Medical genetics and its tasks
Heredity there is a property of living beings and body cells to transmit their characteristics (anatomical and physiological features) to their descendants. It ensures the relative stability of the species. The basis for natural and artificial selection, for the evolution of a species, is provided by variability- a property of an organism and its cells, manifested in the emergence of new signs. The material carriers of hereditary information are genes - sections of the DNA molecule.
The science of heredity and variation is called genetics. The branch of genetics that studies the heredity and variability of a person from the point of view of pathology is called medical genetics.
The main tasks of medical genetics are as follows:
^ The study of hereditary forms of pathology . This means studying their etiology, pathogenesis, improving diagnostics, developing methods for prevention and treatment. The fatal nature of hereditary diseases exists only until the specific causes and mechanisms of their development are known. Establishing the patterns of development of a number of hereditary diseases made it possible not only to treat, but also, to a certain extent, to prevent rather severe forms of hereditary pathology.
^ The study of the causes and mechanisms of hereditarily determined predisposition and resistance to various (including infectious nature) diseases.
Study of the role and significance of the genetic apparatus in the development of adaptation reactions, compensation and decompensation phenomena(See "The Dual Nature of Disease").
Detailed Comprehensive study of the processes of mutagenesis and antimutagenesis and their role in the development of diseases.
^ The study of a number of general biological problems : molecular genetic mechanisms of carcinogenesis, the role of the genetic apparatus in the phenomena of tissue incompatibility, autoimmune reactions of the body, etc.
^ 2. The spread of hereditary forms of pathology.
Let's start by distinguishing far from ambiguous concepts « hereditary diseases» and« congenital diseases» . Congenital diseases that appear immediately after birth are called. They can be both hereditary and non-hereditary - due to the action of adverse environmental factors on the developing fetus during pregnancy and not affecting its genetic apparatus. To the number hereditary diseases include only those based on structural changes in the genetic material. Some of them are clinically manifested already in the first days after birth, others in adolescence, mature, and sometimes in old age.
In this paragraph, we will talk about hereditary diseases and developmental anomalies.
Today, the number of known hereditary diseases exceeds 2500, only hereditarily determined metabolic disorders accompanied by mental disability, about a thousand. For every 500-800 newborns, there is one child with Down's disease, a high frequency of birth of children with other fairly serious chromosomal diseases such as Klinefelter's syndrome (1.39-1.98; an average of 1.3 per 1000 boys), trisomy X -chromosome (1 in 750 girls). From 1/3 to 1/2 of the blind suffer from hereditary defects in the organ of vision. According to the USA, Canada, Great Britain, up to 25% of hospital beds in children's hospitals are occupied by patients with hereditary forms of pathology. Only in the territory of the former USSR about 60,000 children were born annually with hereditary pathology, including about 5,000 children with such hereditary developmental defects as cleft lip ("cleft lip"), palate ("cleft palate"), microcephaly, hydrocephalus, anencephaly.
Half of spontaneous abortions and preterm births are genetically determined. The list can be continued for a long time.
During the 20th century, a significant absolute and relative increase in the number of hereditary diseases and developmental anomalies was noted. There are many reasons for this. Let's name the most important ones:
Significant advances in medicine in the treatment and prevention of many infectious and alimentary diseases have practically eliminated such especially dangerous infections as plague, smallpox, cholera, which claimed tens of millions of lives in past centuries, and poliomyelitis, which left tens of thousands of cripples. Tuberculosis, which occupied the first place in the last century due to mortality in most developed countries of the world, has now moved to 10-15th place. In such a situation, those forms of pathology, the success in the treatment and prevention of which is much more modest, came to a more prominent place;
Improving diagnostic methods;
Increasing pollution of the environment by mutagenic agents;
Advances in molecular biology, which made it possible to establish the genetic nature of a number of serious diseases that were not previously associated with genome abnormalities (an example is chromosomal diseases);
Increasing the average life expectancy of a person. On the territory of Belarus, for example, in 1898 it was 37.5 years, in 1978 - 72 years, and many forms of hereditary diseases, as already mentioned, manifest themselves many years after birth (gout - after 30-40, chorea of Huntington - after 40-50 years).
Possible reasons that hereditary diseases have "their age" of development may be the following:
1) for the time being, an abnormal gene can be in a repressed state, and then, under the influence, for example, of a changed hormonal background of the body, it derepresses and begins to show its activity;
2) in some cases, the implementation of the action of an abnormal gene requires a more or less long-term specific - "manifesting" effect of the environment (for gout, a number of forms of diabetes mellitus);
3) with age, the activity of repair processes decreases.
^ 3. Classification of hereditary forms of pathology
In the development of any disease, as well as in the life of a healthy organism, various kinds of environmental influences (external factor) and heredity (internal factor) are involved. As an etiological factor of the disease or a component of its pathogenesis. The share of participation of each of them in various diseases is different.
Taking into account the specific weight of heredity and environment, 4 groups of diseases are distinguished, between which there is no sharp boundary (N.P. Bochkov).
The first group consists of hereditary diseases proper, in the occurrence and development of which the decisive role belongs to anomalies in the genetic apparatus. It includes monogenically caused diseases (alkaptonuria, phenylketonuria, hepatocerebral dystrophy, hemophilia, etc.) and chromosomal diseases. The environment determines only penetrance (the manifestation of the action of the gene in a population of individuals with the given gene 1) and expressivity (the degree of expression of the action of the gene in a particular individual).
In the development of diseases of the second group, as well as in the first, heredity is of fundamental importance, but a specific, so-called "manifesting" action of the environment is necessary, without which the disease, despite the presence of a pathological mutation, does not manifest itself clinically. So, in heterozygous carriers of H in S (autosomal recessive or semi-dominantly inherited hemoglobinopathy - sickle cell anemia), hemolytic crises leading to anemia occur only in conditions of hypoxia or acidosis; in hereditary fermentopathy associated with deficiency of glucose-6-phosphate dehydrogenase, the use of oxidizing drugs, the use of horse beans, and sometimes a viral infection can play a similar role. The appearance of clinical signs of gout, in which a violation of uric acid metabolism is genetically determined, is promoted by systematic overeating, excessive consumption of meat food, grape wines and other substances, the metabolism of which leads to the formation of excess amounts of uric acid salts deposited in the joints and causing their damage.
The main etiological factor of the third group of diseases are environmental factors. Hypersensitivity to the so-called "risk factors" is genetically determined. These are diseases with a hereditary predisposition, multifactorial polygenic diseases. These include the vast majority of diseases of mature and old age: hypertension, atherosclerosis, coronary heart disease, peptic ulcer of the stomach and duodenum, malignant neoplasms, etc.
