythrocytes, but an epistating suppressor gene in a recessive homozygous state (h / h) suppresses the action of gene B, so that the corresponding antigens are not formed, and blood type 0 appears phenotypically. the suppressor gene locus is not linked to the AB0 locus. Suppressor genes are inherited independently of the genes that determine the ABO blood groups. The Bombay phenomenon has a frequency of 1 in 13,000 among Maharati-speaking Hindus living in the vicinity of Bombay. It is also distributed as an isolate on Reunion Island. Apparently, the sign is determined by a violation of one of the enzymes involved in the synthesis of the antigen.

complementarity- this is a type of interaction in which several non-allelic genes are responsible for the trait, and a different combination of dominant and recessive alleles in their pairs changes the phenotypic manifestation of the trait. But in all cases, when the genes are located in different pairs of chromosomes, the splittings are based on the digital laws established by Mendel.

So, for a person to have normal hearing, the coordinated activity of several pairs of genes is necessary, each of which can be represented by dominant or recessive alleles. Normal hearing develops only if each of these genes has at least one dominant allele in the diploid set of chromosomes. If at least one pair of alleles is represented by a recessive homozygote, then the person will be deaf. Let us explain what has been said with a simple example. Let's assume that normal hearing is formed by pair of genes. In this case, people with normal hearing have the genotypes AABB, AABb, AaBB, AaBb. Hereditary deafness is determined by genotypes: aabb, Aabb, AAbb, aaBb, aaBB . Using Mendel's laws for dihybrid crossing, it is easy to calculate that deaf parents (aaBB x AAbb) can have children with normal hearing (AaBb), and normally hearing parents with the appropriate combination of AaBb x AaBb genotypes with a high degree of probability (more than 40%) - deaf children.

Polymerism- the conditionality of a certain trait by several pairs of non-allelic genes that have the same effect. Such genes are called polymeric. If the number of dominant alleles affects the severity of the trait, the polymer is called cumulative. The more dominant alleles, the more intense the trait. According to the type of cumulative polymer, traits that can be quantified are usually inherited: skin color, hair color, height.

The color of human skin and hair, as well as the color of the iris of the eyes, provides the pigment melanin. Forming the color of the integument, it protects the body from exposure to ultraviolet rays. There are two types of melanin: eumelanin (black and dark brown) and feumelanin (yellow and red). Melanin is synthesized in cells from the amino acid tyrosine in several steps. Synthesis is regulated in many ways and depends, in particular, on the rate of cell division. When cell mitosis is accelerated, feumelanin is formed at the base of the hair, and eumelanin is formed when it slows down. Some forms of malignant degeneration of skin epithelial cells, accompanied by the accumulation of melanin (melanoma), are described.

All hair colors, with the exception of red, form a continuous series from dark to light (corresponding to a decrease in the concentration of melanin) and are inherited polygenically according to the type of cumulative polymer. It is believed that these differences are due to purely quantitative changes in the content of eumelanin. The color of red hair depends on the presence of feumelanin. Hair color usually changes with age and stabilizes with the onset of puberty.

The color of the iris of the eye is determined by several factors. On the one hand, it depends on the presence of melanin granules, and on the other hand, on the nature of light reflection. The black and brown colors are due to the numerous pigment cells in the anterior layer of the iris. In light eyes, the pigment content is much less. The predominance of blue in the light reflected from the anterior layer of the iris, which does not contain pigment, is explained by the optical effect. Different pigment content determines the entire range of eye color.

According to the type of cumulative polymer, human skin pigmentation is also inherited. Based on genetic studies of families whose members have different intensity of skin pigmentation, it is assumed that the color of a person's skin is determined by three or four pairs of genes.

Recognition of the principle of interaction of genes suggests that all genes are somehow interconnected in their action. If one gene affects the work of other genes, then it can affect the manifestation of not only one, but also several traits. This multiple action of a gene is called pleiotropy. The most striking example of the pleiotropic effect of a gene in humans is Marfan's syndrome, the already mentioned autosomal dominant pathology. Arachnodactyly ("spider" fingers) is one of the symptoms of Marfan's syndrome. Other symptoms are tall stature due to severe limb elongation, joint hypermobility leading to myopia, lens subluxation, and aortic aneurysms. The syndrome occurs with equal frequency in men and women. These symptoms are based on a defect in the development of connective tissue that occurs at the early stages of ontogenesis and leads to multiple phenotypic manifestations.

Many hereditary pathologies have a pleiotropic effect. Certain stages of metabolism are provided by genes. The products of metabolic reactions, in turn, regulate and possibly control other metabolic reactions. Therefore, metabolic disturbances at one stage will be reflected in subsequent stages, so that a violation of the expression of one gene will affect several elementary traits.

Heredity and environment

The phenotypic manifestation of a trait is determined by the genes responsible for this trait, the interaction of those that determine it with other genes, and environmental conditions. Therefore, the degree of phenotypic expression of a deterministic trait ( expressiveness) can change: increase or decrease. For many dominant traits, it is characteristic that the gene is manifested in all heterozygotes, but to varying degrees. Many dominant diseases show significant individual variability both in age of onset and severity of manifestation, both within the same family and across families.

In some cases, a trait may not be expressed phenotypically at all, despite the genotypic predetermination. The frequency of phenotypic manifestation of a given gene among its carriers is called penetrance and is expressed as a percentage. Penetrance is complete if the trait is manifested in all carriers of a given gene (100%), and incomplete if the trait is manifested only in a part of the carriers. In the case of incomplete penetrance, sometimes one generation is skipped during the transmission of a trait, although an individual deprived of it, judging by the pedigree, should be heterozygous. Pe-netness is statistical concept. Estimation of its value often depends on the methods of examination used.

Sex Genetics

Of the 46 chromosomes (23 pairs) in the human karyotype, 22 pairs are the same in men and women (autosomes), and one pair, called the sex pair, differs in different sexes: in women - XX, in men - XY. The sex chromosomes are present in every somatic cell of an individual. When gametes are formed during meiosis, homologous sex chromosomes diverge into different germ cells. Therefore, each egg cell, in addition to 22 autosomes, carries one sex chromosome X. All spermatozoa also have a haploid set of chromosomes, of which 22 are autosomes, and one is sexual. Half of the spermatozoa contain an X, the other half a Y chromosome.

Since the female sex chromosomes are the same and all eggs carry the X chromosome, the female sex in humans is called homogametic. The male sex, due to the difference in sex chromosomes (X or Y) in spermatozoa, is called heterogametic.

The sex of a person is determined at the time of fertilization. A woman has one type of gametes - X, a man - two types of gametes: X and Y, and, according to the laws of meiosis, they are formed in equal proportions. During fertilization, the chromosome sets of gametes unite. Recall that the zygote contains 22 pairs of autosomes and one pair of sex chromosomes. If the egg is fertilized by a sperm with an X chromosome, then the zygote will have a pair of sex chromosomes XX, a girl will develop from it. If fertilization was produced by a sperm with a Y chromosome, then the set of sex chromosomes in the zygote is XY. Such a zygote will give rise to the male body. Thus, the sex of the unborn child is determined by a man heterogametic for sex chromosomes. The sex ratio at birth, according to statistics, corresponds to approximately 1:1.

Chromosomal sex determination is not the only level of sexual differentiation. An important role in this process in humans is played by hormonal regulation, which occurs with the help of sex hormones, which are synthesized by the gonads.

The laying of the human genital organs begins at a five-week-old embryo. Primary cells of the germinal pathway migrate from the yolk sac to the rudiments of the gonads, which, multiplying by mitosis, differentiate into gonia and become the precursors of gametes. In embryos of both sexes, migration proceeds in the same way. If the cells of the rudiments of the gonads contain a Y-chromosome, then the testes begin to develop, and the beginning of differentiation is associated with the functioning of the euchromatic region of the Y-chromosome. If the Y chromosome is absent, then the ovaries develop, which corresponds to the female type.

Man is by nature bisexual. The rudiments of the reproductive system are the same in the embryos of both sexes. If the activity of the Y - chromosome is suppressed, then the rudiments of the genital organs develop according to the female type. In the complete absence of all elements of the formation of the male sex, female genital organs are formed.

The type of secondary sexual characteristics is due to the differentiation of the gonads. The reproductive organs are formed from the Müllerian and Wolf canals. In women, the Müllerian ducts develop into the fallopian tubes and uterus, while the Wolfian ducts atrophy. In males, the Wolfian ducts develop into the seminal ducts and seminal vesicles. Under the influence of the mother's chorionic gonadotropin, the Leydig cells lying in the embryonic testes synthesize steroid hormones (testosterone), which are involved in the regulation of the development of the individual according to the male type. At the same time, a hormone inhibiting the differentiation of the Müllerian ducts is synthesized in the testes in the Sertoli cells. Normal males develop only if all the hormones that act on the rudiments of the external and internal genital organs "work" at a certain time in a given place.

Currently, about 20 various gene defects have been described, which, with a normal (XY) karyotype for sex chromosomes, lead to a violation of the differentiation of external and internal sexual characteristics (hermaphroditism). These mutations are associated with a violation of: a) the synthesis of sex hormones; b) the susceptibility of receptors to them; c) the work of enzymes involved in the synthesis of regulatory factors, etc.

