What are the causes of gene mutations. Types of mutations in humans

• Antimorphicmutations.

.

• Neomorphicmutations.

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By genotype:

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

Base substitutions result in three types of mutant codons: with a changed meaning (missense mutations), with an unchanged meaning (neutral mutations) and meaningless or stop codons (nonsense mutations).

Mutations that change the sequence of nucleotides in a gene, i.e. the structure of the gene itself.

1. Gene duplications- doubling of a pair or several pairs of nucleotides (doubling G-C pairs).

2. Gene insertions- insertion of a pair or several nar nucleotides (insertion of a G-C pair between A-T and T-A).

3. Gene deletions - loss of nucleotides (loss of the complementary T-A pair between A-T and G-C).

4. Gene inversions- rearrangement of a gene fragment (in the fragment the original sequence nucleotides T-A, G-C is replaced by reverse G-C, T-A).

5. Nucleotide substitutions- replacement of a pair of nucleotides with another; in this case, the total number of nucleotides does not change (replacement of T-A with C-G). One of the most common types of mutations. Duplications, insertions and deletions can lead to changes in the reading frame of the genetic code. Let's look at this with an example. Let's take the following initial sequence of nucleotides in DNA (for simplicity, we will consider only one of its chains): ATGACCTGCG... It will be read by the following triplets: ATG, ACC, GCG, A... Let's say a deletion has occurred, and at the very beginning of the sequence between A and G, nucleotide T has dropped out. As a result of this mutation, a changed nucleotide sequence will be obtained: AGACCTGCG, which will already be read by completely different triplets: AGA, CCG, CGA. Therefore, completely different amino acids will be combined into the polypeptide chain and, thus, a mutant protein will be synthesized, completely different from the normal one. In addition, as a result of gene mutations leading to a frameshift, stop codons TAA, TAG or TGA can be formed, stopping synthesis. The loss of an entire triplet leads to less severe genetic consequences than the loss of one or two nucleotides. Let's consider the same nucleotide sequence: ATGACCTGCCGA... Let's say a deletion occurred and a whole ACC triplet fell out. The mutant gene will have an altered nucleotide sequence ATGGCGA, which will be read by the following triplets: ATG, HCG, A... It can be seen that after the loss of the triplet, the reading frame has not moved; the synthesized protein, although it will differ by one amino acid from the normal one, will generally be very similar to him. However, this difference in amino acid composition can lead to a change in the tertiary structure of the protein, which mainly determines its function, and the function of the mutant protein is likely to be reduced compared to the normal protein. This explains the fact that mutations are usually recessive.

Gene mutations manifest themselves phenotypically as a result of the synthesis of the corresponding proteins:

Gene mutations lead to changes in the structure of protein molecules and to the appearance of new characteristics and properties (for example, albinos in animals and plants, doubleness in flowers due to the transformation of stamens into petals and a decrease in their fertility, the formation of lethal and semi-lethal genes causing the death of the organism, etc. .d.). Gene mutations occur under the influence of mutagenic factors (biological, physical chemical) or spontaneously (accidentally). Gene mutations are also characteristic of genetic RNA viruses.

• Genomic mutations - These are mutations that lead to the addition or loss of one, several or a complete haploid set of chromosomes ( rice. 118 , B). Different types genomic mutations are called heteroploidy and polyploidy.

Genomic mutations characterized by changes in the number of chromosomes. In humans, polyploidy (including tetraploidy and triploidy) and aneuploidy are known.

Polyploidy - an increase in the number of sets of chromosomes, a multiple of the haploid one (Зn, 4n, 5n, etc.). Reasons: double fertilization and absence of the first meiotic division. In humans, polyploidy, as well as most aneuploidies, lead to the formation of lethal cells.

An exceptionally great role polyploidy in the origin of cultivated plants and their selection. All or most cultivated varieties of wheat, oats, rice, sugar cane, peanuts, beets, potatoes, plums, apples, pears, oranges, lemons, strawberries, and raspberries are polyploid. To this list should be added timothy, alfalfa, tobacco, cotton, roses, tulips, chrysanthemums, gladioli and many other human-cultivated crops. Autopolyploid plant mutants are usually larger than the original form. Tetraploids, as a rule, have a large vegetative mass. However, their fertility may sharply decrease due to non-disjunction of polyvalents in meiosis. Triploids are large and powerful plants, but completely or almost completely sterile, since the gametes they produce contain an incomplete set of chromosomes. Autopolynloid species are propagated vegetatively, since the fruits of such plants do not contain seeds.

Aneuploidy- change (decrease - monosomy, increase - trisomy) number chromosomes in the diploid set, i.e. not a multiple of haploid (2n+1, 2n-1, etc.). Mechanisms of occurrence: chromosome nondisjunction (chromosomes in anaphase move to one pole, while for each gamete with one extra chromosome there is another - without one chromosome) and “anaphase lag” (in anaphase, one of the moving chromosomes lags behind all the others).

*Trisomy - the presence of three homologous chromosomes in the karyotype (for example, on the 21st pair, which leads to the development of Down syndrome; on the 18th pair - Edwards syndrome; on the 13th pair - Patau syndrome).

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

*Tetrasomy and pentasomy:Tetrasomy (4 homologous chromosomes instead of a pair in a diploid set) and pentasomy (5 instead of 2) are extremely rare. Examples of tetrasomy and pentasomy in humans are karyotypes XXXX, XXYY, XXXY, XYYY, XXXXX, XXXXY, XXXYY, XYYYY and XXYYY. As a rule, with an increase in the number of “extra” chromosomes, the severity and severity of clinical symptoms increases.

Haploidy, - oppositepolyploidya phenomenon consisting of a multiple decrease in the number chromosomes in the offspring compared to the mother. Haploidy , as a rule, is the result of the development of an embryo from reduced (haploid) gametes or from cells functionally equivalent to them byapomixis, i.e. without fertilization. Haploidy rare in the animal world, but common in flowering plants: registered in more than 150 plant species from 70 genera of 33 families (including from the family of cereals, nightshades, orchids, legumes, etc.). Known in all major cultivated plants: wheat, rye, corn, rice, barley, sorghum, potatoes, tobacco, cotton, flax, beets, cabbage, pumpkin, cucumbers, tomatoes; at forage grasses: bluegrass, bromegrass, timothy, alfalfa, vetch, etc. Haploidy genetically determined and occurs in some species and varieties with a certain frequency (for example, in corn - 1 haploid per 1000 diploid plants). In the evolution of species Haploidy serves as a kind of mechanism that reduces the levelploidy . Haploidyused to solve a number of genetic problems: identifying the effect of gene dosage, obtaining aneuploids, studying the genetics of quantitative traits, genetic analysis, etc. In plant breedingHaploidyused to receive fromhaploids by doubling the number of chromosomes of homozygous lines, equivalent to self-pollinated lines in the production of hybrid seeds (for example, in corn), as well as for transferring the selection process from the polyploid to the diploid level (for example, in potatoes). Special shape Haploidy - androgenesis , in which the sperm nucleus replaces the egg nucleus, is used to produce male sterile analogues in corn.

Chromosomal mutations(aberrations) are characterized by changes in the structure of individual chromosomes. With them, the sequence of nucleotides in genes usually does not change, but a change in the number or position of genes due to aberrations can lead to a genetic imbalance, which has a detrimental effect on the normal development of the body.

Types of aberrationsand their mechanisms are presented in the figure.

There are intrachromosomal, interchromosomal and isochromosomal aberrations.

Chromosomal aberrations (chromosomal mutations, chromosomal rearrangements)- type of mutations that change the structure chromosomes . Classify deletions (loss of a chromosome section), inversions (changing the order of the genes of a chromosome region to reverse), duplications (repetition of a chromosome section), translocations (transfer of a chromosome section to another), as well as dicentric and ring chromosomes. Isochromosomes are also known to have two identical arms. If a rearrangement changes the structure of one chromosome, then such a rearrangement is called intrachromosomal (inversions, deletions, duplications, ring chromosomes), if two different ones, then interchromosomal (duplications, translocations, dicentric chromosomes). Chromosomal rearrangements are also divided into balanced and unbalanced. Balanced rearrangements (inversions, reciprocal translocations) do not lead to the loss or addition of genetic material during formation, therefore their carriers are, as a rule, phenotypically normal. Unbalanced rearrangements (deletions and duplications) change the dosage ratio of genes, and, as a rule, their carriage is associated with clinical deviations from the norm.