The fourth group consists of diseases, the occurrence of which is due to environmental factors, to the action of which the body has no means of protection - extreme. These are injuries (mechanical, electrical), exposure to ionizing radiation, burns, frostbite, especially dangerous infections. The genetic factor in these cases determines the severity of the disease, its outcome, in some cases - the likelihood of occurrence. It is known, for example, that the occurrence of even diseases caused by such highly pathogenic pathogens as the causative agents of plague, smallpox, cholera, to a certain extent, is associated with a blood group, which is determined, as is known, genetically. People with the first blood group are predisposed to plague, those with the second group are prone to smallpox and cholera.
So, according to the above classification, hereditary forms of pathology are divided into actually hereditary diseases (needing and not needing the action of specific - "manifesting" environmental factors) and diseases with a hereditary predisposition.
According to the number of genes affected by damage (mutation), monogenic and polygenic diseases are distinguished. The latter include diseases with a hereditary predisposition, since they are multifactorial, as well as a large separate group of diseases associated with chromosomal or genomic mutations - chromosomal.
Monogenic diseases inherited according to the laws of Mendel, in turn, are divided according to the type of inheritance: into autosomal dominant, autosomal recessive and inherited linked to sex (usually X) chromosomes. Among the most common autosomal dominant diseases and developmental anomalies, the total frequency of which is 7 per 1000 newborns (C.O. Carler, I969), are polydactyly (more often - hexodactyly), achondroplasia, neurofibromatosis, thallaesemia, Huntington's chorea, congenital otosclerosis, osteogenesis imperfecta and others. Autosomal recessive (total frequency 2 per 1000 newborns) include childhood retinoblastoma, xeroderma pigmentosum, Addison-Birmer anemia, alkaptonuria, phenylketonuria, familial hypercholesterolemia, hepatocerebral dystrophy, galactosemia, microcephaly, anencephaly, one form of hydrocephalus, etc. .
Examples of forms of pathology inherited linked to the X chromosome are:
Recessively inherited (total frequency 0.4 per 1000 births) hemophilia A and B, Duchenne muscular dystrophy, ichthyosis, color blindness, albinism, fermentopathy associated with deficiency of glucose-6-phosphate hydrogenase, optic nerve atrophy;
Dominantly inherited hypoplasia of tooth enamel, vitamin D-resistant rickets.
The system-organ classification of hereditary forms of pathology is often used, which is based on the accounting of predominantly affected organs (hereditary diseases and anomalies in the development of the cardiovascular system, endocrine, nervous system, etc.). This classification is rather arbitrary, since genetic defects very often affect many organs and systems.
Clinically, the most significant is the classification according to the primary biochemical defect, the detection of which allows not only to diagnose the disease with a sufficient degree of reliability, but also to carry out pathogenetically substantiated treatment of the disease. However, so far, the primary biochemical defect has been identified for a relatively small number of hereditary diseases.
^ 4. Methods for determining the hereditary nature
diseases and developmental anomalies
Genealogical metosis, based on the compilation of genealogical tables using the symbols accepted in genetics, makes it possible to identify the hereditary nature of the trait or disease being studied and to establish the type of inheritance (dominant, recessive, sex-linked). Dominant traits and diseases are inherited in a straight line (from parents to children, from offspring to offspring and appear both in homozygotes and heterozygotes); recessive - not in a straight line, intermittently, appear only in the homozygous state.
The twin method (comparison of intrapair concordance - the identity of signs or forms of pathology in identical and dizygotic twins living in the same and different environmental conditions) makes it possible to identify the relative role of heredity and environment in the development of the analyzed pathological phenomenon. The high concordance of identical twins living in different conditions, according to the studied trait, testifies in favor of its hereditary nature. The high concordance of fraternal twins, especially those living in the same conditions, speaks of the decisive importance in the development of a particular form of pathology of environmental factors.
The demographic (statistical) method is based on a statistical analysis of the incidence of isolates - a group of people (at least 50 people) who, due to geographical conditions, religious or tribal traditions, are often forced to enter into closely related marriages. The latter significantly increase the likelihood of two identical pathological recessive genes meeting and the birth of children homozygous for this trait. The harmfulness of marriages between close relatives is manifested in a higher incidence of recessive forms of pathology, premature births, the number of stillbirths and early infant mortality, since the lethal and semi-lethal genes that determine these phenomena are also classified as recessive.
The karyological or cytogenetic method is a method of studying the karyotype (structural organization of the nucleus, characterized by the number and structure of chromosomes) in the patient's dividing cells, which makes it possible to identify and determine the nature of chromosomal diseases, which are based on gene mutations and chromosomal aberrations.
The method of studying sex chromatin (Barr bodies) in leukocytes and epithelium of a patient also makes it possible to identify patients with chromosomal diseases.
The sex chromatin or chromatin body, located under the shell of the nucleus, in neutrophils resembles a drumstick in shape, is formed by an inactive X chromosome in a state of spiralization. Normally, one sex chromatin is found only in the cells of women, since they have 2 X chromosomes: one active and one in a state of spiralization. The detection of sex chromatin in the cells of the male body, as well as an increase in the number or absence of sex chromatin in the cells of the female body, along with the results of the karyological research method, allows us to determine the types of chromosomal diseases associated with a change in the number of sex chromosomes (Klinefelter's syndrome, trisomy-X, Shereshevsky's syndrome - Turner, etc.).
The biochemical method, based on the determination of biochemical differences in the composition of urine and blood, contributes to the identification of a number of serious hereditary diseases. Thus, the detection of H in S in the patient's erythrocytes makes it possible to diagnose sickle cell anemia in him, the determination of phenylpyruvic acid in the urine is used to diagnose phenylketonuria.
The study of the nature and patterns of development of hereditary forms of pathology is also facilitated by the experimental method of research, for which they identify and create conditions for the reproduction of animals with various kinds of hereditary defects similar to those inherent in humans. Dogs suffer from hemophilia, rabbits have achondroplasia, mice have pituitary dwarfism, obesity, etc.