Inheritance of sex-linked traits

X- and Y-chromosomes are homologous, since they have common homologous regions where allelic genes are localized. However, despite the homology of individual loci, these chromosomes differ in morphology. Indeed, in addition to common areas, they carry a large set of differing genes. The X chromosome contains genes that are not on the Y chromosome, and a number of Y chromosome genes are absent from the X chromosome. Thus, in males, on the sex chromosomes, some genes do not have a second allele on the homologous chromosome. In this case, the trait is determined not by a pair of allelic genes, like a normal Mendelian trait, but by only one allele. A similar state of the gene is called hemizygous, and the signs, the development of which is due to a single allele located in one of the alternative sex chromosomes, are called sex-linked. It predominantly develops in one of the two sexes and is inherited differently in men and women.

Traits linked to the X chromosome can be recessive or dominant. Recessive ones include: hemophilia, color blindness (inability to distinguish between red and green colors), optic nerve atrophy, and Duchenne myopathy. The dominant ones are rickets, which cannot be treated with vitamin D, and dark tooth enamel.

Consider X-linked inheritance using the recessive hemophilia gene as an example. In a man, the hemophilia gene located on the X chromosome does not have an allele on the Y chromosome, that is, it is in the hemizygous state. Therefore, despite the fact that the trait is recessive, in men it manifests itself:

N- normal blood clotting gene

h - hemophilia gene;

X h Y - a man with hemophilia;

X N Y - the man is healthy.

In women, the trait is determined by a pair of allelic genes on the XX sex chromosomes, therefore, hemophilia can only appear in the homozygous state:

X N X N - the woman is healthy.

X N X h - heterozygous woman, carrier of the hemophilia gene, healthy,

X h X h - a woman with hemophilia.

The laws of transmission of traits linked to X chromosomes were first studied by T. Morgan.

In addition to X-linked traits, males also have Y-linked traits. They are called hollandic. The genes that determine them are localized in those regions of the Y chromosomes that have no analogues in the X chromosomes. Hollandic traits are also determined by only one allele, and since their genes are only on the Y chromosome, they are detected in men and are transmitted from father to son, or rather, to all sons. Holandric signs include: hairiness of the ears, webbing between the toes, ichthyosis (the skin has a deep striation and resembles fish scales).

Homologous regions of the X and Y chromosomes contain allelic genes that are equally likely to occur in males and females.

Among the signs they define are general color blindness (lack of color vision) and xeroderma pigmentosum. Both of these traits are recessive. Traits associated with allelic genes located on the X and Y chromosomes are inherited according to the classical Mendelian laws.

Inheritance limited and controlled by sex

The signs of a person, the inheritance of which is somehow related to sex, are divided into several categories.

One of the categories is signs, ohfloor-wounded. Their development is due to genes located in the autosomes of both sexes, but manifested only in one sex. For example, the genes that determine the width of a woman's pelvis are localized in autosomes, inherited from both father and mother, but appear only in women. The same applies to the age of puberty for girls. Among the male characteristics, limited by sex, one can name the amount and distribution of hair on the body.

Another category includes recognizedsex-controlled ki, or sex dependent. The development of somatic traits is due to genes located in autosomes, they appear in men and women, but in different ways. For example, in men, early baldness is a dominant trait, it manifests itself both in dominant homozygotes (Aa) and in heterozygotes (Aa). In women, this trait is recessive, it appears only in recessive homozygotes (aa) . Therefore, bald men are much more than women. Gout is another example, in men its penetrance is higher: 80% versus 12% in women. This means that men are more likely to get gout. The expressiveness of sex-controlled traits is determined by sex hormones. For example, the type of singing voice (bass, baritone, tenor, soprano, mezzo-soprano and alto) is controlled by the sexual constitution. Starting from puberty, the trait is under the influence of sex hormones.

Linkage of genes and maps of chromosomes

The chromosome theory of heredity was formulated and experimentally proved by T. Morgan and his collaborators. According to this theory, genes are located on chromosomes and are arranged linearly in them. Genes located on the same chromosome are called linked, are inherited together and form a linkage group. The number of linkage groups corresponds to the number of pairs of homologous chromosomes. A person has 46 chromosomes: 22 pairs of autosomes and one pair of sex chromosomes (XX or XY), therefore, women have 23 linkage groups, and men have 24, since the male sex chromosomes (XY) are not completely homologous to each other. Each of the male sex chromosomes has genes that are characteristic only for the X and only for the Y chromosome, which correspond to the linkage groups of the X and Y chromosomes.

Genes located on the same chromosome and forming a linkage group are not absolutely linked. In the prophase zygotene of the first meiotic division, homologous chromosomes fuse together to form bivalents; then, in pachytene, a crossing-over exchange occurs between chromatids of homologous chromosomes. Crossover is a must. It is carried out in each pair of homologous chromosomes. The farther apart the genes are located on the chromosome, the more often crossing over occurs between them. Due to this process, the diversity of the combination of genes in gametes increases. For example, a pair of homologous chromosomes contains linked AB and ab genes. In the prophase of meiosis, homologous chromosomes conjugate and form a bivalent: AB ab

If crossing over between genes A and B does not occur, then as a result of meiosis, two types of non-crossover gametes are formed: AB and ab. If the crossing-over takes place, then crossover gametes will be obtained: Ab and aB, that is, the linkage groups will change. The more distant genes A and B are from each other, the more the probability of formation and, accordingly, the number of crossover gametes increases.

If the genes in a large chromosome are located at a sufficient distance from each other and numerous crossovers occur between them during meiosis, then they can be inherited independently.

The discovery of crossing over allowed T. Morgan and his school in the first two decades of the 20th century to develop the principle of constructing genetic maps of chromosomes. The linkage phenomenon was used by them to determine the localization of genes located on the same chromosome and to create gene maps for the fruit fly Drosophila melanogaster. On genetic maps, genes are arranged linearly one after another at a certain distance. The distance between genes is determined in percent of crossing over, or in morganids (1% of crossing over is equal to one morganid).

To build genetic maps in plants and animals, analyzing crosses are carried out, in which it is enough to simply calculate the percentage of individuals formed as a result of crossing over and build a genetic map for three linked genes. In humans, the analysis of gene linkage by classical methods is impossible, since experimental marriages are impossible. Therefore, to study linkage groups and map human chromosomes, other methods are used, primarily genealogical, based on the analysis of pedigrees.

T E M A No. 7 Human hereditary diseases

The problem of human health and genetics are closely interrelated. Genetic scientists are trying to answer the question why some people are prone to various diseases, while others remain healthy under these or even worse conditions. This is mainly due to the heredity of each person, i.e. properties of its genes enclosed in chromosomes.

In recent years, there has been a rapid pace of development of human genetics and medical genetics. This is due to many reasons and, above all, a sharp increase in the share of hereditary pathology in the structure of morbidity and mortality of the population. Statistics show that out of 1000 newborns, 35-40 have various types of hereditary diseases, and in the mortality of children under the age of 5 years, chromosomal diseases account for 2-3%, gene diseases - 8-10%, multifactorial diseases - 35-40%. Every year in our country 180 thousand children are born with hereditary diseases. More than half of them have congenital defects, about 35 thousand. - chromosomal diseases and more than 35 thousand - gene diseases. It should be noted that the number of hereditary diseases in humans is growing every year, new forms of hereditary pathology are noted. In 1956, 700 forms of hereditary diseases were known, and by 1986 their number had increased to 2000. In 1992, the number of known hereditary diseases and signs had increased to 5710.

All hereditary diseases are divided into three groups:

Genetic (monogenic - at the heart of the pathology is one pair of allelic genes)

Chromosomal

Diseases with hereditary predisposition (multifactorial).

human gene diseases

Genetic diseases are a large group of diseases resulting from DNA damage at the gene level.

The general frequency of gene diseases in the population is 1-2%. Conventionally, the frequency of gene diseases is considered high if it occurs with a frequency of 1 case per 10,000 newborns, medium - 1 per 10,000-40,000, and then - low.

Monogenic forms of gene diseases are inherited in accordance with the laws of G. Mendel. According to the type of inheritance, they are divided into autosomal dominant, autosomal recessive and linked to X or Y chromosomes.

Most gene pathologies are caused by mutations in structural genes that perform their function through the synthesis of polypeptides - proteins. Any mutation of a gene leads to a change in the structure or amount of the protein.

The onset of any gene disease is associated with the primary effect of the mutant allele. The main scheme of gene diseases includes a number of links:

mutant allele;

modified primary product;

the chain of subsequent biochemical processes of the cell;

organism.

As a result of gene mutation at the molecular level, the following options are possible:

abnormal protein synthesis;

production of an excess amount of a gene product;

lack of production of the primary product;

production of a reduced amount of a normal primary product.