Intrachromosomal aberrations- aberrations within one chromosome. These include deletions, inversions and duplications.

*Deletion - loss of one of the chromosome sections (internal or terminal), which can cause disruption of embryogenesis and the formation of multiple developmental anomalies (for example, deletion in the region of the short arm of chromosome 5, designated as 5p-, leads to underdevelopment of the larynx, congenital heart defects, and mental retardation ). This symptom complex is designated as cry-cat syndrome, since in sick children, due to an anomaly of the larynx, the crying resembles a cat's meow.

*Inversion - insertion of a chromosome fragment into its original place after a rotation of 180°. As a result, the order of genes is disrupted.

*Duplication- doubling (or multiplication) of any part of a chromosome (for example, trisomy on the short arm of chromosome 9 leads to the appearance of multiple congenital defects, including microcephaly, delayed physical, mental and intellectual development).

Interchromosomal aberrations- exchange of fragments between non-homologous chromosomes. They are called translocations. There are three types of translocations: reciprocal (exchange of fragments of two chromosomes), non-reciprocal (transfer of a fragment of one chromosome to another), Robertsonian (connection of two acrocentric chromosomes in the region of their centromeres with the loss of short arms, resulting in the formation of one metacentric chromosome instead of two acrocentric ones) .

* Reciprocal crosses - two crossing experiments characterized by directly opposite combinations gender and the characteristic being studied. In one experiment, a male with a certain dominant trait , crossed with a female having recessive trait . In the second, accordingly, a female with a dominant trait is crossed and a male with a recessive trait.
Reciprocal translocations are a balanced chromosomal rearrangement; during their formation, there is no loss of genetic material. They are one of the most common chromosomal abnormalities in the human population, with carrier frequencies ranging from 1/1300 to 1/700 . Carriers of reciprocal translocations, as a rule, are phenotypically normal, but have an increased likelihood of infertility, reduced fertility, spontaneous miscarriages and the birth of children with congenital hereditary diseases, since half of their gametes are genetically unbalanced due to the unbalanced divergence of rearranged chromosomes in meiosis.

Isochromosomal aberrations- formation of identical, but mirror fragments of two different chromosomes containing the same sets of genes. This occurs as a result of the transverse breaking of chromatids through the centromeres (hence the other name - centric connection).

(aberrations, rearrangements) - changes in the position of chromosome sections; lead to changes in the size and shape of chromosomes. These changes can involve both sections of one chromosome and sections of different, non-homologous chromosomes, therefore chromosomal mutations (rearrangements) are divided into intra- and interchromosomal.

A. Intrachromosomal mutations

1. Chromosomal duplications - doubling of a chromosome section.

2. Chromosomal deletions - loss of a chromosome region.

Chromosomal inversions are a chromosome break, turning the detached section 180° and inserting it into its original place. B. Interchromosomal mutations

1. Translocation - exchange of sections between non-homologous chromosomes (in meiosis). type chromosomal mutations , in which a portion of a chromosome is transferred to a non-homologous chromosome . Separately allocate reciprocal translocations, in which there is a mutual exchange of sections between non-homologous chromosomes, andRobertson'stranslocations, or centric fusions, in which acrocentric chromosomes merge with complete or partial loss of material from the short arms.Translocations, just like others, leukemia.

2. Transposition - inclusion of a chromosome section into another, non-homologous chromosome without mutual exchange.

Score for work: 5

Amelina Svetlana Sergeevna - professor of the department for the course of genetics and laboratory genetics, Doctor of Medical Sciences. Geneticist doctor of the highest qualification category

Degtereva Elena Valentinovna - assistant of the department for the course of genetics and laboratory genetics, geneticist of the first category

Page editor: Kutenko Vladimir Sergeevich

GENE MUTATIONS AND HEREDITARY DISEASES

A recently published catalog of hereditary anomalies includes more than a thousand different clinical syndromes, each of which can be explained by the action of a single altered gene. These abnormalities vary widely in their presentation and severity. Some of them are detected in newborns or in early childhood; others appear only in adults - in middle and old age. Some progress steadily and lead to death; in others, only minor disturbances are noted. In fact, hereditary diseases can affect any organ or tissue to a greater or lesser extent. Thus, this wide variety of disorders affects essentially all branches of medicine. Judging by the rate at which the list of hereditary anomalies in the medical literature is growing, it is likely that we will soon become acquainted with many completely new diseases of this group.

Typically, such diseases are classified depending on whether they are inherited in a dominant or recessive manner, and also depending on the localization of this abnormal gene in one or another of the 22 autosomes or in the sex chromosomes (X and Y); in the latter case they speak of sex-linked anomalies. Among the hereditary diseases currently known, more than half can be classified as autosomal dominant and about 40% as autosomal recessive. The rest (about 8%) are mainly X-linked recessive diseases. To date, not a single case of a pathological condition has been identified that could be attributed to an abnormal gene localized on the Y chromosome.

An important feature of the so-called autosomal dominant diseases is that almost all patients with obvious clinical symptoms are heterozygous. In the genome of such heterozygotes there is one dose of the abnormal gene, which they received from one of the parents, and one dose of its normal allele, received from the other parent. Because most of the abnormal genes that cause such dominant diseases are rare, homozygotes are usually not detected. It should be expected, however, that in the homozygous state the pathological manifestations should be much more pronounced than in affected heterozygotes, and a fatal outcome in early childhood is very likely.

In cases of autosomal recessive diseases, symptomatic individuals are often homozygous and carry two doses of the altered gene, one from each parent. Heterozygotes carrying one dose of an abnormal gene and one dose of a normal allele, in normal conditions, apparently, are quite healthy. However, there are cases when, at a particular genetic locus, two or more different abnormal genes are possible, giving unequal recessive disorders in the homozygous state. Heterozygotes for two of these alleles usually develop disorders similar to those characteristic of. two corresponding homozygous conditions, and if the latter differ from each other in symptoms or severity of the disease, then such a “double” heterozygote usually exhibits intermediate manifestations. A well-known example of this kind is sickle cell in combination with hemoglobin C.

In so-called X-linked recessive diseases, the pathological condition manifests clinically mainly in men, although they have only one X chromosome. In women, who have two X chromosomes, the disease will manifest itself only if the abnormal gene is present on both X chromosomes. chromosomes. If, as is often the case, the altered gene that causes the disease is rare, women may never develop it at all.

1. MOLECULAR PATHOLOGY OF HEREDITARY DISEASES

If the general theory, according to which genes exert their action by directing the synthesis of proteins, is correct in its main provisions, then for each of the diseases under consideration, in principle, it is possible to trace the connection of a characteristic combination of clinical symptoms with a certain defect in an enzyme or other protein caused by a single gene mutation. A complete description of the pathogenesis of the disease would have to begin with the change in the sequence of DNA bases caused by a given mutation; further, it must reflect how this change has perverted the synthesis of a particular protein, what are the secondary biochemical consequences of this perversion, and, finally, how these latter cause the observed pathological symptoms.

For the vast majority of hereditary diseases this Full description not yet feasible. The characteristic manifestations of a particular disease that we observe often arise as a consequence of a very complex chain of events involving the interaction of biochemical and physiological organization on different levels. At present, only a relatively small number of diseases have been studied to such an extent that it is possible to trace the details of at least some stages in this series of causes and effects.