^ 5. Etiology of hereditary forms of pathology
The causes of hereditary diseases and developmental anomalies are factors that can change the qualitative or quantitative characteristics of the genotype (the structure of individual genes, chromosomes, their number), that is, cause mutations. Such factors are called mutagens. Mutagens are classified into exogenous and endogenous. Exogenous mutagens can be of a chemical, physical or biological nature. Chemical exogenous mutagens include many substances of industrial production (benzpyrene, aldehydes, ketones, epoxide, benzene, asbestos, phenol, formalin, xylene, etc.), pesticides. Alcohol has a pronounced mutagenic activity. In the blood cells of alcoholics, the number of defects in the genetic apparatus occurs 12-16 times more often than in non-drinkers or light drinkers. Much more often in families of alcoholics, children are born with Down syndrome, Klinefelter, Patau, Edwards and other chromosomal diseases. Mutagenic properties are also inherent in some drugs (cytostatics, quinacrine, clonidine, mercury compounds, etc.), substances used with food (a strong mutagen, hydrazine is found in large quantities in edible mushrooms, tarragon and piperine in black pepper; many substances that have genotoxic properties, formed during the cooking of fat, etc.). A significant genetic risk arises from long-term human consumption of milk and meat from animals whose feed is dominated by herbs containing many mutagens (for example, lupine). The group of exogenous physical mutagens consists of all types of ionizing radiation (α-, β-, γ-, x-rays), ultraviolet radiation. Measles viruses are producers of biological exogenous mutagens. , rubella, hepatitis.
Endogenous mutagens can also be chemical (H 2 O 2 , lipid peroxides, free radicals) and physical (K 40 , C 14 , radon) nature.
There are also true and indirect mutagens. The latter include compounds that in their normal state do not have a damaging effect on the genetic apparatus, however, once in the body, they acquire mutagenic properties in the process of metabolism. For example, some widespread nitrogen-containing substances (nitrates of nitrogenous fertilizers) are converted in the body into highly active mutagens and carcinogens (nitrites).
The role of additional conditions in the etiology of hereditary diseases in some cases is very significant (if the development of a hereditary disease, its clinical manifestation is associated with the action of certain "manifesting" environmental factors), in others it is less significant, limited only by the effect on the expressiveness of the disease, not associated with the action of any or specific environmental factors.
^ 6. General patterns of pathogenesis of hereditary diseases
Mutations are the initial link in the pathogenesis of hereditary diseases - a sudden abrupt change in heredity due to a change in the structure of a gene, chromosomes or their number, that is, the nature or amount of hereditary information.
Taking into account various criteria, several classifications of mutations have been proposed. According to one of them, spontaneous and induced mutations are distinguished. The first ones arise in the conditions of the natural background of the surrounding and internal environment of the body, without any special effects. They can be caused by external and internal natural radiation, the action of endogenous chemical mutagens, etc. Induced mutations are caused by a special targeted action, for example, under experimental conditions.
According to another classification, specific and nonspecific mutations are distinguished. Let us make a reservation that most genotypes do not recognize the presence of specific mutations, believing that the nature of mutations does not depend on the quality of the mutagen, that the same mutations can be caused by different mutagens, and the same mutagen can induce different mutations. Proponents of the existence of specific mutations are I.P. Dubinin, E.F. Davydenkova, N.P. Bochkov.
According to the type of cells damaged by the mutation, there are somatic mutations that occur in the cells of the body, and gametic mutations - in the germ cells of the body. The consequences of both are ambiguous. With somatic mutations, the disease develops in the carrier of the mutations; the offspring do not suffer from this kind of mutation. For example, a point mutation or amplification (multiplication) of a proto-oncogene in a somatic cell can initiate tumor growth in a given organism, but not in its children. In case of gametic mutations, on the contrary, the host organism of the mutation does not get sick. The offspring suffers from such a mutation.
According to the volume of the genetic material affected by the mutation, mutations are divided into gene or point mutations (changes within a single gene, the sequence or composition of nucleotides is disturbed), chromosomal aberrations or rearrangements that change the structure of individual chromosomes, and genomic mutations, characterized by a change in the number of chromosomes.
Chromosomal aberrations, in turn, are divided into the following types:
Deletion (lack) is a type of chromosomal rearrangement in which certain sections and the corresponding genes of the chromosome fall out. If the sequence of genes in the chromosome is depicted as a series of numbers 1, 2, 3, 4, 5, 6, 7, 8 ....... 10000, then with the deletion of the 3-6 region, the chromosome is shortened, and the sequence of genes in it changes (1 , 2, 7, 8...... 10000). An example of a congenital pathology associated with a deletion is the "cat's cry" syndrome, which is based on the deletion of the p1 segment - p-eg (short arm) of the 5th chromosome. The disease is manifested by a number of developmental defects: a moon-shaped face, an anti-Mongoloid incision of the eyes, microcephaly, a flaccid epiglottis, a peculiar arrangement of the vocal cords, as a result of which the crying of the child resembles the cry of a cat. With the deletion of one to four copies of H in - genes, the development of one of the forms of hereditary hemoglobinopathies - α-thalassemia is associated (see the section "Pathophysiology of the blood system");
Duplication is a type of chromosomal rearrangement in which a portion of a chromosome and the corresponding block of genes are doubled. With the above numbering of genes in a chromosome and duplication at the level of 3-6 genes, the sequence of genes in such a chromosome will look like this - 1, 2, 3, 4, 5, 6, 3, 4, 5, 6, 7, 8 - 10000 Today, various variants of duplications (partial trisomies) are known for almost all autosomes. They are relatively rare.
Inversion - a type of chromosomal rearrangement in which a portion of the chromosome (for example, at the level of genes 3-6) rotates 180 ° - 1, 2, 6, 5, 4.3 , 7, 8 .... 10000;
Translocation is a type of chromosomal rearrangement, characterized by the movement of a chromosome segment to another place on the same or another chromosome. In the latter case, the genes of the translocated site fall into a different linkage group, a different environment, which may contribute to the activation of “silent” genes or, conversely, suppress the activity of normally “working” genes. Examples of a serious pathology based on the phenomena of translocation in somatic cells can be Burkitt's lymphoma (reciprocal translocation between the 8th and 14th chromosomes), myelocytic leukemia - reciprocal translocation between the 9th and 22nd chromosomes (for more details see below). in the "Tumours" section).
The final link in the pathogenesis of hereditary diseases is the realization of the action of an abnormal gene (genes). There are 3 main options:
1. If an abnormal gene has lost the program code for the synthesis of a structural or functionally important protein, the synthesis of the corresponding messenger RNA and protein is disrupted. In the absence or insufficient amount of such a protein, the processes in the implementation of which at a certain stage this protein plays a key role are disrupted. So, a violation of the synthesis of antihemophilic globulin A (factor VIII), B (factor IX), the plasma precursor of thromboplastin (factor XI), which are extremely important in the implementation of various stages of the internal mechanism of phase I of blood coagulation, leads to the development of hemophilia (respectively: A , B and C). Clinically, the disease manifests itself as a hematoma type of bleeding with damage to the musculoskeletal system. Hemorrhages in the large joints of the extremities predominate, profuse bleeding even with minor injuries, hematuria. Hemophilia A and B are inherited linked to the X chromosome, recessively. Hemophilia C is inherited in a dominant or semi-dominant manner, autosomal.