Not ending at the molecular level in the primary links, the pathogenesis of gene diseases continues at the cellular level. In various diseases, the point of application of the action of the mutant gene can be both individual cell structures - lysosomes, membranes, mitochondria, and human organs. The clinical manifestations of gene diseases, the severity and rate of their development depend on the characteristics of the organism's genotype (modifier genes, dose of genes, the duration of the mutant gene, homo- and heterozygosity, etc.), the patient's age, environmental conditions (nutrition, cooling, stress, fatigue) and other factors.

A feature of gene (as well as in general all hereditary) diseases is their heterogeneity. This means that the same phenotypic manifestation of a disease can be due to mutations in different genes or different mutations within the same gene.

Genetic diseases in humans include numerous metabolic diseases. They may be associated with impaired metabolism of carbohydrates, lipids, steroids, purines and pyrimidines, bilirubin, metals, etc. There is still no unified classification of hereditary metabolic diseases. The WHO scientific group proposed the following classification:

1) diseases of amino acid metabolism (phenylketonuria, alkaptonuria, etc.);

hereditary disorders of carbohydrate metabolism (galalugosemia, glycogen

illness, etc.);

diseases associated with impaired lipid metabolism (Niemann's disease)

Pick, Gaucher's disease, etc.);

hereditary disorders of steroid metabolism;

hereditary diseases of purine and pyrimidine metabolism (gout,

Lesch-Nayan syndrome, etc.);

6) diseases of metabolic disorders of connective tissue (Marfan's disease,

mucopolysaccharidoses, etc.);

7) hereditary disorders of hema- and porphyrin (hemoglobinopathies, etc.);

diseases associated with impaired metabolism in erythrocytes (hemolytic

anemia, etc.);

hereditary disorders of bilirubin metabolism;

hereditary diseases of metal metabolism (Konovalov-Wilson disease

hereditary syndromes of malabsorption in the digestive

tract (cystic fibrosis, lactose intolerance, etc.).

Consider the most common and genetically most studied gene diseases at present.

Mutations at the gene level are molecular structural changes in DNA that are not visible in a light microscope. These include any transformation of deoxyribonucleic acid, regardless of their impact on viability and localization. Some types of gene mutations do not have any effect on the function and structure of the corresponding polypeptide (protein). However, most of these transformations provoke the synthesis of a defective compound that has lost its ability to perform its tasks. Next, we consider gene and chromosomal mutations in more detail.

Characteristics of transformations

The most common pathologies that provoke human gene mutations are neurofibromatosis, adrenogenital syndrome, cystic fibrosis, phenylketonuria. This list can also include hemochromatosis, Duchenne-Becker myopathy and others. These are not all examples of gene mutations. Their clinical signs are usually metabolic disorders (metabolic process). Gene mutations can be:

Change in the base codon. This phenomenon is called a missense mutation. In this case, a nucleotide is replaced in the coding part, which, in turn, leads to a change in the amino acid in the protein.
Changing the codon in such a way that the reading of information is suspended. This process is called nonsense mutation. When a nucleotide is replaced in this case, a stop codon is formed and translation is terminated.
Reading error, frame shift. This process is called "frameshift". With a molecular change in DNA, triplets are transformed during the translation of the polypeptide chain.

Classification

According to the type of molecular transformation, the following gene mutations exist:

duplication. In this case, repeated duplication or duplication of a DNA fragment from 1 nucleotide to genes occurs.
deletion. In this case, there is a loss of a DNA fragment from a nucleotide to a gene.
Inversion. In this case, a 180 degree turn is noted. section of DNA. Its size can be either two nucleotides or a whole fragment consisting of several genes.
Insertion. In this case, DNA segments are inserted from the nucleotide to the gene.

Molecular transformations involving from 1 to several units are considered as point changes.

Distinctive features

Gene mutations have a number of features. First of all, it should be noted their ability to be inherited. In addition, mutations can provoke the transformation of genetic information. Some of the changes can be classified as so-called neutral. Such gene mutations do not provoke any disturbances in the phenotype. So, due to the innate nature of the code, the same amino acid can be encoded by two triplets that differ in only 1 base. However, a certain gene can mutate (transform) into several different states. It is this kind of change that provokes most of the hereditary pathologies. If we give examples of gene mutations, then we can refer to blood groups. So, the element that controls their AB0 system has three alleles: B, A and 0. Their combination determines blood groups. Relating to the AB0 system, it is considered a classic manifestation of the transformation of normal signs in humans.

Genomic transformations

These transformations have their own classification. The category of genomic mutations includes changes in the ploidy of structurally unaltered chromosomes and aneuploidy. Such transformations are determined special methods. Aneuploidy is a change (increase - trisomy, decrease - monosomy) in the number of chromosomes of the diploid set, not multiple of the haploid one. With a multiple increase in the number, they speak of polyploidy. These and most aneuploidies in humans are considered lethal changes. Among the most common genomic mutations are:

Monosomy. In this case, only one of the 2 homologous chromosomes is present. Against the background of such a transformation, healthy embryonic development is impossible for any of the autosomes. Monosomy on the X chromosome is the only one compatible with life. It provokes the Shereshevsky-Turner syndrome.
Trisomy. In this case, three homologous elements are revealed in the karyotype. Examples of such gene mutations: Down syndrome, Edwards, Patau.

Provoking factor

The reason why aneuploidy develops is considered to be the non-disjunction of chromosomes in the process cell division against the background of the formation of germ cells or the loss of elements due to anaphase lag, while when moving towards the pole, the homologous link may lag behind the non-homologous. The concept of "nondisjunction" indicates the absence of separation of chromatids or chromosomes in mitosis or meiosis. This disruption can lead to mosaicism. In this case, one cell line will be normal and the other monosomic.

Nondisjunction in meiosis

This phenomenon is considered the most frequent. Those chromosomes that should normally divide during meiosis remain connected. In anaphase, they move to one cell pole. As a result, 2 gametes are formed. One of them has an extra chromosome, while the other lacks an element. In the process of fertilization of a normal cell with an extra link, trisomy develops, gametes with a missing component - monosomy. When a monosomic zygote is formed for some autosomal element, development stops at the initial stages.

Chromosomal mutations

These transformations are structural changes in the elements. As a rule, they are visualized in a light microscope. Chromosomal mutations usually involve tens to hundreds of genes. This provokes changes in the normal diploid set. As a rule, such aberrations do not cause sequence transformation in DNA. However, when the number of gene copies changes, a genetic imbalance develops due to a lack or excess of material. There are two broad categories of these transformations. In particular, intra- and interchromosomal mutations are isolated.

Environmental influence

Humans have evolved as groups of isolated populations. They lived long enough in the same environmental conditions. We are talking, in particular, about the nature of nutrition, climatic and geographical characteristics, cultural traditions, pathogens, and so on. All this led to the fixation of combinations of alleles specific for each population, which were the most appropriate for living conditions. However, due to the intensive expansion of the range, migrations, and resettlement, situations began to arise when useful combinations of certain genes that were in one environment in another ceased to ensure the normal functioning of a number of body systems. In this regard, part of the hereditary variability is determined by an unfavorable complex of non-pathological elements. Thus, changes in the external environment and living conditions act as the cause of gene mutations in this case. This, in turn, became the basis for the development of a number of hereditary diseases.

Natural selection

Over time, evolution proceeded in more specific forms. It also contributed to the expansion of hereditary diversity. So, those signs were preserved that could disappear in animals, and vice versa, what remained in animals was swept aside. In the course of natural selection, people also acquired undesirable traits that were directly related to diseases. For example, in humans, in the process of development, genes have appeared that can determine sensitivity to polio or diphtheria toxin. Becoming Homo sapiens, the biological species of people in some way "paid for its rationality" by accumulation and pathological transformations. This provision is considered the basis of one of the basic concepts of the doctrine of gene mutations.

MAIN CAUSES OF GENE MUTATIONS AT THE PRESENT STAGE

Pylaykina Vladlena Vladislavovna

Nikonova Anna Valerievna

1st year students, Department of Dentistry, PSU, RF, Penza

Saldaev Damir Abesovich

scientific supervisor, Ph.D. biol. Sciences, Associate Professor, PSU, RF, Penza

Genetics is the biological science of the heredity and variability of organisms and the methods of managing them. It is the scientific basis for the development of breeding methods, for the creation of new breeds of animals, plant species, etc.

The major discoveries of modern genetics are due to the ability of genes to rearrange, or in other words, organisms are able to mutate.

Gene mutations - violations of the sequence of nucleotides.

In our time, scientists have discovered the main factors leading to mutations - mutagens. It is known that mutations are caused by the conditions in which the organism is located: its nutrition, temperature regime, etc., or the action of factors such as certain chemicals or radioactive elements. Viruses are the most dangerous mutagen.

The consequences of mutations can be different. Mutations can be both lethal and sublethal, as well as neutral and vital. There are such strong mutations that the body dies from them. In this case we are talking about lethal mutations.

Organisms die in the presence of any lethal genes at all stages of their development. Most often, the destructive effect of such genes is recessive: it manifests itself only when they are in a homozygous state. An organism dies without leaving any offspring if a mutation occurs with a dominant lethal effect.

Sublethal genes reduce the viability of an organism, neutral ones do not affect its vital functions, and vital ones are useful mutations.