So far, it has not been possible to establish primary genetic disorders for any disease by directly studying the sequence of the bases of the abnormal gene. However, since this gene defines an altered protein that can be isolated, and it is possible to determine what the violation in its structure is, it is often possible to draw conclusions about the nature of the DNA changes that underlie it. Examples of this kind are discussed in the description of various hemoglobinopathies. For example, in sickle cell disease, all pathological changes and clinical manifestations can be explained by the synthesis of abnormal hemoglobin, in the molecule of which in the β-chain, instead of glutamic acid, there is valine in the sixth position. Since the normal β-chain consists of 146 amino acids, and each amino acid is encoded by a sequence of three bases in DNA, we can conclude that the gene defining this polypeptide chain is a 438-nucleotide long stretch of DNA and that the mutation causing the sickle cell allele is occurred in the sixth triplet of this sequence (bases No. 16, 17, 18). Further, given what is known about the genetic code and the general nature of mutations that cause single amino acid changes, we can come to the logical conclusion that in this triplet base number 17 has been changed (adenine instead of thymine in one of the two complementary DNA strands).

Similarly, it was possible to draw conclusions regarding the localization of the primary change in the gene in other hemoglobinopathies. In most of these cases there is a single amino acid substitution in the protein and, as with sickle cell, the mutation can usually be attributed to a change in a specific base. However, in some cases, other protein defects were identified, from the nature of which it could be concluded that the mutational change in the structure of the gene must be completely different. For example, in Lepore hemoglobins, the abnormal polypeptide chain in its first part is identical to the amino acid sequence of the first half of the δ-chain of normal hemoglobin A2, and then has a sequence characteristic of the terminal part of the normal β-chain of hemoglobin A. The easiest way to explain this anomaly is by assuming that the nucleotide sequence constituting the terminal part of the 6-strand gene and the initial part of the adjacent β-strand locus was lost. Since the altered polypeptide chain defined by the new gene contains 146 amino acids, the same as the normal β- or δ-chain, we can conclude that the primary genetic disorder consisted of the deletion (division) of a DNA segment of at least 438 nucleotides in length. Other abnormal hemoglobins, characterized by the loss of part of the polypeptide sequence, are Hb-Freiburg and Hb-Gan-Hill. The first one is missing 1 amino acid in the β-chain, and the last one is missing a sequence of 5 amino acids, indicating a 15-base division.

Thus, the abnormal genes that cause the disease may be the result of different mutations. On the nature of an event (or events) that can cause the replacement of one base.; very little is known. As for deletions, they can probably arise in at least two ways. One of them is unequal crossing over between homologous chromosomes due to their incorrect conjugation during meiosis. Most likely, this is precisely the mechanism of deletions that caused the appearance of Lepore hemoglobins, and possibly some other known hemoglobins with the loss of a section of the molecule. The likelihood of unequal crossing over is especially high if, as a result of previous duplication of genetic material, two similar sections of DNA sequence are adjacent to each other on the same chromosome. The longer the homologous regions, the more likely aberrant conjugation is. Thus, it can be assumed that some genes are more likely to have this type of mutation than others. Another way of occurrence of deletions is the random break of two chromosomes (or chromatids), occurring more or less simultaneously and accompanied by incorrect reunification, as a result of which the intermediate segment falls out if the break occurs in the same chromosome; if breaks occur in different chromosomes, then a translocation of genetic material from one chromosome to another will occur, accompanied by the loss of some part of it.

Data obtained from studies of the structure of abnormal hemoglobins show that both mutations associated with the replacement of one base and mutations caused by deletion can lead to pathology; The same is probably true for other proteins, in particular enzymes. However, assess the relative role various types mutations as the causes of numerous hereditary diseases currently known are not possible. All available data are obtained from the study of cases in which the abnormal protein can be isolated and characterized structurally. However, it is possible that such cases constitute only a very small and, moreover, atypical part of hereditary diseases in general. Even for some hemoglobinopathies (for example, thalassemia), the study of protein structure in itself does not yet allow definite conclusions to be made regarding the nature of the mutational change in DNA. Apparently, in these cases, in order to better understand the nature of mutations, a more in-depth study of disturbances in the mechanisms of protein synthesis, as well as structural studies at the RNA level, is necessary.

In cases where it is possible to identify a specific abnormal protein, analysis of its physicochemical properties represents an important stage in elucidating the pathogenesis of this disease. For example, in case of sickle cell disease, a sharp decrease in the solubility of hemoglobin in the reduced state is extremely important. It is believed to be caused by a change in a very small part of the surface of the protein molecule due to the replacement of the hydrophilic glutamic acid residue with the hydrophobic valine residue. The following is amazing. Many other amino acid substitutions are known in various parts of the hemoglobin molecule, but the sharp change in its solubility during sickle cell disease is unique to this substitution. This change in solubility causes morphological changes in red blood cells placed in conditions of low partial pressure of oxygen - the so-called sickling phenomenon. In vivo, the same deformation of red blood cells occurs in the venous part of the circulatory system, in particular in small veins and venous capillaries, which leads to an increase in blood viscosity. This in turn can cause localized thrombosis and tissue damage. In addition, deformed red blood cells are much more easily destroyed, which leads to chronic anemia and causes other pathological changes. Thus, although many details still remain unclear, the main sequence of events that causes the clinical syndrome of sickle cell disease can be envisioned. The initial mutational change affects only a very small portion of the DNA of a given gene, but its consequences are further enhanced, first by a small change in the fine structure of hemoglobin, as a result of which its solubility decreases, and then by the influence of this fact on circulating red blood cells, resulting in a complex set of pathological changes.

One of physical properties protein, which can be significantly affected by the slightest modification of the structure, is stability. If the stability of an abnormal protein is significantly lower than that of a normal protein, its rate of denaturation in vivo should increase dramatically, and the resulting loss of functional activity can have serious consequences. For example, it has been shown that some hereditary forms of severe chronic anemia are associated with the presence of altered hemoglobin variants, which are predominantly unstable. Such unstable hemoglobins denature in erythrocytes much faster than normal hemoglobin, and this is obviously the main reason for the various pathological phenomena observed in such cases. Some abnormal enzymes, such as the Gd-Mediterranean variant of glucose-6-phosphate dehydrogenase, are also characterized by reduced stability, and the secondary biochemical and clinical abnormalities observed in its carriers may again be largely dependent on this circumstance. It is likely that many other hereditary disorders have similar causes.

Apparently, any change in the primary structure of the protein, leading to a significant disruption of its normal three-dimensional conformation, can lead to a decrease in stability. In cases where a single amino acid substitution occurs, the degree of such effect will depend on the chemical properties and size of the amino acid residue being replaced, as well as on the location of the substitution. Moreover, a variety of substitutions occurring in different parts of the protein molecule can, as it turns out, lead to essentially the same consequences regarding the stability of a given protein and thus cause the same pathological processes. Consequently, different mutations can cause a group of specific disorders, which, however, in all respects except the primary structure of the abnormal protein will be indistinguishable from one another. It can also be noted that various small deletions in the gene, causing the loss of one or more amino acids and, consequently, shortening the polypeptide chain, can in each case cause a significant violation of the three-dimensional structure, expressed in a sharp decrease in the stability of the corresponding protein. Deletions bigger size, causing even greater shortening of the polypeptide, can often lead to the absence of this protein altogether. Similar effects are also possible as a result of mutations consisting in the replacement of one base, leading to the transformation of a triplet encoding a particular amino acid into a triplet encoding chain termination.

When studying the properties of an abnormal enzyme protein, it is of undoubted interest to study the kinetics of the corresponding enzymatic reaction. For example, an important factor in the development of the disease may be a change in the affinity of the enzyme protein for the substrate or coenzyme, which will affect the kinetics. An example of this kind is the change in the kinetics of argininosuccinate synthetase with citrullinemia, the “atypical” form of serum cholinesterase with sensitivity to suxamethonium, and the Gd-Oklahoma glucose-6-phosphate dehydrogenase variant, which causes a special form of chronic hemolytic anemia. In all these cases, it turned out that the Michaelis constants (Kt) with the substrate significantly exceed normal values, and this, apparently, is sufficient to explain the pathological phenomena characteristic of these diseases.