The development of hepato-cerebral dystrophy is based on a protein deficiency - cerruloplasmin, which is associated with an increase in absorption, impaired metabolism and excretion of copper, and its excessive accumulation in tissues. The toxic effect of copper has a particularly strong effect on the state and function of the nervous system and liver (a process that ends with cirrhosis). The first symptoms of the disease appear at the age of 10-20 years, progress rapidly and end in death. Inheritance is autosomal recessive.
2. Loss of the mutant gene code of the program for the synthesis of one or another enzyme ends with a decrease or cessation of its synthesis, its deficiency in the blood and tissues, and a violation of the processes catalyzed by it. As examples of the development of hereditary forms of pathology along this path, one can name a number of diseases of amino acid, carbohydrate metabolism, etc. Phenylpyruvine oligophrenia, for example, is associated with a violation of the synthesis of phenylalanine hydroxylase, which normally catalyzes the conversion of phenylalanine consumed with food into tyrosine. Enzyme deficiency leads to excess phenylalanine in the blood , diverse changes in the metabolism of tyrosine, the production of significant amounts of phenylpyruvic acid, brain damage with the development of microcephaly and mental retardation. The disease is inherited in an autosomal recessive manner. Its diagnosis can be made in the first days after the birth of a child, even before the manifestation of pronounced symptoms of the disease by the detection of phenylpyruvic acid and phenylalaninemia in the urine. Early diagnosis and timely treatment (a diet low in phenylalanine) helps to avoid the development of the disease, its most severe manifestation - mental disability.
The absence of homogentisic acid oxidase involved in the metabolism of tyrosine leads to the accumulation of an intermediate product of tyrosine metabolism - homogentisic acid, which is not oxidized into maleylacetoacetic acid, but is deposited in the joints, cartilage, connective tissue, causing with age (usually after 40 years) the development of severe arthritis. In this case, too, the diagnosis can be made very early: in the air, the urine of such children turns black due to the presence of homogentisic acid in it. It is inherited in an autosomal recessive manner.
3. Often, as a result of a mutation, a gene with a pathological code is formed, as a result of which abnormal RNA and an abnormal protein with altered properties are synthesized. The most striking example of this type of pathology is sickle cell anemia, in which in the 6th position of the β-chain of hemoglobin, the glutanic amino acid is replaced by valine, an unstable H in S is formed. In the reduced state, its solubility sharply decreases, and its ability to polymerize increases. Crystals are formed that disrupt the shape of erythrocytes, which are easily hemolyzed, especially under conditions of hypoxia and acidosis, leading to the development of anemia. Inheritance is autosomal recessive or semi-dominant (more details in the section "Pathology of the blood system").
An important condition for the occurrence and implementation of the action of mutations is the failure of the DNA repair system, which can be genetically determined or develop in the course of life, under the influence of adverse factors of the external or internal environment of the body.
So, in the genotype of healthy people there is a gene with the code for the program for the synthesis of the exonuclease enzyme, which ensures the “cutting out” of pyrimidine dimers, which are formed under the influence of ultraviolet radiation. The anomaly of this gene, expressed in the loss of the code for the exonuclease synthesis program, increases the sensitivity of the skin to sunlight. Under the influence of even a short inhalation, dry skin occurs, its chronic inflammation, pathological pigmentation, later neoplasms appear that undergo malignant degeneration. Two-thirds of patients die before the age of 15 years. The disease, xeroderma pigmentosa, is inherited in an autosomal recessive manner.
The functional potency of the DNA repair system weakens with age.
A certain role in the pathogenesis of hereditary forms of pathology can apparently belong to persistent disturbances in the regulation of gene activity, which, as already noted, may be one of the possible causes of the manifestation of a hereditary disease only many years after birth.
So, the main mechanisms for the development of hereditary pathology are associated with:
1) mutations that result in
A) loss of normal hereditary information,
B) an increase in the volume of normal hereditary information,
C) replacement of normal hereditary information with pathological information;
2) impaired repair of damaged DNA;
3) persistent changes in the regulation of gene activity.
^ 7. Chromosomal diseases
A special group of diseases associated with structural changes in the genetic material consists of chromosomal diseases, conditionally classified as hereditary. The fact is that in the vast majority of cases, chromosomal diseases are not transmitted to offspring, since their carriers are most often infertile.
Chromosomal diseases are caused by genomic or chromosomal mutations that have occurred in the gamete of one of the parents, or in a zygote formed by gametes with a normal set of chromosomes. In the first case, all cells of the unborn child will contain an abnormal chromosome set (a complete form of a chromosomal disease), in the second, a mosaic organism develops, only a part of the cells of which have an abnormal set of chromosomes (a mosaic form of the disease). The severity of pathological signs in the mosaic form of the disease is weaker than in the complete form.
The phenotypic basis of chromosomal diseases is formed by violations of early embryogenesis, as a result of which the disease is always characterized by multiple malformations.
The frequency of chromosomal disorders is quite high: out of every 1000 live-born babies, 3-4 have chromosomal diseases, in stillborn children they make up 6%; about 40% of spontaneous abortions are caused by an imbalance of chromosomes (N.P. Bochkov, 1984). The number of variants of chromosomal diseases is not as great as one might theoretically expect. An imbalance affecting all pairs of chromosomes causes such significant disturbances in the body that they, as a rule, turn out to be incompatible with life already in the early or later stages of embryogenesis. So, monoploidy was not found either in newborns or in abortuses. Rare cases of triploidy and tetraploidy in abortuses and in live births are described, which, however, died in the first days of life. Changes in the number or structure of individual chromosomes are more common. A lack of genetic material causes more significant defects than an excess. Complete monosomy, for example, on autosomes is practically not found. Apparently, such an imbalance causes a lethal outcome already in gametogenesis or at the stage of the zygote and early blastula.
The basis for the development of chromosomal diseases associated with a change in the number of chromosomes is formed in gametogenesis, during the first or second meiotic divisions or during the crushing of a fertilized egg, most often as a result of nondisjunction of chromosomes. Moreover, one of the gametes instead of a single set of chromosomes contains extremely rarely - a diploid set of all chromosomes, or 2 chromosomes of any of the pairs of chromosomes, the second gamete does not contain any such chromosomes. When an abnormal egg is fertilized by a sperm with a normal set of chromosomes or a normal egg by an abnormal sperm, less often when two gametes containing an altered number of chromosomes are combined, prerequisites for the development of a chromosomal disease are created.
The likelihood of such disorders, and, consequently, the birth of children with chromosomal diseases, increases with the age of the parents, especially the mother. Thus, the frequency of nondisjunction of the 21st pair of chromosomes in the 1st meiotic division is 80% of all its cases, of which 66.2% in the mother and 13.8% in the father; the total risk of having a child with trisomy on the 13th, 18th, 21st chromosome for a woman aged 45 years and older is 60 times higher than the risk for a woman 19-24 years old (N.P. Bochkov et al. 1984).