A distinction is also made between spontaneous and induced mutations. Spontaneous mutations occur throughout the life of an organism by chance under normal conditions. environment.

Induced mutations are inherited changes in the genome that result from various mutations in artificial conditions or adverse environmental influences.

Mutations occur constantly, due to processes occurring in a living cell. The main processes that lead to the occurrence of mutations are violations of DNA repair during replication, transcription, as well as genetic recombination.

Association of mutations with DNA replication. Most random chemical changes in nucleotides lead to mutations that occur during replication. At the moment, it has been established that one of the causes of thrombophilia is the Leiden mutation of the gene V of the blood coagulation factor, which is characterized by the replacement of the nucleotide guanine with the nucleotide adenine at position 1691. This leads to the replacement of the amino acid arginine with the amino acid glutamine at position 506 in the protein chain, which is the product of this gene. This mutation is involved in the pathogenesis of acute deep vein thrombosis of the lower extremities. The development of thrombophilia can lead to the development of thrombosis of the vascular bed of the kidneys in any of its areas, including the formation of kidney infarction and thrombotic microangiopathy. This is a serious problem of modern pediatric nephrology.

Association of mutations with DNA recombination. Unequal crossing over often leads to mutations. It usually occurs when there are several duplicated copies of the original gene on the chromosome that have retained a similar nucleotide sequence. As a result of unequal crossing over, a duplication occurs in one of the recombinant chromosomes, and a deletion occurs in the other.

Association of mutations with DNA repair. Spontaneous DNA damage is also very common. To eliminate the consequences of such damage, there are special repair mechanisms (for example, an erroneous DNA segment is cut out and the original one is restored in this place). Mutations occur when the repair mechanism for some reason does not work or cannot cope with the repair of damage. The consequence of violations of DNA repair is a severe hereditary disease - progeria.

Gene repair mutations lead to a multiple change in the mutation frequency of other genes. In 1964, F. Hanawalt and D. Petitjohn proved that mutations in the genes of many enzymes of the excisional repair system lead to a sharp increase in the frequency of somatic mutations in humans, and this leads to the development of xeroderma pigmentosum and malignant tumors of the integument.

Mutagenic environmental factors in our time are well studied by researchers. At the moment, scientists distinguish three main groups of factors: physical, chemical and biological. Physical factors - ionizing cure, ultraviolet sun rays, natural radiation background of the earth. Chemical factors (mutagens) - mustard gas, pesticides, preservatives, etc. Biological factors - viruses, bacteria. The antimutagenic mechanisms of the body are: the degeneracy of the genetic code - amino acids are encoded by several codons; removal of the damaged section of DNA by enzymes; double helix of DNA; reparative superstructures.

Transpositional activity of MGE is the main cause of spontaneous mutations. The study of the primary sequence of MGE revealed that their structure contains a large number of regulatory sites and signal sequences, which means that MGEs can very intensively affect the operation of a gene without destroying the gene itself.

Mutational changes, in contrast to modification variability, appear before changes in environmental conditions. Modification variability, as is known, depends on environmental conditions and the intensity of their impact on the body.

Changes in the structure of the DNA that forms the gene are divided into three groups. Mutations of the first group - the replacement of some bases by others (about 20%). The second group of mutations is a change in the number of nucleotide pairs in a gene, as a result, a shift in the reading frame. The last group of mutations is associated with the inversion of nucleotide sequences within the gene.

Geneticists also single out point mutations separately. These mutations are characterized by the fact that one nitrogenous base is replaced by another.

Point mutations can result from spontaneous mutations that occur during DNA replication. They can also appear as a result of external factors (exposure to ultraviolet or x-ray radiation, heat or chemicals) and during the synthesis of a DNA molecule in which there are damages.

It is believed that the main reason for the formation of base substitution mutations is sporadic errors in DNA polymerases. Watson and Crick explained it this way: “When a DNA molecule comes into contact with water molecules, the tautomeric states of the DNA bases can change. One of the reasons for the formation of base substitution mutations is the deamination of 5-methylcytosine.

The causes of mutations (changes in gene information) are not fully understood, but modern genetics is on final stage studying this issue.

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Gene mutations - a change in the structure of one gene. This is a change in the sequence of nucleotides: dropout, insertion, replacement, etc. For example, replacing a with m. Causes - violations during doubling (replication) of DNA

Gene mutations are molecular changes in the structure of DNA that are not visible under a light microscope. Gene mutations include any changes in the molecular structure of DNA, regardless of their location and impact on viability. Some mutations have no effect on the structure and function of the corresponding protein. Another (most) part of gene mutations leads to the synthesis of a defective protein that is unable to perform its proper function. It is gene mutations that determine the development of most hereditary forms of pathology.

The most common monogenic diseases in humans are: cystic fibrosis, hemochromatosis, adrenogenital syndrome, phenylketonuria, neurofibromatosis, Duchenne-Becker myopathies and a number of other diseases. Clinically, they are manifested by signs of metabolic disorders (metabolism) in the body. The mutation may be:

1) in a base substitution in a codon, this is the so-called missense mutation(from English, mis - false, incorrect + lat. sensus - meaning) - a nucleotide substitution in the coding part of the gene, leading to an amino acid substitution in the polypeptide;

2) in such a change in codons, which will lead to a stop in reading information, this is the so-called nonsense mutation(from Latin non - no + sensus - meaning) - replacement of a nucleotide in the coding part of the gene leads to the formation of a terminator codon (stop codon) and the termination of translation;

3) a violation of reading information, a shift in the reading frame, called frameshift(from the English frame - frame + shift: - shift, movement), when molecular changes in DNA lead to a change in triplets during the translation of the polypeptide chain.

Other types of gene mutations are also known. According to the type of molecular changes, there are:

division(from lat. deletio - destruction), when there is a loss of a DNA segment ranging in size from one nucleotide to a gene;

duplications(from lat. duplicatio - doubling), i.e. duplication or re-duplication of a DNA segment from one nucleotide to entire genes;

inversions(from lat. inversio - turning over), i.e. a 180° turn of a DNA segment ranging in size from two nucpeotides to a fragment that includes several genes;

insertions(from lat. insertio - attachment), i.e. insertion of DNA fragments ranging in size from one nucleotide to the whole gene.

Molecular changes affecting one to several nucleotides are considered as point mutations.

Fundamental and distinctive for a gene mutation is that it 1) leads to a change in genetic information, 2) can be transmitted from generation to generation.

A certain part of gene mutations can be classified as neutral mutations, since they do not lead to any changes in the phenotype. For example, due to the degeneracy of the genetic code, the same amino acid can be encoded by two triplets that differ only in one base. On the other hand, the same gene can change (mutate) into several different states.

For example, the gene that controls the blood group of the AB0 system. has three alleles: 0, A and B, combinations of which determine 4 blood groups. The AB0 blood group is a classic example of the genetic variability of normal human traits.

It is gene mutations that determine the development of most of the hereditary forms of pathology. Diseases caused by such mutations are called gene, or monogenic, diseases, i.e. diseases, the development of which is determined by a mutation of one gene.

Genomic and chromosomal mutations

Genomic and chromosomal mutations are the causes of chromosomal diseases. Genomic mutations include aneuploidy and changes in the ploidy of structurally unchanged chromosomes. Detected by cytogenetic methods.

Aneuploidy- change (decrease - monosomy, increase - trisomy) of the number of chromosomes in the diploid set, not multiple of the haploid one (2n + 1, 2n - 1, etc.).

Polyploidy- an increase in the number of sets of chromosomes, a multiple of the haploid one (3n, 4n, 5n, etc.).

In humans, polyploidy, as well as most aneuploidies, are lethal mutations.

The most common genomic mutations include:

trisomy- the presence of three homologous chromosomes in the karyotype (for example, for the 21st pair, with Down syndrome, for the 18th pair for Edwards syndrome, for the 13th pair for Patau syndrome; for sex chromosomes: XXX, XXY, XYY);

monosomy- the presence of only one of the two homologous chromosomes. With monosomy for any of the autosomes, the normal development of the embryo is impossible. The only monosomy in humans that is compatible with life - monosomy on the X chromosome - leads (to Shereshevsky-Turner syndrome (45, X0).

The reason leading to aneuploidy is the non-disjunction of chromosomes during cell division during the formation of germ cells or the loss of chromosomes as a result of anaphase lagging, when one of the homologous chromosomes can lag behind all other non-homologous chromosomes during the movement to the pole. The term "nondisjunction" means the absence of separation of chromosomes or chromatids in meiosis or mitosis. The loss of chromosomes can lead to mosaicism, in which there is one e uploid(normal) cell line, and the other monosomic.

Chromosome nondisjunction is most commonly observed during meiosis. Chromosomes, which normally divide during meiosis, remain attached together and move to one pole of the cell in anaphase. Thus, two gametes arise, one of which has an extra chromosome, and the other does not have this chromosome. When a gamete with a normal set of chromosomes is fertilized by a gamete with an extra chromosome, trisomy occurs (i.e., there are three homologous chromosomes in the cell), when a gamete without one chromosome is fertilized, a zygote with monosomy occurs. If a monosomal zygote is formed on any autosomal (non-sex) chromosome, then the development of the organism stops at the earliest stages of development.