It can be expected that many single amino acid substitutions in an enzyme protein will in one way or another affect its kinetic parameters, causing changes either in the conformation or in the chemical structure of the active center. The same substitutions can also lead to changes in other chemical properties of the enzyme protein, such as its stability. It is clear that assessing the relative role of these changes may be important for elucidating the pathology of a particular disease. In this regard, it is interesting to consider the variant of Gd-Mediterranean glucose-6-phosphate dehydrogenase. Although the structural changes in this abnormal enzyme protein are not yet known in detail, some significant differences in its properties from the normal enzyme have been identified. It is significantly less stable, has lower Michaelis constants for both the substrate (glucose-6-phosphate) and the coenzyme (NADP), and, in addition, it uses the substrate analogue 2-deoxyglucose-6-phosphate more efficiently. The clinical disorder associated with this abnormal enzyme, favism, is almost certainly due to the very low level of enzyme activity in the altered erythrocytes, and this latter circumstance depends mainly on the pronounced instability of the enzyme protein. The altered kinetics probably plays only a minor role or has no significance in the development of this pathology, especially since reduced Michaelis constants for the substrate and coenzyme should be associated with increased activity.

Various mutations can lead to deficiency of a particular enzyme, causing either the synthesis of an abnormal enzyme protein with altered kinetics or stability, or a decrease in the rate of enzyme protein synthesis, or a cessation of synthesis altogether. For many hereditary diseases, it has even been possible to accurately identify the enzyme whose deficiency plays a central role in the development of pathologies, although in most cases the true molecular basis of the enzyme abnormality remains unclear. These diseases are usually classified as “congenital metabolic disorders”, but in principle any hereditary disease should be classified as such. However, for historical reasons, this division remained. Various examples of such diseases have been discussed above.

Another unusual type of biochemical disorder is known, which is characterized by an abnormally high content of certain substances in body fluids or cells with a relative deficiency of other substances. What these changes are depends on the function of the enzyme in normal metabolism and on its localization in tissues. Their degree, and to some extent their distribution, depends on how much the enzymatic activity is reduced. In some diseases there may be no activity at all, while in others it is only reduced to a greater or lesser extent.

The clinical picture observed with these metabolic abnormalities is likely a secondary result of biochemical disturbances caused by a deficiency of a particular enzyme. However, the nature of the causal relationships in such cases is often difficult to ascertain. Let's take phenylketonuria as an example. This disease has been well studied, and much has now been learned regarding the nature of metabolic disorders and changes in the concentrations of a number of metabolites in phenylketonuria, but it is still impossible to satisfactorily explain why the most characteristic symptom of this disease is severe mental retardation. Obviously, this biochemical disturbance somehow damages the neurons of the developing brain. However, the essence of this process is still not clear.

It is perhaps worth reiterating how unexpected the association between clinical syndromes and biochemical abnormalities often is; which underlie them. A good example of this situation is the disease known as homocystinuria. The clinical syndrome with this metabolic disorder is very complex, and includes characteristic symptoms There are such very different manifestations as mental retardation, ectopia of the lens, a tendency to arterial and venous thrombosis and abnormalities of bone development. A systematic examination of a large group of patients with mental retardation (the content of amino acids in the urine was determined) revealed a characteristic increase in the level of homocystine in the urine. This discovery led to the discovery of a severe disorder of methionine metabolism caused by deficiency of the enzyme cystathionine synthetase (L-seride dehydrogenase). Despite the fact that the metabolic pathway for the conversion of methionine to cystine was studied in detail even before the discovery of homocystinuria, biochemists would hardly have been able to predict that disruption of this metabolic pathway could cause the complex of pathological manifestations that are observed in this disease. Although there is little doubt that the occurrence of these clinical symptoms is in some way related to primary cystathionine synthetase deficiency, we still do not know what the in this case specific causal connection.

Another example is Pompe disease. It has long been established that in this disease there is a progressive accumulation of glycogen in various tissues, especially in the myocardium. However, despite the fact that the main pathways for the synthesis and breakdown of glycogen had apparently been established and the enzymes associated with them had been studied, the essence of the chemical processes underlying Pompe disease remained unclear. The discovery that this disease is caused by a specific deficiency of α-(1,4)-glucosidase, which is normally present along with other hydrolases in intracellular organelles called lysosomes, was a complete surprise, since no one had previously thought that this enzyme plays a significant role in any significant role in the breakdown of glycogen.

Using these examples, we are convinced that there are still many such hereditary disorders for which the enzymes (or other proteins) whose deficiency causes them are completely unknown, or even the metabolic site with which these enzymes are associated. The key to all these problems is probably contained in all the symptoms of the disease, but in most cases we do not know how to find it, and so far no one has been able to understand on this basis which biochemical systems should be studied in each specific case.

1. II. DOMINANCE AND RECESSIVITY

As more and more deep penetration In the molecular pathology of a particular disease, we are learning more and more about the nature of its inheritance and, therefore, why it should occur predominantly in a heterozygous state, i.e., be inherited in a dominant manner, or manifest itself only in a homozygous state and so way to treat recessive diseases.

We illustrate this using the example of sickle cell disease, which is inherited in a recessive manner. The clinical disorders characteristic of this disease are due to the fact that hemoglobin found in red blood cells is extremely poorly soluble when it loses oxygen; As a result, a characteristic deformation of red blood cells (sickling) occurs in vivo in those parts of the bloodstream where oxygen pressure is reduced. In heterozygotes for the sickle cell gene, about 65% of the hemoglobin found in red blood cells is usually its normal form, and only about 35% is the altered form. At the same time, the total amount of hemoglobin per cell remains almost normal. A mixture of both forms of hemoglobin generally has reduced solubility compared to normal hemoglobin, and sickling of red blood cells can be easily demonstrated in vitro by sufficiently lowering the oxygen tension. However, the required degree of reduction in oxygen tension under these conditions exceeds that which normally occurs in vivo, and therefore adverse effects do not usually occur in heterozygotes, so that they are generally quite healthy.

This implies one important circumstance, namely, the terms “dominant” and “recessive”, generally speaking, have meaning only in relation to a specific trait or phenotype. Sickle cell disease is inherited as a recessive trait; however, the phenomenon of sickle cell itself, i.e., the characteristic deformation of erythrocytes with appropriate treatment in vitro, is inherited as a dominant trait, since it occurs in both heterozygotes and homozygotes for the abnormal gene.

Now let’s compare “recessive” sickle cell disease with dominantly inherited forms of chronic anemia caused by so-called unstable hemoglobins. With these anemias, both unstable and normal hemoglobin are synthesized in the erythrocytes of heterozygotes. However, due to the rapid denaturation of the unstable form, its quantity, and consequently the total amount of hemoglobin in a functionally active state, decreases during the maturation of erythrocytes. The result is chronic anemia, which is further complicated by the precipitation of denatured abnormal hemoglobin, which accelerates the destruction of red blood cells and their removal from the bloodstream. Thus, in contrast to what is observed in heterozygotes for the sickle cell gene, the normal hemoglobin synthesized by such heterozygotes is not able to compensate for the adverse effects of the abnormal form of hemoglobin on red blood cells. The genes that determine the various variants of unstable hemoglobin are extremely rare, so corresponding homozygotes have not been observed. Can; however, it is foreseeable that in a homozygous state these genes should cause extremely severe forms of anemia, often accompanied by death in early childhood.