Down syndrome is the most common chromosomal disorder. The karyotype of patients in 94% consists of 47 chromosomes due to trisomy on chromosome 21. In about 4% of cases, there is a translocation of the extra 21st chromosome to the 14th or 22nd, the total number of chromosomes is 46. The disease is characterized by a sharp delay and impaired physical and mental development of the child. Such children are undersized, they start walking and talking late. The appearance of the child is striking (the characteristic shape of the head with a sloping occiput, a wide, deeply sunken bridge of the nose, a Mongoloid incision in the eyes, an open mouth, abnormal tooth growth, macroglossia, muscular hypotension with loose joints, brachydactyly, especially the little finger, a transverse crease in the palm of the hand, etc. .) and severe mental retardation, sometimes to complete idiocy. Violations are noted in all systems and organs. Malformations of the nervous (in 67%), cardiovascular (64.7%) systems are especially frequent. As a rule, the reactions of humoral and cellular immunity are changed, the system of repair of damaged DNA suffers. Associated with this is an increased susceptibility to infection, a higher percentage of the development of malignant neoplasms, especially leukemia. In most cases, patients are infertile. However, there are cases of the birth of children by a sick woman, some of them suffer from the same disease.
The second most common (1:5000-7000 births) pathology due to a change in the number of autosomes is Patau's syndrome (trisomy 13). The syndrome is characterized by severe malformations of the brain and face (defects in the structure of the bones of the brain and facial skull, brain, eyes; microcephaly, cleft lip and palate), polydactyly (more often - hexodactyly), defects in the heart septa, unhinged rotation of the intestine, polycystic kidney disease, defects development of other organs. 90% of children born with this pathology die within the first year of life.
The third place (1:7000 births) among polysemy of autosomes is occupied by trisomy 18 (Edwards syndrome). The main clinical manifestations of the disease: numerous defects of the skeletal system (pathology of the structure of the facial part of the skull: micrognathia, epicanthus, ptosis, hypertelorism), cardiovascular (defects of the interventricular septum, defects of the valves of the pulmonary artery, aorta), nail hypoplasia, horseshoe kidney, cryptorchidism in boys. 90% of patients die in the first year of life.
Chromosomal diseases associated with non-disjunction of sex chromosomes are much more common. Known variants of gonosomal polysomy are shown in the table.
Types of gonosomal polysomies found in newborns
(according to N.P. Bochkov, A.F. Zakharov, V.I. Ivanov, 1984)
| ^ X-polysomy in the absence of a y-chromosome | X-polysomy in the presence of one y-chromosome | y-polysomy in the presence of one X chromosome | Polysomy on both chromosomes |
| 47XXX (1,3: 1000) | 47 XXY (1,5: 1000) | 47 HUU (1: 1000) | 48 XXYU |
| 48 XXXX (30 known cases) | 48 XXX (rarely) | 48 HUUU (very rarely) | 49 XXXXY (1:25000) |
| 49 XXXXX (number of cases Not specified) | 49 XXXXX (about 100 known cases) | 49 HUUUU (number of cases not specified) |
As follows from the table, the overwhelming number of polysymy on sex chromosomes falls on trisomy XXX, XXV, XVV.
With trisomy X-chromosome (“superwoman”), clinical signs of the disease are often absent or minimal. The disease is diagnosed by the detection of two Barr bodies instead of one and by the 47,XXX karyotype. In other cases, patients have hypoplasia of the ovaries, uterus, infertility, various degrees of mental disability. An increase in the number of X chromosomes in the karyotype increases the manifestation of mental retardation. Such women are more likely than in the general population to suffer from schizophrenia.
Variants of polysomy involving Y-chromosomes are more numerous and diverse. The most common of them - Klinefelter's syndrome - is due to an increase in the total number of chromosomes up to 47 due to the X chromosome. A sick man (the presence of the Y-chromosome dominates with any number of X-chromosomes) is distinguished by high growth, a female type of skeletal structure, inertia and mental retardation. Genetic imbalance usually begins to manifest itself during puberty, underdevelopment of male sexual characteristics. The testicles are reduced in size, there is aspermia or oligospermia, often gynecomastia. A reliable diagnostic sign of the syndrome is the detection of sex chromatin in the cells of the male body. The supercline-felter syndrome (ХХХУ, two Barr bodies) is characterized by a greater severity of these signs, mental failure reaches the degree of idiocy.
The owner of karyotype 47, HUU - "super man" is distinguished by impulsive behavior with pronounced elements of aggressiveness. A large number of such individuals are found among prisoners.
Gonosomal monosomy is much less common than polysomy, and is limited only to monosomy X (Shereshevsky-Turner syndrome). The karyotype consists of 45 chromosomes, there is no sex chromatin. Patients (women) are characterized by short stature, short neck, cervical lateral skin folds. Characterized by lymphatic edema of the feet, poor development of sexual characteristics, absence of gonads, hypoplasia of the uterus and fallopian tubes, primary amenorrhea. Such women are infertile. Mental ability, as a rule, does not suffer.
No cases of Y monosomy were found. Apparently, the absence of the X chromosome is incompatible with life, and individuals of the “OU” type die at the early stages of embryogenesis.
Chromosomal diseases caused by structural changes in chromosomes are less common and, as a rule, lead to more severe consequences: spontaneous abortions, prematurity, stillbirth, and early infant mortality.
8. Phenocopies
Phenocopies are called forms of pathology that are formed during the period of embryogenesis under the influence of environmental factors, not associated with changes in the genetic apparatus, but in their main manifestations similar to hereditary forms of pathology.
The causes of phenocopies can be:
Oxygen starvation of the fetus, prolonged exposure to which is fraught with damage to the central nervous system;
Infectious diseases of a pregnant woman, especially in the early period of pregnancy. Such infections as tokeoplasmosis, rubella, syphilis, etc., are extremely dangerous, causing severe deformities in a significant percentage of cases (up to 60-70%) (microcephaly, hydrocephalus, eye anomaly, deaf-mutism, cleft palate, etc.);
Endocrine disorders in the body of a pregnant woman, up to 2-2.5 times or more increasing the likelihood of various kinds of abnormalities in the unborn child;
Mental trauma and emotional overstrain of a woman during pregnancy;
Drugs with cytotoxic or antimetabolic effects. At one time, the whole world was shocked by the severe consequences of the use by pregnant women of the widely advertised sleeping pill - thalidamide (tens of thousands of children with severe forms of deformities and malformations;
Lack of trace elements (iron, cobalt, copper), vitamins (C, E, B 1, PP, etc.) in the woman's food;
Alcoholism of parents (for comparison: intellectual impairment, malformations in children of non-drinking parents are about 2%, in moderate drinkers - up to 9%, in heavy drinkers - about 74%);
Illiterate use of contraceptives, as well as the use of various kinds of means for abortion.