Chromosomal mutations- These are structural changes in individual chromosomes, usually visible in a light microscope. A large number (from tens to several hundreds) of genes is involved in a chromosomal mutation, which leads to a change in the normal diploid set. Although chromosomal aberrations generally do not change the DNA sequence in specific genes, changing the copy number of genes in the genome leads to a genetic imbalance due to a lack or excess of genetic material. There are two large groups of chromosomal mutations: intrachromosomal and interchromosomal.

Intrachromosomal mutations are aberrations within one chromosome. These include:

—deletions(from lat. deletio - destruction) - the loss of one of the sections of the chromosome, internal or terminal. This can cause a violation of embryogenesis and the formation of multiple developmental anomalies (for example, division in the region of the short arm of the 5th chromosome, designated as 5p-, leads to underdevelopment of the larynx, heart defects, and mental retardation). This symptom complex is known as the "cat's cry" syndrome, since in sick children, due to an anomaly of the larynx, crying resembles a cat's meow;

—inversions(from lat. inversio - turning over). As a result of two points of breaks in the chromosome, the resulting fragment is inserted into its original place after turning by 180°. As a result, only the order of the genes is violated;

— duplications(from Lat duplicatio - doubling) - doubling (or multiplication) of any part of the chromosome (for example, trisomy along one of the short arms of the 9th chromosome causes multiple defects, including microcephaly, delayed physical, mental and intellectual development).

Schemes of the most frequent chromosomal aberrations:
Division: 1 - terminal; 2 - interstitial. Inversions: 1 - pericentric (with capture of the centromere); 2 - paracentric (within one chromosome arm)

Interchromosomal mutations, or rearrangement mutations- exchange of fragments between non-homologous chromosomes. Such mutations are called translocations (from Latin tgans - for, through + locus - place). It:

Reciprocal translocation, when two chromosomes exchange their fragments;

Non-reciprocal translocation, when a fragment of one chromosome is transported to another;

- "centric" fusion (Robertsonian translocation) - the connection of two acrocentric chromosomes in the region of their centromeres with the loss of short arms.

With a transverse rupture of chromatids through the centromeres, "sister" chromatids become "mirror" arms of two different chromosomes containing the same sets of genes. Such chromosomes are called isochromosomes. Both intrachromosomal (deletions, inversions, and duplications) and interchromosomal (translocations) aberrations and isochromosomes are associated with physical changes structures of chromosomes, including those with mechanical breaks.

Hereditary pathology as a result of hereditary variability

The presence of common species characteristics makes it possible to unite all people on earth into a single species of Homo sapiens. Nevertheless, we easily, with one glance, single out the face of a person we know in a crowd of strangers. The extraordinary diversity of people, both within a group (for example, diversity within an ethnic group) and between groups, is due to their genetic difference. It is now believed that all intraspecific variability is due to different genotypes that arise and are maintained. natural selection.

It is known that the human haploid genome contains 3.3x10 9 pairs of nucleotide residues, which theoretically allows to have up to 6-10 million genes. However, the data contemporary research indicate that the human genome contains approximately 30-40 thousand genes. About a third of all genes have more than one allele, that is, they are polymorphic.

The concept of hereditary polymorphism was formulated by E. Ford in 1940 to explain the existence of two or more distinct forms in a population, when the frequency of the rarest of them cannot be explained only by mutational events. Since gene mutation is a rare event (1x10 6 ), the frequency of the mutant allele, which is more than 1%, can only be explained by its gradual accumulation in the population due to the selective advantages of the carriers of this mutation.

The multiplicity of splitting loci, the multiplicity of alleles in each of them, along with the phenomenon of recombination, creates an inexhaustible genetic diversity person. Calculations show that in the entire history of mankind there has not been, is not and in the foreseeable future there will not be a genetic repetition on the globe, i.e. each person born is a unique phenomenon in the universe. The uniqueness of the genetic constitution largely determines the characteristics of the development of the disease in each individual person.

Humanity has evolved as groups of isolated populations living for a long time in the same environmental conditions, including climatic and geographical characteristics, diet, pathogens, cultural traditions, etc. This led to the fixation in the population of specific combinations of normal alleles for each of them, the most adequate to environmental conditions. In connection with the gradual expansion of the habitat, intensive migrations, resettlement of peoples, situations arise when combinations of specific normal genes that are useful under certain conditions in other conditions do not ensure the optimal functioning of some body systems. This leads to the fact that part of the hereditary variability, due to an unfavorable combination of non-pathological human genes, becomes the basis for the development of so-called diseases with a hereditary predisposition.

In addition, in humans, as a social being, natural selection proceeded over time in more and more specific forms, which also expanded hereditary diversity. What could be swept aside in animals was preserved, or, conversely, what animals saved was lost. Thus, the full satisfaction of the needs for vitamin C led in the process of evolution to the loss of the L-gulonodactone oxidase gene, which catalyzes the synthesis of ascorbic acid. In the process of evolution, humanity also acquired undesirable signs that are directly related to pathology. For example, in humans, in the process of evolution, genes appeared that determine sensitivity to diphtheria toxin or to the polio virus.

Thus, in humans, like in any other biological species, there is no sharp line between hereditary variability, leading to normal variations in signs, and hereditary variability, causing the occurrence of hereditary diseases. Man, having become a biological species of Homo sapiens, as if paid for the "reasonableness" of his species by the accumulation of pathological mutations. This position underlies one of the main concepts of medical genetics about the evolutionary accumulation of pathological mutations in human populations.

The hereditary variability of human populations, both maintained and reduced by natural selection, forms the so-called genetic load.

Some pathological mutations can persist and spread in populations for a historically long time, causing the so-called segregation genetic load; other pathological mutations arise in each generation as a result of new changes in the hereditary structure, creating a mutation load.

The negative effect of the genetic load is manifested by increased mortality (death of gametes, zygotes, embryos and children), reduced fertility (reduced reproduction of offspring), reduced life expectancy, social disadaptation and disability, and also causes an increased need for medical care.

The English geneticist J. Hodden was the first to draw the attention of researchers to the existence of a genetic load, although the term itself was proposed by G. Meller back in the late 40s. The meaning of the concept of "genetic load" is associated with a high degree of genetic variability necessary for a biological species in order to be able to adapt to changing environmental conditions.

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MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS

EDUCATIONAL INSTITUTION "GRODNO STATE MEDICAL UNIVERSITY"

Department of Medical Biology and General Genetics

ESSAY

at the rate "Medical biology and general genetics" on the topic:

« Gene mutations as a cause of human hereditary diseases »

Completed by a 1st year student

Faculty of Pediatrics,

Savko Anton Iosifovich

Lecturer: Ambrushkevich

Yuri Georgievich

Grodno GrSMU 2016

Introduction

Heredity has always been one of the most difficult to explain phenomena in the history of mankind. Many scientists put forward their hypotheses about the occurrence of hereditary pathology. However, their assumptions were not based on rigorous scientific observations. In the 20th century, with the development of genetics, it was found out and scientifically confirmed that such pathologies are of a hereditary nature. Prior to this, such diseases were considered diseases of unknown etiology. Medical genetics is the study of hereditary diseases.

Recent years have been characterized by the rapid development of general and medical genetics.

The introduction into clinical practice of biochemical and cytogenetic research methods at the tissue, molecular and submolecular levels contributed to the deciphering of many forms of diseases that were previously considered nosological forms with an unexplained etiology. An increase in the level of diagnostics has led to the identification of many diseases that until recently were classified as clinical rarities - rare and rarest forms of pathology.

Currently, about 2000 hereditary diseases and genetically determined syndromes are known. Their number is constantly growing, dozens of new forms of hereditary pathology are described annually. On the present stage In the development of medicine, the recognition of diverse hereditary diseases and genetically determined syndromes is of exceptional importance.

Mutations and their classification

Mutamtion- persistent (that is, one that can be inherited by the descendants of a given cell or organism) transformation of the genotype that occurs under the influence of the external or internal environment.

The term "mutation" was introduced by Hugo de Vries (1901), a Dutch botanist and geneticist, to characterize random genetic changes. There are spontaneous and induced mutational processes.

Spontaneous mutations occur in any population without any visible external influence. The frequency of spontaneous mutations is low: 10-5 - 10-8 per gene/generation.

Induced mutations result from artificial mutagenesis, i.e. due to mutagenic factors such as temperature, exposure x-rays, chemical substances and biochemical factors.

Mutation properties:

mutations occur suddenly, abruptly;

mutations are inherited, i.e. passed down from generation to generation;

non-directed mutations - any locus can undergo mutations, causing changes in both minor and vital signs;

the same mutations can occur repeatedly;

For the manifestation of mutations can be beneficial and harmful, dominant and recessive.

Mutations can be classified in the following order.

According to the place of occurrence of the mutation and the nature of inheritance, there are:

Generative mutations that occur in the cells of the reproductive germ, germ cells and are inherited.

Somatic mutations that occur in the cells of the body and are not inherited.