The question of whether a given disease caused by deficiency of a particular enzyme is inherited in a recessive or dominant manner may depend largely on the average level of activity of the enzyme in homozygotes for the normal allele and, in particular, on the normal level of its excess compared to the minimum level required to maintain function. In the heterozygous state, the level of a particular enzyme is usually intermediate between normal and that observed in homozygotes for a similar gene. In extreme cases, when an abnormal gene causes complete loss of enzymatic activity, heterozygotes usually exhibit about half the average activity characteristic of homozygotes for the normal gene. If, as seems to be usually the case, the level of activity in homozygotes for the normal allele is on average many times greater than the minimum required for normal metabolic function, then the reduced activity observed in heterozygotes also appears to be somewhat excessive and does not cause adverse consequences. Clinical abnormalities will therefore appear only in homozygotes for the abnormal gene, in whom activity is likely to be so reduced that it is insufficient to maintain normal function. In fact, most of the so-called inborn errors of metabolism identified so far are inherited in a repressive manner, and it can be concluded that normally the level of the corresponding enzymes is significantly higher than the critical level (i.e., the minimum level necessary to maintain normal function). Thus, there is, as it were, a significant “margin of safety”.

The dominant type of inheritance of diseases caused by enzyme deficiency is most likely in cases where this enzyme limits the rate of the metabolic pathway in which it takes part: the level of activity of such enzymes is normally generally close to the minimum required to maintain normal function.

III. HETEROGENEITY OF HEREDITARY DISEASES

Very often it turned out that the syndrome, which was initially considered an independent nosological unit caused by one abnormal gene, is in fact nothing more than a whole group of different diseases that arise as a result of various mutations and each have their own specific pathogenesis. The degree of genetic heterogeneity that can be detected for diseases that at first glance appear to be monoetiological can be quite significant, and there seems to be no doubt that such heterogeneity is a widespread phenomenon.

The fact that several completely different abnormal genes often have very similar or even identical clinical manifestations is not surprising. Loss of function of one or another of the enzymes involved in the same metabolic pathway, or of enzymes that are associated with each other in complex physiological relationships, can naturally give the same or very similar end results at the clinical level. Thus, a variety of abnormal genes, affecting different enzymes, can lead to very similar clinical consequences. Further, a decrease in the activity of a given enzyme or other protein may be caused by a change in the structure of various polypeptide chains encoded by different gene loci, or may be the result of a mutation in any locus specifically associated with the regulation of the rate of synthesis of a given protein. Finally, different mutations can occur at the same locus, and although they change the structure of the corresponding polypeptide chain in different ways, in each case these changes can lead to loss of a specific function and, therefore, to very similar clinical manifestations. Thus, the same clinical picture may actually be due to mutations at several different loci or at a single locus.

Congenital methemoglobinemia is a well-studied case that illustrates this situation. The characteristic clinical manifestation of this rare syndrome is severe cyanosis, due to the fact that a significant part of the hemoglobin iron in erythrocytes and circulating blood is in a trivalent state and is unable to carry oxygen. Methemoglobinemia appears at birth or in early childhood and remains throughout life without significant fluctuations. The majority of those affected do not experience any severe clinical manifestations, although sometimes this anomaly is associated with some degree of mental retardation. Congenital methemoglobinemia should be distinguished from other causes of chronic cyanosis, such as congenital heart defects, which, however, is usually easily determined by clinical examination.

Already the first studies of this disease showed that at the genetic level the anomaly occurs in two forms. In some cases, this disorder appears to be inherited in an autosomal recessive manner, and in others, in an autosomal dominant manner. In the recessive form, a specific, severe deficiency of erythrocyte methemoglobin reductase was discovered. In affected individuals, the activity of this enzyme was very low and often barely detectable. In their parents, children and other relatives who could be considered heterozygous for the corresponding gene, the level of activity of this enzyme was partially reduced, but the degree of suppression of activity was apparently not sufficient to lead to severe methemoglobinemia or cyanosis. Data from electrophoretic studies of residual enzymatic activity in some patients indicate that, at least in some cases, the cause of enzyme deficiency may be a change in the structure of the enzyme protein, and this change is not the same in patients from different families. Thus, at the gene locus (or loci) encoding methemoglobin reductase, there are likely to be several different abnormal alleles that can cause this disease.

In the dominant form, the activity of methemoglobin reductase does not differ from normal. In most of these cases, the structure of hemoglobin itself turns out to be altered, and a number of different deviations from the norm have been identified. Each of them is associated with the replacement of one specific amino acid, occurring in the region of the molecule where the heme group is attached to the polypeptide chain. In this case, both α- and β-chains can be affected, which, of course, are encoded by different gene loci. It has been established that in cases of mutations in the a-chain, cyanosis is noted from the moment of birth, since the a-chain is contained in both embryonic (α 2 γ 2) and adult (α 2 β 2) hemoglobins, whereas in β-mutants chain cyanosis appears a few weeks after birth, when adult hemoglobin becomes predominant.

Thus, congenital methemoglobinemia syndrome can be caused by mutations in at least three different gene loci. One of them specifies the structure of methemoglobin reductase, while the others encode the α- and β-chains of hemoglobin, and at each of these loci there may apparently be several different abnormal alleles causing this syndrome. There is a report of another form of congenital methemoglobinemia, which is inherited, apparently, as an autosomal dominant disease, but is not associated with any changes in either hemoglobin or methemoglobin reductase, therefore, the same clinical disorder can also be caused by mutations in other gene loci in addition to the three named.

Congenital methemoglobinemia is an extremely rare disease; in most populations it occurs no more often than one in several hundred thousand newborns. However, at least 8 different abnormal genes have already been identified that cause this disease, and the syndromes that each causes are difficult, if not impossible, to distinguish by clinical manifestations alone. It can be assumed that the same degree of genetic heterogeneity will be found for many other hereditary diseases that are currently described only clinically or, at most, at the level of secondary biochemical or physiological disorders caused by an abnormality of the corresponding enzyme or other protein.

Consider, for example, phenylketonuria. The characteristic biochemical changes observed in the blood, cerebrospinal fluid and urine in this disease can be explained by the fact that due to deficiency of the enzyme phenylalanine 4-hydroxylase, the normal metabolic conversion of phenylalanine to tyrosine does not occur. The disease is inherited as an autosomal recessive disorder, and it was generally believed that all patients were homozygous for the same abnormal gene. However, in fact, there are a number of different abnormal genes that can lead to the loss of activity of a given enzyme in different ways. If this is so, then among patients there may be homozygotes for one or another of these genes, as well as heterozygotes for two of them. In addition, the disease can be caused by mutations in two or more different gene loci. At present, too little is known about the structure of this enzyme protein and the regulation of the rate of its synthesis to try to assess how plausible such an assumption is. There are also no known linkage markers that could help determine whether this disease can actually be caused by genes located at different loci.

The various mutations causing deficiency of a given enzyme can, of course, vary in the degree of impairment they cause and, therefore, in the severity of its clinical manifestations. Some mutations can lead to the complete loss of a functionally active enzyme, and mutants in which this happened for different reasons can often be affected by the “identical” disease. However, in cases where enzymatic activity disappears incompletely, the degree of deficiency in different mutants can vary widely. And until the molecular and genetic differences underlying different cases of the disease are identified, it may seem that we are dealing with a single hereditary disease, apparently caused by a specific abnormal gene, the clinical manifestations and severity of which are high degree of variability. It is almost certain that many commonly observed clinical variants of the disease, considered as a nosological entity, are due to this common cause.

An example of such a situation, when fluctuations in the functional activity of a particular enzyme and clinical manifestations are caused by various mutations that damage a given enzyme protein, is the case of glucose-6-phosphate dehydrogenase, for which many variants are known. Almost 30 variant forms of this enzyme protein have been discovered. They differ in electrophoretic mobility, Michaelis constants, thermal stability and pH optima. They all appear to be determined by a series of alleles, each of which causes a specific structural change. Since these alleles are located at a locus located on the X chromosome, in men it is possible to study the effect of each of these alleles separately on the level of enzymatic activity. Most of these studies have been conducted on red blood cells; It was found that cells containing different variants of the enzyme differ significantly in average G-6-PD activity. In some cases, only traces of activity are detected, in others there is a less dramatic, but nevertheless clearly pronounced decrease in enzymatic activity. There are also variants of the enzyme that differ only slightly in average activity from the normal enzyme. These differences in activity levels can often be due to differences in the stability of enzyme proteins. However, in some cases, changes in the kinetic or other properties of the enzyme may play an important role.