^ 9. Principles of prevention of hereditary pathology and phenocopies
The principles of prevention of hereditary forms of pathology and phenocopies are briefly reduced to the following main provisions:
1. Protecting the environment from pollution by mutagens and creating conditions that limit (better - prevent) their entry into the human body.
2. Prevention of the negative effects of mutagens on the body.
3. Competent, well-established genetic counseling of people who are going to marry or are preparing for childbearing with the determination of the possible risk of having a sick child. This is especially important in cases where at least one of the parents or their relatives suffer (suffered) from hereditary diseases or had deformities and other developmental anomalies.
4. Avoiding closely related marriages and explaining to the population the harmfulness of marriage between close relatives.
5. Healthy lifestyle.
7. Protecting the health of a pregnant woman.
8. Avoidance of criminal abortions and the use of means to terminate pregnancy.
Let us dwell on the first two of these provisions in more detail.
Today, 3 ways are proposed to combat environmental pollution, mutagenic agents and limit the degree of their harmful effects on the body:
A) technological - the transfer of industrial production to closed cycles (wasteless production) - the most radical, but extremely expensive, practically unattainable way (in conditions of intensive transport) of mutagens and lack of insurance against possible accidents, the consequences of which sometimes turn out to be catastrophic (for example, the Chernobyl accident) ;
B) component - involving the identification of environmental mutagens and their removal - is also a very tempting, incredibly expensive and limited path for implementation, if only because humanity today is not able to refuse the use of many mutagens (from the use of X-rays, radioisotopes, cytostatics, other medicines and diagnostic procedures with a mutagenic side effect - in medicine, from the use of pesticides in agriculture, some chemical compounds in metallurgy, chemical and coke production, etc.;
C) compensatory - designed to reduce the likelihood of mutation frequency by increasing the resistance of the genetic apparatus to mutagenic effects and eliminating mutations that have already occurred - the most promising, most often used way to combat the consequences of environmental pollution.
The process of suppression of spontaneous and induced mutations is called antimutagenesis, and substances with such properties are called antimutagens. Antimutagens include compounds that 1) neutralize the mutagen before it reacts with the DNA molecule, 2) remove damage to the DNA molecule caused by the mutagen or increase its resistance to them, 3) prevent the transformation of indirect mutagens into true mutagens in the body. Today, about 200 natural and synthetic compounds are known that have all or part of the listed properties. These are some amino acids (arginine, histidine, methionine, etc.), enzymes (peroxidase, NADP oxidase, catalases, glutamine peroxidase, etc.), a number of drugs (sulfonamides, interferon, antioxidants, etc.). Vitamins E, C, A, K have a high antimutagenic activity. The first two of them are universal antimutagens that block various links of mutagenicity: they increase the activity of enzymes that neutralize mutagens, suppress the process of converting indirect mutagens into true ones, protect DNA from the damaging effects of mutagens, inhibit the activity of free radicals, activate the process of DNA repair, i.e. increase its resistance to genotoxic influences (Alekperov U.K., 1989). Pronounced antimutagenic properties are inherent in many vegetables and fruits. They are especially strong in cabbage, apples, mint, green pepper, pineapple, eggplant, grapes. The toxic effect of mutagens decreases many times (from 4 to 11 times) in the experiment. That is why a properly balanced diet rich in fruits and vegetables can be one of the effective means of individual prevention of the genotoxic effect of environmental factors.
^ 10. Principles of treatment of hereditary diseases and developmental defects
For the treatment of hereditary diseases, as well as in the treatment of diseases of a non-hereditary nature (infectious, alimentary, metabolic, and others), symptomatic, pathogenetic, etiological treatment is used using all types of therapeutic effects: from the use of drugs, diet therapy, physio-, balneo-climatotherapy to surgical intervention .
Symptomatic treatment is most often used (in contrast to non-hereditary forms of pathology, in which this method is usually used only as an adjuvant). For many hereditary diseases, symptomatic treatment is the only one. Drug therapy is especially often used: analgesics for hereditary forms of migraine; pilocarpine for glaucoma; special, relieving itching and pain, ointments for many skin diseases; mucolytic (thinning mucus) agents in combination with antibiotics in cystic fibrosis, the main and most painful manifestation of one of the forms of which is the abundant formation of very thick and viscous mucus in the ducts of the exocrine glands of the bronchi.
Pathogenetic treatment, designed to interrupt the pathological chain of pathogenesis of the disease, is the most reasonable and effective for hereditary, as well as for non-hereditary forms of diseases. Pathogenetic treatment options for hereditary forms of pathology can be as follows:
1. Exchange correction achieved
Exclusion or restriction in the patient's diet of substances that, as a result of the action of the mutant gene and the associated impaired metabolism, become toxic to the body (phenylalanine in phenylketonuria, galactose in galactosemia, etc.);
Compensation for a product whose production is impaired as a result of a gene mutation (administration of insulin in diabetes mellitus, antihemophilic globulin A or B in the corresponding forms of hemophilia, thyroid hormones in case of hypothyroidism, etc.);
Exemption from metabolic products that are intensively accumulating in the body (prescription of BAL preparations, Unitod, D-penicillamine, which promote the excretion of copper; with hepato-cerebral dystrophy; drugs that ensure the excretion of uric acid salts with gout; in some cases, they resort to the use of sorption methods of detoxification) ;
Metabolic inhibition (allopurinod, for example, is used in gout to inhibit the synthesis of xanthine oxidase and thus reduce the concentration of uric acid).
2. Addition to the patient's diet of certain substances that compensate for the violation of their synthesis.
3. Exclusion of drugs, the use of which provokes an exacerbation of a hereditary disease (for example, antimalarial drugs for glucose-6-phosphate dehydrogenase deficiency).
An important place in the treatment of hereditary forms of pathology is occupied by surgical treatment, which in some cases can be regarded as symptomatic (corrective surgery for cleft lip), in others - as pathogenetic (removal of a tumor in retinoblastoma, colon polyps, elimination of defects in the heart septa, kidney transplantation). with their polycystic, etc.).
The etiological treatment of hereditary diseases involves serious "maneuvering" with genetic material (gene transplantation, turning off a mutant gene, inducing reverse mutations that turn a pathological gene into its normal allele, etc.). So far, genetic engineering is being carried out in experimental studies. Before its application in a clinical setting, many more complex issues, including those of an ethical nature, need to be resolved.
In the treatment of hereditary diseases, a special method is also used.