Depending on the effect on the viability and fertility of the organism, mutations can be divided into:

Lethal - the embryo dies in the early stages of development

Semi-lethal - lead to a decrease in the viability of an individual that does not survive to the reproductive period

Conditionally lethal - can not manifest itself in some conditions and lead to the death of the organism in other conditions

Sterile - affect fertility, up to infertility

Neutral - the most common

According to the localization of the altered genetic material, mutations are:

1. Nuclear (chromosomal)

2. Cytoplasmic (mitochondrial, plastid).

According to the nature of the change in the level of organization of genetic material, there are:

Gene, or point, mutations, as a result of which the structure of a particular gene changes

Chromosomal mutations, or chromosomal aberrations, lead to disruption of existing linkage groups of genes on a particular chromosome.

Genomic mutations resulting in the addition or loss of one or more chromosomes or a complete haploid set of chromosomes.

Gene mutations

Gene mutations are changes in the number and / or sequence of nucleotides in the DNA structure (insertions, deletions, displacements, substitutions of nucleotides) within individual genes, leading to a change in the quantity or quality of the corresponding protein products.

Overall frequency of gene diseases in human populations - 2-4%.

Gene mutations in humans are the causes of many forms of hereditary pathology. More than 3,000 such hereditary diseases have been described so far. Fermentopathy is the most common manifestation of gene diseases. Also, mutations that cause hereditary diseases can affect structural, transport, and embryonic proteins. Pathological mutations can be realized in different periods of ontogeny. Most of them manifest themselves in utero (up to 25% of all hereditary pathology) and in prepubertal age (45%). About 25% of pathological mutations appear in puberty and adolescence, and only 10% of monogenic diseases develop over the age of 20 years.

sickle cell anemia

This autosomal recessive disease does not begin to manifest until a few months after birth, since the fetal hemoglobin present in the baby's blood in the first few months after birth does not contain the abnormal chain. In addition, high levels of fetal hemoglobin in young children after the appearance of an abnormal circuit reduces the crescent of red blood cells due to increased affinity for oxygen. For carriers, symptoms of the disease appear only when the level of oxygen in the air is very low (for example, at high altitude) or during severe dehydration. Typically, these crises occur about 0.8 times a year in one patient. Sickle cell anemia occurs when glutamic acid is replaced by valine, which causes a change in its structure and functions.

The most characteristic manifestation of sickle cell anemia in young children is the defeat of the bone-articular system: a sharp pain in the joints. mutation gene disease genomic therapy

cystic fibrosis

Cystic fibrosis, or cystic fibrosis of the pancreas, is a systemic hereditary disease caused by a mutation in the cystic fibrosis transmembrane regulator gene and characterized by damage to the external secretion glands, severe dysfunction of the respiratory system and the gastrointestinal tract.

The disease is caused by a gene mutation. The pathological gene is localized in the middle of the long arm of the 7th chromosome. Cystic fibrosis is inherited in an autosomal recessive manner and is registered in most European countries with a frequency of 1: 2000 newborns. If both parents are heterozygous, then the risk of having a child with cystic fibrosis is 25%. According to studies, the frequency of heterozygous carriage of a pathological gene is 2-5%.

Currently, about 1000 mutations of the cystic fibrosis gene have been identified. The consequence of a gene mutation is a violation of the structure and function of the protein, which leads to thickening of the secretions of the external secretion glands, difficulty in evacuating the secret and changing its physicochemical properties, which, in turn, determines the clinical picture of the disease. Changes in the pancreas, respiratory organs, gastrointestinal tract are recorded already in the prenatal period.

The first symptoms of the disease appear in most cases during the first year of life. In 30-40% of patients, cystic fibrosis is diagnosed in the first days of life in the form of intestinal obstruction. Often on the 3-4th day of life, pneumonia joins, which takes a protracted character. Intestinal obstruction can develop at a later age of the patient.

The prognosis for cystic fibrosis to date remains serious. Mortality is 50-60%, and among young children it is higher. Late diagnosis of the disease and inadequate therapy significantly worsen the prognosis. Currently, it is possible to diagnose this disease in early pregnancy, therefore great importance acquires medical genetic counseling for families in which there are patients with cystic fibrosis.

Marfan syndrome

This is a hereditary disease characterized by a systemic lesion of the connective tissue, manifested by "pathological changes in the musculoskeletal system, eyes and cardiovascular system.

It has been established that in Marfan's syndrome, the main defect is associated with collagen disorders, although the possibility of damage to the elastic fibers of the connective tissue is not ruled out. Both sexes are equally affected.

Separate Clinical signs syndromes can be observed already at birth, for example, arachnodactyly is an elongation of the fingers and toes, but the symptom complex is most pronounced in schoolchildren. Patients have a pronounced asthenic type addition (high growth, thinning of subcutaneous tissue, muscle weakness). Characteristic features diseases are dolichocephaly - a change in the shape of the head, when the longitudinal size significantly exceeds the transverse one, the so-called bird's face - narrow, with closely spaced eyes, a thin nose and a protruding upper jaw (prognathia); deformation of the auricles, high palate. Sometimes there is a splitting of the hard palate (cleft palate). The limbs, fingers and toes are elongated, the chest is funnel-shaped or keeled, the ribs are thin and long, the intercostal spaces are wide, the spine is curved , marked looseness of the joints, sometimes with hyperextension in the knee joints, flat feet. At x-ray examination bones reveal thinning of the cortical layer and bone crossbars.

Intelligence in patients with Marfan's syndrome is usually preserved.

Chromosomal mutations

Chromosomes are carriers of genetic information at a more complex - cellular level of organization. Hereditary diseases can also be caused by chromosomal defects that have arisen during the formation of germ cells.

Each chromosome contains its own set of genes, located in a strict linear sequence, that is, certain genes are located not only in the same chromosomes for all people, but also in the same parts of these chromosomes.

Normal body cells contain a strictly defined number of paired chromosomes (hence the pairing of the genes in them). In humans, in each cell, except for the sex, 23 pairs (46) of chromosomes. Sex cells (eggs and sperm) contain 23 unpaired chromosomes - a single set of chromosomes and genes, since paired chromosomes diverge during cell division. During fertilization, when the spermatozoon and the egg merge, a fetus develops from one cell (now with a complete double set of chromosomes and genes) - an embryo.

But the formation of germ cells sometimes occurs with chromosomal "errors". These are mutations that lead to a change in the number or structure of chromosomes in a cell. That is why a fertilized egg may contain an excess or deficiency of chromosomal material compared to the norm. It is obvious that such a chromosomal imbalance leads to gross violations of the development of the fetus. This manifests itself in the form of spontaneous miscarriages and stillbirths, hereditary diseases, syndromes, called chromosomal. The most famous among chromosomal diseases are: Shereshevsky-Turner syndrome, Klinefelter's syndrome, cat's cry syndrome, children's progeria.

Shereshevsky-Turner syndrome

Monosomy for the X chromosome is the only known monosomy for the human sex chromosomes. This anomaly is observed in phenotypically female individuals with growth retardation and sexual development with underdeveloped internal genital organs. Most feature is the absence of gonads, due to poor development or absence of secondary sexual characteristics during puberty.

In a child with this disease, strands of connective tissue are formed instead of the ovaries, the uterus is underdeveloped. Very often, the syndrome is combined with the underdevelopment of other organs. Already at birth, the girl is found to have a thickening of the skin folds on the back of her head, a typical swelling of the hands and feet. Often a child is born small, with low body weight.

For a child still in early age typical appearance:

Proportionately low growth (the final height of patients does not exceed 150 cm);

Shortening of the lower jaw;

Protruding, low-lying ears;

Short neck with pterygoid folds running from the head to the shoulders (sphinx neck), on which a low hairline is noted;

Broad chest with far apart inverted nipples;

Often there is a curvature of the arms in the area of the elbow joints;

Shortened 4th and 5th metacarpal bones, which makes the fingers short;

Bulging nails;

Possible malformations from other organs and systems:

Cardiovascular system - heart defects;

Urinary tract - underdevelopment of the kidneys, doubling of the ureters, doubling and horseshoe kidney;

Organs of vision - ptosis (omission of the eyelid), strabismus, the formation of the "third eyelid".

Secondary sexual characteristics are weakly expressed (sometimes absent altogether) and manifest themselves in the following:

Underdevelopment of the mammary glands;

Abnormal development of large and small labia, uterus, vagina;

The ovaries are not defined;

Amenorrhea (absence of menstruation);

Hair on the pubis and in the armpits is not expressed.

With early detection and timely treatment, increased growth can be achieved. The prognosis of the disease in relation to complete recovery is unfavorable. Patients remain infertile.

With this disease, a lethal outcome (death) is possible, which is primarily due to congenital defects of the vital organs. There is no significant mental retardation in patients; they can successfully study and perform any work that is not associated with physical and significant neuropsychic stress. The frequency of occurrence of the syndrome is one in three thousand born girls.