In some cases, the degree of enzyme deficiency and disturbances in red blood cell metabolism are severe enough to cause a state of chronic hemolytic anemia (due to premature destruction of red blood cells). In other cases, affected individuals are normally healthy but tend to develop symptoms of hemolysis when exposed to agents that are harmless to other individuals. For example, carriers of the variant allele Gd Mediterranean are sensitive to some substances contained in faba beans, and carriers of the allele Gd A, which is widespread among blacks, are sensitive to primaquine and some sulfa drugs. There are also other variants of G6PD that do not appear to be associated with the development of any pathology; in general, the degree of enzymatic deficiency, which varies widely, to some extent correlates with the severity of the clinical consequences.

The same kind of relationship is shown in relation to disorders of other enzymes. A particularly interesting example is hypoxanthine: guanine phosphoribosyltransferase, an enzyme normally associated with the formation of uric acid. Lesh and Nyhan described a complex and very severe neurological syndrome in children, which is characterized by mental retardation, spastic paralysis of central origin, choreoathetosis and a peculiar behavior disorder manifested in self-torturing bites. This condition has been found to be associated with hyperuricemia due to increased production of uric acid, which in some cases is accompanied by urate stones in the urinary tract and symptoms of gout. It turned out that this disease is caused by a complete lack of activity of hypoxanthine: guanine phosphoribosyltransferase; the deficiency is caused by a normal gene localized on the X chromosome.

Since this enzyme is involved in the formation of uric acid, it was further studied in adult patients with a typical clinical picture of acute gouty arthritis or nephrolithiasis, as well as in individuals with hyperuricemia due to increased production of uric acid. In such patients, insufficiency of this enzyme was found in several cases, although not as pronounced as in Lesch-Nyhan syndrome. It is clear that several completely different types of abnormalities leading to hyperuricemia occur, but in the same family, all affected individuals exhibit the same abnormality. Thus, in one family, the enzymatic activity in affected individuals, according to determinations (determinations were carried out on erythrocytes, hypoxactin and guanine were used as substrates), was only about 1% of the normal value, and the enzymatic protein was significantly more thermolabile than the normal enzyme. In another family, patients also showed significantly reduced enzymatic activity, but its decrease when using guanine as a substrate was much more pronounced than with hypoxanthine; this indicates an altered nature of substrate specificity. In addition, the enzyme in this case. turned out to be less thermolabile than normal.

All this indicates that different abnormal genes occur in different families, each of which controls the formation of a structurally different form, an enzyme protein, with abnormal properties. Each of them, obviously, leads to a pronounced enzyme deficiency, manifested in increased formation of uric acid, which is accompanied by hyperuricemia, and clinical manifestations (gout and kidney stones) in different cases are very similar to each other. However, the clinical picture differs sharply from Lesch-Nyhan syndrome, which appears to result from the complete or almost complete absence of the enzyme and is accompanied by severe neurological impairment that appears in childhood.

In conclusion, the following should be noted. Differences in the manifestation of certain hereditary diseases in individuals may depend not only on the fact that they are caused by different mutant genes that determine the characteristic change in the enzyme or other protein that is the main cause of the disease; they also depend on the characteristics of the entire genetic constitution of the carrier of this abnormal gene. Because different normal alleles may be present at many gene loci, it is likely that no two individuals, other than monozygotic twins, will be found to be exactly the same in their “genetic background.” These differences in “genetic background” can certainly influence the manifestations of a particular disorder, since from they depend on many biochemical conditions and physiological environment, in which it should be realized activity of this abnormal gene. Some gene combinations in unaffected loci can weaken pathological manifestations, while others, on the contrary, - strengthen them. But because these various combinations of genes are often practically do not lead to visible differences between individuals, not having this abnormal gene, determine the mechanism, by which they affect the expression of an abnormal gene, the matter is extremely difficult.

It is necessary to distinguish between variation due to loci other than the one at which the abnormal gene is located and variation due to the presence of different “normal” alleles at the same locus. The second source of variability, of course, is only possible if the patients are heterozygotes (i.e., with “dominant” diseases). It has been established that several different alleles can occur at the same gene locus, affecting function differently and not necessarily causing overt disease. Sometimes two or more of these alleles are relatively widespread, so that the abnormal gene in question may be in heterozygous combination with one or another of these various "normal" alleles. It may; influence the manifestation of disease symptoms. This effect is often called allelic modification. It determines the fact that between sibs the similarity in the manifestation of a certain form of the disease is greater than between parents and children.

1. IV. HEREDITARY AND ENVIRONMENT

The characteristic features of an individual depend not only on the set of his genes, and, consequently, on the set of enzymes and other proteins that are formed in his body, but also on the environment in which he develops and lives. The relationships between what Francis Galton calls “nature” and “nurture” are often very complex and difficult to interpret. However, we are unconditionally clear about the importance of these relationships in determining the criteria for what exactly should be considered hereditary diseases. Let us consider this issue using the example of several diseases for which a hereditary anomaly has been identified at the enzyme level and the environmental factors influencing its manifestation have been more or less clarified.

First of all, galactosemia should be mentioned. This disease is expressed in the inability to metabolize the monosaccharide galactose due to a genetically determined deficiency of the enzyme galactose-1-phosphate uridyl transferase. Galactose in the disaccharide lactose is the main carbohydrate component of milk, and therefore infants usually receive it in large quantities. In the absence of this transferase, galactose metabolism is disrupted. The galactose content in the blood increases, galactose-1-phosphate accumulates in the cells; all this causes severe clinical symptoms. The child's development is disrupted, he slowly gains weight, liver and brain damage is often observed, and cataracts develop. If, however, the child is given food that does not contain galactose, but is complete in other respects, then rapid improvement occurs. In practice, if the diagnosis is made early enough, before irreversible changes occur, the child can grow up normal and healthy.

Therefore, galactosemia can in some sense be considered as a congenital loss of the ability to respond appropriately to one of the normal environmental factors, namely lactose contained in milk. With appropriate changes in the environment, the violation can be prevented. Although a given individual will still lack the enzyme under new environmental conditions, this will not have clinical consequences. He will remain susceptible to the disease, but it will not manifest itself clinically.

Hereditary fructose intolerance further illustrates this phenomenon. In this case we're talking about about deficiency of liver aldolase (aldolase B), necessary for normal fructose metabolism. Ingestion of fructose or sucrose in food causes severe symptoms. If fructose is excluded from the diet, then there will be no damaging effect. Unlike galactose, fructose is not an essential part of the normal diet of infants. As a result, the manifestations and severity of this disease vary widely. Apparently, an important factor in this case is the moment of stopping breastfeeding. If a child is early transferred to artificial feeding, in which he receives sucrose, then his condition quickly worsens. If the nature of the violation is not recognized, then irreversible changes may occur. If, however, the child continues to be breastfed for several months, then he often begins to reject food that harms him; at this time it is much more likely that the anomaly will be recognized. In addition, such children usually develop an aversion to sugar, sweets and fruits, and in this way they protect themselves. So, it is clear that the severity of manifestations of hereditary diseases can largely depend on completely random and apparently unrelated environmental factors. In this case, the factor is the time of weaning. By the way, this example also shows that preference for one food or another can be a direct consequence of an enzyme abnormality.

The dependence of heredity on environmental factors appears especially clearly to us in the example of favism. This. the disease, expressed in severe intermittent hemolytic anemia, attacks of which are provoked by the ingestion of faba beans (Vicia faba), has been known for a long time. Favism is especially common in the Middle East and parts of southern Europe, i.e. in areas where beans are a common food product. However, not all people who eat beans develop favism. It occurs only in people with genetically determined G6PD deficiency, usually caused by the presence of the Gd-Mediterranean variant. Thus, in order for the disease to manifest itself, the individual must be a carrier of the corresponding gene and eat beans. So, both genetic and environmental factors are important for the development of the disease. In reality, the situation is even more complex, since not all individuals with this specific enzyme deficiency who eat fava beans will develop the blood disease, and those who do may not have the same severity of the disease. The reasons for this are not entirely clear, but there are some indications that it may be due to some additional genetic factors, as well as differences in the amount of beans eaten and in the form in which they are taken in food.