1 in recessive diseases, of course, only individuals that are homozygous for the analyzed gene are taken into account.
MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS
BELARUSIAN STATE MEDICAL UNIVERSITY
DEPARTMENT OF PATHOLOGICAL PHYSIOLOGY
S. A. Zhadan, T. N. Afanas'eva, F. I. Vismont
THE ROLE OF HEREDITY IN PATHOLOGY
Teaching aid
Minsk BSMU 2012
GENERAL CHARACTERISTICS OF HEREDITARY PATHOLOGY
Medical genetics and its tasks
Heredity- this is the property of living beings and cells of the body to transmit their characteristics (anatomical and physiological features) to their descendants. It ensures the relative stability of the species. The material carriers of hereditary information are genes - sections of the DNA molecule.
Variability is a property of an organism and its cells, manifested in the emergence of new signs.
AT Currently, about 2000 types of hereditary pathology are known.
and genetically determined syndromes. Their number is constantly growing, dozens of new forms of hereditary diseases are described annually.. The main reasons contributing to the increase in the growth of hereditary pathology are:
– significant advances in medicine in the treatment and prevention of many infectious diseases;
– increasing environmental pollution with mutagenic agents;
- an increase in the average life expectancy of a person.
Along with this, the improvement of diagnostic methods and advances in molecular biology make it possible to reveal the genetic nature of a number of serious diseases that were not previously associated with genome abnormalities (for example, chromosomal diseases).
Genetics is the science of heredity and variation in an organism. The section of genetics that studies the heredity and variability of a person from the point of view of pathology is called medical genetics.
The main tasks of medical genetics are:
1. Study of hereditary forms of pathology, their etiology, pathogenesis, improvement of diagnostics, development of prevention and treatment methods.
2. The study of the causes and mechanisms of hereditary predisposition and resistance to various (including infectious nature) diseases.
3. Study of the role and significance of the genetic apparatus in the development of adaptation reactions, compensation and decompensation phenomena.
4. A detailed comprehensive study of the processes of mutagenesis and antimutagenesis, their role in the development of diseases.
5. The study of a number of general biological problems: molecular genetic mechanisms of carcinogenesis, the role of the genetic apparatus in the phenomena of tissue incompatibility, autoimmune reactions of the body, etc.
The concept of hereditary and congenital pathology. Phenocopies
The concepts of "hereditary diseases" and "congenital diseases" are far from unambiguous.
Congenital refers to any disease that occurs immediately after the birth of a child. They can be hereditary or non-hereditary.
To the number hereditary diseases include only those based on structural changes in the genetic material. Some of them are clinically manifested already in the first days after birth, others - in youthful, mature, and sometimes in old age.
Non-hereditary diseases are caused by the action of unfavorable environmental factors on the developing fetus during pregnancy and do not affect its genetic apparatus.
Phenocopies, the reasons for their development
In medical genetics, another concept is distinguished - phenocopies. Phenocopy is a clinical syndrome that occurs under the influence of environmental factors during the period of embryonic development, similar in its manifestations to a hereditary disease, but having a non-genetic nature of occurrence. For example, such anomalies as “ cleft palate”, “ cleft lip”, can be both hereditary (Patau syndrome) and non-hereditary, resulting from a violation of embryonic development. Hypothyroidism is inherited as an autosomal recessive trait, but can also occur as a phenocopy in people living in areas where drinking water is poor in iodine. Early deafness can be inherited as a recessive or dominant trait, and can occur as a phenocopy in children born to women who have had rubella during pregnancy.
Thus, phenocopies are diseases that are outwardly similar to hereditary diseases, but are not associated with a change in the genotype.
The causes of phenocopy can be:
– oxygen starvation of the fetus (intrauterine hypoxia), causing the development of serious defects in the structure of the brain and skull, microcephaly;
– endocrine disorders in the body of a pregnant woman (the probability of having a sick child in such a woman is about 2.5 times higher);
– infectious diseases of a pregnant woman (toxoplasmosis, rubella, syphilis, etc.), especially in the early period of pregnancy, causing a significant percentage of cases (up to 60-70%) severe deformities (microcephaly, deaf-mutism, cleft palate, etc.);
– severe mental trauma and prolonged emotional overstrain of a woman during pregnancy;
– drugs that have a cytotoxic or antimetabolic effect;
– chronic alcoholism of parents (malformations in children of non-drinking parents are about 2%, in moderate drinkers - up to 9%, in heavy drinkers - 74%), etc.
Classification of diseases taking into account the relationship of hereditary and environmental factors in their development. concept
about penetrance and expressiveness
AT the development of the disease, as well as in the life of a healthy organism, two main factors take part: the impact of the external environment
(external factor ) and heredity ( internal factor).
Taking into account the proportion of internal and external factors in the development of the disease, the following groups of diseases are distinguished (N. P. Bochkov, 2002):
1. Actually hereditary diseases. The cause of these diseases are anomalies in the genetic apparatus of the cell, i.e. mutations (genetic, chromosomal and genomic). The environment only determines penetrance (frequency of manifestation of an abnormal gene in a population of individuals with this gene)
and expressiveness(the degree of expression of the action of the gene in a particular individual). This group includes such monogenic diseases as alkaptonuria, phenylketonuria, hepatocerebral dystrophy, hemophilia, etc., as well as all chromosomal diseases.
2. Ecogenetic diseases. This group of hereditary diseases is caused by a mutation, the effect of which is manifested only when the body is exposed to a certain environmental factor specific to this mutant gene. For these diseases, both genetic and environmental
the component is represented by a single factor: an individual gene is an environmental factor specific to this gene. Such diseases include, for example, sickle cell anemia (semi-dominantly inherited hemoglobinopathies). In heterozygous carriers of HbS, hemolytic crises leading to anemia occur only in conditions of hypoxia or acidosis. In hereditary fermentopathy associated with deficiency of glucose-6-phosphate dehydrogenase, the use of oxidizing drugs, the use of fava beans, and sometimes a viral infection can play a similar role.
3. Diseases with hereditary predisposition. They are the result of the interaction of genetic and environmental factors, both of which are numerous. Sometimes these diseases are called multifactorial, or multifactorial. These include the vast majority of diseases of mature and old age: hypertension, atherosclerosis, coronary heart disease, peptic ulcer and 12 duodenal intestines, malignant neoplasms, etc.
There is no clear difference between the second and third groups of diseases. They are often combined into one group of diseases with a hereditary predisposition, distinguishing between monogenic and polygenic predisposition.
4. Diseases caused by environmental factors, from the action of which the body has no means of protection (extreme). These are various injuries.
(mechanical, electrical), diseases arising under the influence of ionizing radiation, burns, frostbite, especially dangerous infections, etc. In these cases, the genetic factor determines only the severity of the disease, its outcome, and in some cases the likelihood of occurrence.