Klinefelter syndrome

The origin of an additional X chromosome in the karyotype of a patient with the classic variant of Klinefelter's syndrome is due to the nondisjunction of the sex chromosomes during meiosis in the parents. Violation of the correct distribution of sex chromosomes during meiosis leads to the formation of gametes with an abnormal set of sex chromosomes. Their participation in fertilization leads to the appearance of a zygote with a violation in the system of sex chromosomes - aneuploidy.

With nondisjunction of sex chromosomes in meiosis of both parents and subsequent fertilization of such gametes, more complex chromosome complexes are formed (XXXY; XXYU; XXXY; XXXYU, etc.). Non-disjunction or lagging of the sex chromosome during mitotic division can lead to different cell lineages.

The extra X chromosome is inherited from the mother in 60% of cases, especially during late pregnancy. The risk of inheriting the paternal X chromosome does not depend on the age of the father.

It manifests itself for the first time by a delay in the pubertal period, some features of the physique appear (disproportionately long limbs, girlish refinement). Some mental retardation is noted only in 25% of cases. In other patients, against the background of normal mental development, hypo-emotionality, submissiveness, and other behavioral features may be observed. Sexual desire and potency are usually reduced. Although the external genitalia are most often formed correctly, the secondary sexual characteristics are poorly developed. In some adult men, facial hair is completely absent. Most patients have a female type of pubic hair. Hair growth on the body is usually absent. Up to 70% of cases in patients with Klinefelter's syndrome develop bilateral, painless gynecomastia. If gynecomastia has already developed, then, as a rule, it is irreversible and, unlike pubertal or age-related gynecomastia, is not amenable to drug treatment. The testicles are reduced in size, softer, or, conversely, more dense.

The life expectancy of patients with Klinefelter's syndrome does not differ from the average. Clinic of Klinefelter's syndrome in the elderly and old age aggravated by a number of diseases. Some of these diseases are more typical for women: cholelithiasis, obesity, varicose veins.

Klinefelter's syndrome is very common. There is 1 child with this pathology per 500 newborn boys.

Children's Progeria

Progeria, or Hutchinson-Gilford syndrome, is manifested from birth or at an early age by growth retardation and an even more pronounced lag in weight (usually not exceeding 15-20 kg), as well as skin changes. The skin is thin, shiny, dry (due to decreased perspiration), taut. On fingers and toes loose, wrinkled. In the lower abdomen and upper thighs, the skin is thickened, rough, its condition resembles scleroderma. Superficial veins stand out due to the almost complete absence of the subcutaneous fat layer. On clothing-free areas of the body, there may be pigmented brown spots. Characterized by total alopecia, including eyebrows and eyelashes, only vellus hair is preserved. Thinning, brittleness or complete absence of nails. Growth retardation is most pronounced in the first year of life and in puberty. The proportions of the body are normal. The head is relatively large with somewhat prominent frontal tubercles and a reduced size of the facial skull, which leads to a characteristic face with exophthalmos, micrognathia, a small thin beak-shaped nose, overlapping teeth. The ears are protruding, the teeth erupt with a long delay, sometimes they are completely absent. Ophthalmologically revealed clouding of the lens. The chest is narrow, pear-shaped. The limbs are thin, with protruding joints and short distal phalanges of the fingers. Patients lag behind in sexual development, are infertile. Sometimes there are neurological disorders in the form of asymmetric craniocerebral innervation. Intelligence is reduced by more late stage diseases due to progressive atherosclerosis. The life expectancy of such patients is from 7 to 27 years. Death often occurs from myocardial infarction or status epilepticus, the nature of which remains unclear.

This disease is extremely rare, so all its victims are known to medicine today. There are supposedly about a hundred of them all over the world. The etiology and pathogenesis of this disease are not known. In most cases, it occurs sporadically, in several families it has been registered with siblings, incl. from consanguineous marriages, which indicates the possibility of an autosomal recessive type of inheritance.

Genomic mutations

The evolutionary balance in doses of individual genes in a given species and the distribution of these genes by linkage groups remain a stable characteristic of the genome of each species. However, both at the gene and chromosomal levels of the organization of hereditary material, and at the genomic level, it is capable of acquiring mutational changes. These changes can be used as evolutionary material. At the same time, the accelerated pace of the evolutionary process observed at individual stages historical development, as a rule, are caused not so much by the accumulation of gene mutations as by significant changes in the structure of the entire genome. The latter include changes in the dose ratio of various genes and changes in the composition of linkage groups within the genome.

The cause of structural changes in the genome may be a violation of those processes that normally ensure its stability, primarily the processes occurring in meiosis.

Structural changes in the genome can be expressed in a different distribution of genes by linkage groups. When individual chromosomes are connected according to the type of one chromosome, two independent ones are formed, this leads to a change in the number of linkage groups in the genome. When the location of individual genes changes, which often affects the nature of their functioning (position effect).

Any mutational changes in the hereditary material of gametes - generative mutations - become the property of the next generation if such gametes are involved in fertilization. Therefore, deviations in the course of mitosis or meiosis in gamete precursor cells are of great evolutionary importance. If mutations of any rank (gene, chromosomal or genomic) occur in somatic cells - somatic mutations - they are transmitted only to the descendants of these cells, i.e. do not leave the body. The exception is somatic mutations that have arisen in the cells of the organs of vegetative reproduction, from which they are transmitted to a new generation of organisms. One of the causes of somatic mutations are pathological mitoses. If the normal course of mitosis is disturbed (nondisjunction of chromatids of individual chromosomes, multipolar mitoses, etc.), daughter cells receive an abnormal hereditary program and their further development deviates from the norm. Pathological mitoses are often observed in malignant tumor cells.

Thus, despite the existence of mechanisms that ensure the stability of the genome structure, evolutionarily significant changes can appear at this level of organization of the hereditary material. They are able to provide a rather sharp jump in the course of the historical development of living nature.

Down syndrome

According to recent decades, this pathology occurs in every 700 born babies. The statistics of the last few years show a different figure - 1 child born with a pathology per 1100 newborns, which became possible due to high-precision prenatal diagnosis and early termination of such a pregnancy. About 80% of children with this pathology are born to women younger than 35 years old - despite the relatively low risk of developing this chromosomal pathology in the fetus, a peak in fertility is observed in this age group. About 5,000 newborn babies with Down syndrome are added every year around the world.

The causes of Down syndrome lie in the intrauterine formation of fetal chromosomal pathology, characterized by the formation of additional copies of the genetic material of the 21st chromosome, or the entire chromosome (trisomy), or parts of the chromosome (for example, due to translocation). Normal karyotype healthy person consists of 46 chromosomes, and in Down syndrome, the karyotype is formed by 47 chromosomes. The causes of Down syndrome are in no way related to environmental conditions, parental behavior, taking any drugs, and other negative phenomena. These are random chromosomal events that, unfortunately, cannot be prevented or changed in the future.

Trisomy on chromosome 21 (and this is approximately 90% of cases of the disease) is not inherited and is not hereditarily transmitted; the same applies to the mosaic form of pathology. The translocation form of the disease can be hereditary if either of the parents had a balanced chromosomal rearrangement (this means that part of the chromosome changes places with part of some other chromosome without leading to pathological processes). When such a chromosome is passed on to the next generation, an excess of genes on chromosome 21 occurs, leading to a disease.

Signs of Down syndrome in newborns are determined immediately after birth: a shortened skull; small head size; irregular shape of the ears; flattened facial skull; saddle nose; flat bridge; small mouth; small chin; thick, furrowed tongue; oblique cut of the eyes; open mouth; skin folds located on the inner corners of the eyes; short neck; fold of skin on the neck; short upper and lower limbs; short fingers; flattened wide palms; horizontal crease on the palms; concave shape of the little fingers; the apparent distance between the first and second toes; weak muscle tone. When are babies born with Down syndrome? external signs, listed above, will be determined by almost all. The diagnosis is confirmed after the delivery of a genetic analysis for the karyotype.

Edwards syndrome

Edwards syndrome, or trisomy syndrome on chromosome 18, is the second most common genomic disease after Down's disease, which is characterized by a complex of multiple malformations.

The average age of the mother is 32.5 years, the father is 35 years. The duration of pregnancy exceeds the normal (average 42 weeks), weak fetal activity, polyhydramnios, a small placenta, often only one umbilical artery is diagnosed; some children are born in a state of asphyxia, with very low body weight and severe malnutrition.

The phenotypic manifestations of Edwards syndrome are quite characteristic. The skull is dolichocephalic, laterally compressed, with a low forehead and a wide protruding occiput, sometimes microcephaly or hydrocephalus occurs. The palpebral fissures are narrow, epicanthus, ptosis (omission of the organ) is observed, intramural pathology, microphthalmia, coloboma, cataracts occur. The bridges of the nose are depressed, but the back of the nose is thin (protrudes), the auricles are located very low, and the lobe and tragus are often absent. Underdevelopment of the curl and antihelix.

Characteristic microretrognathia (small and receding jaw). The mouth is small, triangular in shape with a short upper lip, the palate is high, sometimes with a slit, the neck is short, often with a pterygoid fold.