There is no doubt that galactosemia is a hereditary disease, since it manifests itself in all individuals with the appropriate genetic constitution. The environmental factor to which they are sensitive is present everywhere. The same is essentially true for hereditary fructose intolerance, but in this case the environmental factor is somewhat more variable, and this entails differences in the severity of the clinical manifestations of the disease. However, favism cannot be considered as a disease caused only by a hereditary factor or only by an environmental factor, and it is possible that this also applies to many other diseases encountered in clinical practice.

In practice, the question of whether a particular disease is classified as hereditary or caused by environmental factors must be decided depending on the relative frequency of the hereditary predisposition and provoking environmental factors. If a hereditary predisposition is relatively rare, and the provoking environmental factor is widespread, if not everywhere (as is the case with galactosemia), then this disease should be classified as hereditary. If, on the contrary, there is a genetic predisposition. relatively common, and unfavorable environmental conditions occur infrequently, then environmental factors apparently have to be considered the most important reason.

Consider scurvy as an example. As far as we know, humans and other primates are unable to synthesize L-ascorbic acid(vitamin C). Consequently, if for one reason or another their food does not contain enough of this vitamin, then they develop scurvy. This does not happen in most other mammals, since they seem to be able to synthesize L-ascorbic acid from D-glucose themselves:

D-glucose → D-glucuronic acid lactone → L-gulonic acid lactone →

L-ascorbic acid.

Apparently, in humans and other primates, the necessary gene was lost during evolution, and with it the enzyme capable of converting L-gulonic acid lactone into L-ascorbic acid. Thus, scurvy is reasonably considered as a disease caused by an unfavorable environmental factor, namely a lack of vitamin C in food. However, with equal grounds it can be argued that it is caused by a congenital metabolic disorder common to all humanity.

In some cases, of course, the hereditary predisposition to this disease may be relatively rare and the occurrence of certain environmental factors that provoke this disease may be low. In such circumstances, the disease must also be rare and very unevenly distributed, and the results of family examinations may not necessarily show that hereditary factors play any role in its occurrence. A simple model for this type of situation is the occurrence of a disorder known as suxamethonium sensitivity. About one in 2,000 cases are highly sensitive to suxamethonium, often used as a muscle relaxant during surgery. This sensitivity is due to either the synthesis of an atypical form of serum cholinesterase, which is much less effective in destroying this drug than the usual enzyme, or the absence of synthesis of this enzyme at all. In both cases, the muscle paralysis and associated respiratory arrest caused by this drug are too long. However, if affected individuals are not exposed to such an unusual and generally artificial environmental factor as suxamethonium, then they are apparently quite healthy. Thus, in order for a clinical deviation from the norm to occur, in this case a combination of a rare hereditary predisposition and unusual conditions environment. It is not surprising, therefore, that the familial nature of this anomaly often cannot be recognized.

If we compare the entire spectrum of diseases and anomalies in humans, then at one extreme there will be diseases such as sickle cell anemia, phenylketonuria, hemophilia, muscular dystrophy, etc., which we consider as hereditary, since they develop in all carriers of the corresponding genes. At the other pole there will be diseases caused primarily by environmental factors: for example, severe infections such as plague, anthrax, typhoid, etc., i.e. those that, as a rule, affect everyone who encounters provoking disease factors. However, there are many diseases, often quite widespread, for the development of which both hereditary and environmental factors appear to be important. Typical examples Such diseases are schizophrenia, diabetes and peptic ulcer. All of these diseases are characterized by a hereditary predisposition, but at the same time it is clear that the disease develops only in a portion of genetically predisposed individuals. However, in all such cases we do not know the nature of the primary effects of the corresponding genes. In addition, we are not able to clearly define those environmental conditions that lead to the onset of the disease in some individuals as opposed to others who are also genetically predisposed to it.

Clinical disorders actually develop only in a small part of the population (shaded sector), that is, in those individuals for whom a genetic predisposition is combined with exposure to unfavorable environmental conditions.

The practical significance of this formulation of the question is that it helps after ways of identifying (using genetic methods) in a given population of individuals predisposed to a particular disease, to further detect critical environmental factors. Essentially, it is necessary to find out under what environmental conditions the genetic predisposition is realized. If this is established, environmental conditions can be adjusted accordingly before predisposed individuals develop clinical disorders.

Of course, for different diseases, the proportion of genetically predisposed people in the population can be different - very small or, conversely, large, and the part of the population exposed to unfavorable environmental conditions can also vary in size. Moreover, it is possible that another type of predisposition is due to several acting differently. But since the effects of such genes are not the same, the degree of predisposition will vary. Thus, in reality, all the lines should not be so clear.

However, the simple approach illustrated by the following diagram is very useful when considering problems arising in connection with pathological conditions, especially the more common ones. We arrive at a remarkable paradox. It turns out that studying the genetics of many diseases can lead to the development of methods for preventing or treating them, which consist solely of environmental changes. It is quite possible that one of the most important social and medical aspects of the application of genetic research will be the regulation of environmental conditions, since the more accurately we can characterize the genetic constitution of an individual, the clearer it will become to us how to change environmental conditions to suit his needs.

Variability- the ability of living organisms to acquire new characteristics and properties. Thanks to variability, organisms can adapt to changing environmental conditions.

There are two main forms of variability: hereditary and non-hereditary.

Hereditary, or genotypic, variability- changes in the characteristics of the organism due to changes in the genotype. It, in turn, is divided into combinative and mutational. Combinative variability arises due to the recombination of hereditary material (genes and chromosomes) during gametogenesis and sexual reproduction. Mutational variability arises as a result of changes in the structure of hereditary material.

Non-hereditary, or phenotypic, or modification, variability- changes in the characteristics of the organism that are not due to changes in the genotype.

Mutations

Mutations- these are persistent, sudden changes in the structure of the hereditary material at various levels of its organization, leading to changes in certain characteristics of the organism.

The term “mutation” was introduced into science by De Vries. Created by him mutation theory, the main provisions of which have not lost their significance to this day.

1. Mutations arise suddenly, spasmodically, without any transitions.
2. Mutations are hereditary, i.e. are persistently passed on from generation to generation.
3. Mutations do not form continuous series, are not grouped around an average type (as with modification variability), they are qualitative changes.
4. Mutations are non-directional - any locus can mutate, causing changes in both minor and vital signs in any direction.
5. The same mutations can occur repeatedly.
6. Mutations are individual, that is, they occur in individual individuals.

The process of mutation occurrence is called mutagenesis, and environmental factors causing mutations are mutagens.

According to the type of cells in which the mutations occurred, they are distinguished: generative and somatic mutations.

Generative mutations occur in germ cells and do not affect symptoms of a given organism, appear only in the next generation.

Somatic mutations arise in somatic cells, manifest themselves in a given organism and are not transmitted to offspring during sexual reproduction. Somatic mutations can be preserved only through asexual reproduction (primarily vegetative).

According to their adaptive value, they are divided into: beneficial, harmful (lethal, semi-lethal) and neutral mutations. Useful- increase vitality, lethal- cause death semi-lethal- reduce vitality, neutral- do not affect the viability of individuals. It should be noted that the same mutation can be beneficial in some conditions and harmful in others.

According to the nature of their manifestation, mutations can be dominant And recessive. If a dominant mutation is harmful, then it can cause the death of its owner in the early stages of ontogenesis. Recessive mutations do not appear in heterozygotes, therefore they remain in the population for a long time in a “latent” state and form a reserve of hereditary variability. When environmental conditions change, carriers of such mutations may gain an advantage in the struggle for existence.

Depending on whether the mutagen that caused this mutation has been identified or not, they distinguish induced And spontaneous mutations. Typically, spontaneous mutations occur naturally, while induced mutations are caused artificially.