Various anomalies of the musculoskeletal system are noted: the chest is expanded, the sternum is shortened, the pelvis is narrow, the limbs are deformed, limited mobility in the hip joints, there is a description of hip dislocations. The hands and fingers are short, the 1st finger is located distally and is hypoplastic. The fingers are clenched into a fist according to the type of "flexor anomaly": II and V fingers are pressed to the palm, the first toe is short and wide, syndactyly of the II and III fingers. Typical for trisomy 18 the shape of the foot in the form of a "swing".

Characteristic general muscular hypotension. Boys often have cryptorchidism (undescended testicles into the scrotum), hypospadias (an anomaly of the anatomical structure of the penis), and clitoral hypertrophy in girls.

An intellectual defect corresponds to oligophrenia in the stage of idiocy or deep imbecility. Often these patients develop convulsive syndrome.

At autopsy with Edwards syndrome, a large number of malformations of almost all organs and systems are found. Anomalies of the central nervous system occur with different frequency: underdevelopment of the corpus callosum, cerebellum, atrophy of the cerebral convolutions.

Nearly 95% of patients with Edwards syndrome have malformations of the heart and large vessels, more common ventricular septal defect and non-closure ductus arteriosus. About half of all cases of trisomy 18 chromosomes are accompanied by congenital anomalies of the digestive system: intestinal placement disorders (Meckel's diverticulum), a sharp narrowing of the esophagus or anus. With the same frequency, there are malformations of the genitourinary system - a segmented or horseshoe-shaped kidney, doubling of the ureters, underdevelopment of the ovaries.

The prognosis for life is unfavorable, the average life expectancy for boys is 2-3 months, for girls - 10 months. 30% of patients die during the first month of life, only 10% of patients live up to a year. With mosaic options, the prognosis for life is somewhat better.

Alzheimer's disease

Alzheimer's disease, or dementia senile progressive, is a hereditary disease. Begins on average at age 55. Two possible variants of the course of the disease are described. In the first, classical, dementia develops relatively quickly, focal symptoms join later. In the second, a slow course is noted with gradually increasing dementia, mnestic disorders and focal symptoms.

Memory disorders occupy a central place in the clinical picture of Alzheimer's disease: a progressive decrease in memory, fixative amnesia, amnestic disorientation, reproductive disorders. Violations of attention, perception, numerous false recognitions are growing. In addition to agraphia, alexia, there is acalculia. There is a growing loss of skills, disinhibition of drives, patients are aimlessly fussy. In the future, the movements are automated. There are speech disorders: sensory aphasia, amnetic aphasia, the transition of speech spontaneity to speech excitation, sometimes logoclonia.

At the end of the disease, dementia has a deep total character. In half of the cases, there are states of hallucinatory confusion, fragmentary crazy ideas, short-term attacks of psychomotor agitation. A third of patients have seizures. In cases of family forms, convulsive seizures are combined with early stage diseases (at 30-35 years). Extrapyramidal disorders (often parkinson-like syndrome) occurs in a number of patients, more often at the end of the disease. In the final stage of the disease, decerebrate rigidity, cachexia, bulimia, oral automatism syndromes, endocrine disorders are detected.

The genetic cause of Alzheimer's disease is a defect in various regions of the 21st chromosome; the genes of these regions control the growth of local groups of neurons.

The defect leads to the formation of accumulations of beta-amyloid (amyloid bodies, Glenner bodies) in the posterior frontal regions of the dominant hemisphere, which disrupt microcirculation.

In pathogenesis, acetylcholine transferase deficiency, a decrease in the synthesis of acetylcholine and a slowdown in neuronal conduction are important. The morphology of dementia of the Alzheimer's type (Alzheimer's disease) has been studied in detail and is characterized by a number of typical features: atrophy of the brain substance, loss of neurons and synapses, granulovacuolar degeneration, gliosis, senile plaques and neurofibrillary tangles, as well as amyloid angiopathy. However, only two of them - senile plaques and neurofibrillary tangles - are considered as key neuromorphological phenomena of the disease and have diagnostic value.

Atrophy of the cortex leads to compensatory hydrocephalus and expansion of the lateral ventricles. With an increase in CSF production, the severity of dementia increases. The autoimmune factor plays a role in the etiology and pathogenesis of the disease. Since amyloid can accumulate around the vessels, the vascular factor also takes part in the pathogenesis. The disease should be differentiated from Pick's disease, brain tumors, cardiovascular diseases.

A dominant type of inheritance is assumed, and polygenic inheritance with a different threshold of manifestation in different families is also possible. Among women, the disease occurs 3-4 times more often than among men.

Treatment of hereditary diseases

Treatment of hereditary diseases is very difficult, lengthy and often ineffective. Three main directions of therapy are known: a direct attempt to "correct" the altered gene, the impact on the main mechanisms of the development of the disease, and, finally, the treatment of individual symptoms that the patient has.

“Correction” of gene defects is possible only with the help of genetic engineering methods, which is understood as the insertion into the cell genome of normal, non-defective genes that perform the same function. Initially, gene therapy was developed for the treatment and prevention of monogenic hereditary diseases. However, in recent years, the focus has shifted towards more common diseases - cancer, cardiovascular disease, AIDS, etc.

Gene therapy is based on replacing defective genes with normal ones. The question of the possibility of treating hereditary diseases arose as soon as scientists developed ways to transfer genes to certain cells, where they are transcribed and translated. The question also arose: which patients should be treated in the first place - those who are more or whose diseases are more studied? Most were inclined to believe that gene therapy should be created for those diseases that are more known: a known affected gene, a protein, the tissues of their localization.

Much attention is currently being paid to research into gene therapy for diseases that affect many people: hypertension, high cholesterol, diabetes, some forms of cancer, and others.

Given that gene therapy is associated with a change in the hereditary apparatus, special clinical trial requirements:

a clear knowledge of the gene defect and how the symptoms of the disease are formed;

reproduction of the genetic model in animals;

lack of alternative therapy, or existing therapy is not possible or effective;

safety for the patient.

Hereditary gene therapy is transgenic and changes all cells in the body. It is not used in humans.

With such treatment, it is possible to isolate cells from the patient's body to introduce the necessary gene into them, after which they return to the patient's body. How the vector is used by retroviruses containing genetic information in the form of RNA. The retrovirus is provided by recombinant RNA (viral RNA + RNA copy of the human gene).

Another approach to gene therapy involves the use of viruses, laboratory-grown cells, and even artificial carriers to introduce genes directly into the patient's body. For example, an adenovirus devoid of disease-causing properties is contained in an aerosol bottle. When an aerosol suspension is inhaled by a patient, the virus enters the lung cells and brings them a functional cystic fibrosis gene. If cells are resistant to genetic manipulation, scientists affect nearby cells. The latter have an effect on cells that are defective in a certain genome. Thus, gene therapy is being tested in mice in which the same area of the brain is damaged as in patients with Alzheimer's disease. The gene for nerve growth factor enters fibroblasts. These cells are implanted into the incision in the brain and secrete a growth factor that neurons need. Neurons begin to grow and produce the appropriate neurotransmitters.

Some success has been achieved with the use of gene therapy in the treatment of malignant neoplasms. A tumor cell is isolated, into which genes encoding such anti-cancer substances of the immune system as interferons and interleukins are introduced. Re-introduced into the tumor, the cells begin to produce these substances, thereby killing themselves and the surrounding malignant cells.

With a number of hereditary diseases, a variety of therapeutic diets have been developed that allow, by eliminating or restricting certain substances in the diet, to achieve normal mental, physical development children and prevention of the progression of metabolic disorders. So, a special diet therapy has been developed for phenylketonuria and other hereditary diseases of amino acid metabolism, galactosemia, fructosemia. Considering that the action of pathological genes is carried out constantly, the treatment of such patients should be long-term, sometimes throughout life. Such treatment requires constant biochemical control and medical supervision.

In some cases, hormone replacement therapy is used, for example, insulin in diabetes mellitus.

In some hereditary diseases, the body is “cleansed” by prescribing special preparations that remove harmful metabolic products, as well as by cleansing the blood (hemosorption), plasma (plasmophoresis), lymph (lymphosorption), etc.

Sometimes surgical treatment is used.

Unfortunately, little is known about most hereditary diseases. In those cases where it is known which tissues are affected, the introduction of a normal gene into them is difficult. Despite this, medical genetics has made significant advances in the treatment of certain diseases.

Conclusion

On this basis, it can be concluded that mutations most often have manifestations in the form of diseases. And of paramount importance for preventing the occurrence and development of a hereditary disease is the prevention of the disease or its timely detection. In this matter, an important place should be occupied by the consultation of a geneticist.

Bibliography

1 - L.O. Badalyan / Hereditary diseases / L.O. Badalyan, Yu.E. Veltischev Publisher: Medicine, 1980, 415s.;

2- E.K. Ginter / Medical genetics / Textbook for medical students. universities / Publisher: Medicine, 2003, 446s.;

3- E.V. Andryushchenko [et al.] / Children's diseases / Reference book / Ed. House: "Russian doctor", 1997, 191 p.;

4- E.K. Ginter, E.V. Balanovskaya, Bukina A.M. [and others] / Hereditary diseases in human populations / Publisher: Medicine, 2002, 936p.;

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