Depending on the level of hereditary material at which the mutation occurred, gene, chromosomal and genomic mutations are distinguished.

Gene mutations

Gene mutations- changes in gene structure. Since a gene is a section of a DNA molecule, a gene mutation represents changes in the nucleotide composition of this section. Gene mutations can occur as a result of: 1) replacement of one or more nucleotides with others; 2) nucleotide insertions; 3) loss of nucleotides; 4) doubling of nucleotides; 5) changes in the order of alternation of nucleotides. These mutations lead to changes in the amino acid composition of the polypeptide chain and, consequently, to changes in the functional activity of the protein molecule. Gene mutations result in multiple alleles of the same gene.

Diseases caused by gene mutations are called genetic diseases (phenylketonuria, sickle cell anemia, hemophilia, etc.). The inheritance of gene diseases obeys Mendel's laws.

Chromosomal mutations

These are changes in the structure of chromosomes. Rearrangements can occur both within one chromosome - intrachromosomal mutations (deletion, inversion, duplication, insertion), and between chromosomes - interchromosomal mutations (translocation).

Deletion— loss of a chromosome section (2); inversion— rotation of a chromosome section by 180° (4, 5); duplication- doubling of the same chromosome section (3); insertion— rearrangement of the area (6).

Chromosomal mutations: 1 - parachromosomes; 2 - deletion; 3 - duplication; 4, 5 — inversion; 6 - insertion.

Translocation- transfer of a section of one chromosome or an entire chromosome to another chromosome.

Diseases caused by chromosomal mutations are classified as chromosomal diseases. Such diseases include the “cry of the cat” syndrome (46, 5p -), translocation variant of Down syndrome (46, 21 t21 21), etc.

Genomic mutation called a change in the number of chromosomes. Genomic mutations occur as a result of disruption of the normal course of mitosis or meiosis.

Haploidy- reduction in the number of complete haploid sets of chromosomes.

Polyploidy— increase in the number of complete haploid sets of chromosomes: triploids (3 n), tetraploids (4 n) etc.

Heteroploidy (aneuploidy) - a multiple increase or decrease in the number of chromosomes. Most often, there is a decrease or increase in the number of chromosomes by one (less often two or more).

The most likely cause of heteroploidy is the nondisjunction of any pair of homologous chromosomes during meiosis in one of the parents. In this case, one of the resulting gametes contains one less chromosome, and the other contains one more. The fusion of such gametes with a normal haploid gamete during fertilization leads to the formation of a zygote with a smaller or larger number of chromosomes compared to the diploid set characteristic of a given species: nullosomia (2n - 2), monosomy (2n - 1), trisomy (2n + 1), tetrasomy (2n+ 2) etc.

The genetic diagrams below show that the birth of a child with Klinefelter syndrome or Turner-Shereshevsky syndrome can be explained by the nondisjunction of sex chromosomes during anaphase 1 of meiosis in the mother or father.

1) Nondisjunction of sex chromosomes during meiosis in the mother

2) Nondisjunction of sex chromosomes during meiosis in the father

Diseases caused by genomic mutations also fall into the chromosomal category. Their inheritance does not obey Mendel's laws. In addition to the above-mentioned Klinefelter or Turner-Shereshevsky syndromes, such diseases include Down syndrome (47, +21), Edwards syndrome (+18), Patau syndrome (47, +15).

Polyploidy characteristic of plants. The production of polyploids is widely used in plant breeding.

The law of homological series of hereditary variability N.I. Vavilova

“Species and genera that are genetically close are characterized by similar series of hereditary variability with such regularity that, knowing the series of forms within one species, one can predict the presence of parallel forms in other species and genera. The closer the genera and species are genetically located in the general system, the more complete the similarity in the series of their variability. Whole families of plants are generally characterized by a certain cycle of variation passing through all the genera and species that make up the family.”

This law can be illustrated by the example of the Poa family, which includes wheat, rye, barley, oats, millet, etc. Thus, the black color of the caryopsis is found in rye, wheat, barley, corn and other plants, and the elongated shape of the caryopsis is found in all studied species of the family. The law of homological series in hereditary variability allowed N.I. himself. Vavilov to find a number of forms of rye, previously unknown, based on the presence of these characteristics in wheat. These include: awned and awnless ears, grains of red, white, black and purple color, mealy and glassy grains, etc.

* Note. The “+” sign means the presence of hereditary forms that have the specified trait.

Open N.I. Vavilov’s law is valid not only for plants, but also for animals. Thus, albinism occurs not only in different groups mammals, but also birds and other animals. Short fingers are observed in humans, large cattle, sheep, dogs, birds, absence of feathers in birds, scales in fish, wool in mammals, etc.

The law of homological series of hereditary variability has great importance for selection, since it allows one to predict the presence of forms not found in a given species, but characteristic of closely related species. Moreover, the desired form can be found in wildlife or obtained by artificial mutagenesis.

Artificial mutations

Spontaneous mutagenesis constantly occurs in nature, but spontaneous mutations are a fairly rare occurrence, for example, in Drosophila, the white eye mutation is formed with a frequency of 1:100,000 gametes.

Factors whose impact on the body leads to the appearance of mutations are called mutagens. Mutagens are usually divided into three groups. Physical and chemical mutagens are used to artificially produce mutations.

Induced mutagenesis is of great importance because it makes it possible to create valuable starting material for breeding, and also reveals ways to create means of protecting humans from the action of mutagenic factors.

Modification variability

Modification variability- these are changes in the characteristics of organisms that are not caused by changes in the genotype and arise under the influence of environmental factors. The habitat plays a big role in the formation of the characteristics of organisms. Each organism develops and lives in a certain environment, experiencing the action of its factors that can change morphological and physiological properties organisms, i.e. their phenotype.

An example of the variability of characteristics under the influence of environmental factors is the different shape of the leaves of the arrowhead: leaves immersed in water have a ribbon-like shape, leaves floating on the surface of the water are round, and those in the air are arrow-shaped. Under the influence ultraviolet rays People (if they are not albinos) develop a tan as a result of the accumulation of melanin in the skin, and the intensity of skin color varies from person to person.

Modification variability is characterized by the following basic properties: 1) non-heritability; 2) the group nature of the changes (individuals of the same species placed in the same conditions acquire similar characteristics); 3) correspondence of changes to the influence of environmental factors; 4) dependence of the limits of variability on the genotype.

Despite the fact that signs may change under the influence of environmental conditions, this variability is not unlimited. This is explained by the fact that the genotype determines specific boundaries within which changes in a trait can occur. The degree of variation of a trait, or the limits of modification variability, is called reaction norm. The reaction norm is expressed in the totality of phenotypes of organisms formed on the basis of a certain genotype under the influence of various environmental factors. As a rule, quantitative traits (plant height, yield, leaf size, milk yield of cows, egg production of chickens) have a wider reaction rate, that is, they can vary widely than qualitative traits (coat color, milk fat content, flower structure, blood type) . Knowledge of reaction norms is of great importance for agricultural practice.

The modification variability of many traits of plants, animals and humans is subject to general patterns. These patterns are identified based on the analysis of the manifestation of the trait in a group of individuals ( n). The degree of expression of the characteristic being studied varies among members of the sample population. Each specific value of the characteristic being studied is called option and denoted by the letter v. The frequency of occurrence of individual variants is indicated by the letter p. When studying the variability of a trait in a sample population, a variation series is compiled in which individuals are arranged in ascending order of the indicator of the trait being studied.

For example, if you take 100 ears of wheat ( n= 100), count the number of spikelets in an ear ( v) and the number of ears with a given number of spikelets, then the variation series will look like this.

Based on the variation series, it is constructed variation curve— graphical display of the frequency of occurrence of each option.

The average value of a characteristic is more common, and variations significantly different from it are less common. It is called "normal distribution". The curve on the graph is usually symmetrical.

The average value of the characteristic is calculated using the formula:

Where M— average value of the characteristic; ∑( v