Classification of hereditary forms of pathology
AT Due to the complex nature of hereditary pathology, there are two main principles for its classification: clinical and genetic.
Clinical classification principle implies the division of hereditary forms of pathology depending on the organ or system most involved in the pathological process. In accordance with this criterion, hereditary diseases of the nervous system, diseasesmusculoskeletalapparatus, skin, blood, etc.
The basis genetic classification hereditary diseases are based on the etiological principle, namely the type of mutations and the nature of their interaction with the environment. In accordance with this criterion, all hereditary pathology can be divided into groups:
1) gene diseases, caused by gene mutations;
2) chromosomal diseases, resulting from chromosomal or genomic mutations;
3) diseases with hereditary predisposition (multifactorial)
- develop in individuals with an appropriate combination of "predisposing" hereditary and "manifesting" external factors;
4) genetic diseases of somatic cells;
5) diseases of genetic incompatibility between mother and fetus.
Each of these groups, in turn, is subdivided according to more detailed genetic characteristics and mode of inheritance.
Etiology of hereditary forms of pathology. Mutations, their types. The concept of mutagens
Individual genes, chromosomes and the genome as a whole are constantly undergoing various changes. Despite the fact that there are mechanisms for DNA repair (restoration), some of the damage and errors remain. Changes in the sequence and number of nucleotides in DNA are called mutations.
Mutations are persistent abrupt changes in the hereditary apparatus of a cell, not associated with the usual recombination of genetic material.
All mutations are classified according to several criteria. one. Due to the occurrence distinguish between spontaneous and induced
Spontaneous mutations - These are mutations that have arisen spontaneously under the influence of natural mutagens of exogenous or endogenous origin. The cause of such mutations can be cosmic radiation, radioactive isotopes, endogenous chemical mutagens (peroxides and free radicals - automutagens) formed in the body during metabolism. Age plays a significant role in the occurrence of spontaneous mutations. In men, with age, gene mutations accumulate in the germ cells. In women, the dependence of gene mutations on age was not noted, but a clear relationship was found between the age of the mother and the frequency of chromosomal diseases in the offspring.
induced mutations - these are mutations caused by the directed action on the body of factors of various origins - physical, chemical or biological mutagens. The prevalence of some mutagens in the human environment is presented in Appendix. one.
To physical mutagens include ionizing radiation (α-, β- and γ-rays, x-rays, neutrons) and UV radiation. The peculiarity of ionizing radiation is that it can induce mutations
in low doses that do not cause radiation damage.
To chemical mutagens include alcohols, acids, heavy metals, salts and other compounds. Chemical mutagens are found in the air (arsenic, fluorine, hydrogen sulfide, lead, etc.), soil (pesticides and other
chemicals), food, water. It has been established that many drugs have a pronounced mutagenic activity (Appendix 2). A very strong mutagen is cigarette smoke condensate, which contains benzpyrene. The smoke condensate and surface crust formed when fish and beef are fried contain tryptophan pyrolysates, which are chemical mutagens. A feature of chemical mutagens is that their action depends on the dose and stage of the cell cycle. The higher the dose of the mutagen, the stronger the mutagenic effect.
To biological mutagens include bacterial toxins, measles, rubella, influenza, herpes, antigens of some microorganisms.
The main medical consequences of mutagenesis in various cell types are shown in Fig. one.
2. According to the type of cells in which the mutation occurred, gametic, somatic and mosaic mutations are distinguished.
Gametic mutations occur in germ cells. They are inherited by descendants and, as a rule, are found in all cells of the body. Their consequences affect the fate of offspring and cause hereditary diseases.
Rice. one . Medical Implications of Mutagenesis in Various Cell Types
Somatic mutations occur in somatic cells, are random in nature, can occur at any stage of development, starting from the zygote. They are not inherited.
Mosaic mutations are mutations that occur in the cells of the embryo or fetus. As a result, cell lines with different genotypes arise. Some cells of the body have a normal karyotype, while others have an abnormal one. The earlier in ontogenesis a somatic mutation occurs, the more cells contain this mutation and the more pronounced its manifestations.
3. By value, pathogenic, neutral and favorable mutations are distinguished.
Pathogenic mutations lead to the death of the embryo (or fetus) or to the development of hereditary and congenital diseases. They are divided into lethal, semi-lethal, non-lethal. Lethality can manifest itself at the level of gametes, zygotes, embryos, fetuses, as well as after birth.
Neutral Mutations usually do not affect the vital activity of the organism (for example, mutations that cause the appearance of freckles on the skin, changes in hair color, iris).
Favorable Mutations increase the viability of an organism or species (for example, the dark color of the skin in the inhabitants of the African continent).
four . Depending on the amount of damaged material mutations are divided into genetic (changes in individual genes), chromosomal (structural chromosomal aberrations), genomic (numerical chromosome aberrations).
Antimutagenesis. Mechanisms of action of antimutagens
Antimutagenesis is the process of suppressing spontaneous and induced mutations. Substances with such properties are called antimutagens. Some of them are given in the appendix. 3.
There are various principles for classifying antimutagens:
1) by origin: exogenous and endogenous, intracellular and extracellular;
2) mechanism of action;
3) chemical structure and anticarcinogenic properties.
Exogenous antimutagens include:
– essential amino acids (methionine, histidine, arginine, glutamic acid, etc.);
– vitamins and provitamins (mainly A, E, C, K);
– polyunsaturated fatty acids;
– trace elements (Se), cobalt chloride;
– alimentary fiber;
2) penetrating into the body by the respiratory route (phytoncides);
3) entering the human body orally in the process of pharmacotherapy or prophylactic use:
– drugs (streptomycin, chloramphenicol, etc., used in small
– specially synthesized drugs (bemitil);
– biologically active additives(indole-3-carbinol, etc.);
– synthetic antimutagens (ionol, dibunol, etc.).
Endogenous antimutagens include:
1) damaged DNA repair system;
2) antioxidant system;
3) enzyme systems;
4) cellular metabolites;
5) thyroid hormones, melatonin;
6) embryonic substances (Co);
7) S-containing compounds (glutathione).
Mechanisms of action of antimutagens
The main mechanisms of action of antimutagens include:
1. Inactivation of mutagens of external origin and protection of DNA from their damaging effects(dismutagens). In most cases, dismutagens stably bind to the mutagen and remove it from the body (extracts of parsley, beets, radishes, celery, plums, blueberries, apples).
2. Suppression of the formation of true mutagens from precursor non-mutagens(vitamins C, E, tannins,
some phenols).
3. Suppresses the activity of free radicals that can damage DNA(antioxidants: superoxide dismutase, glutathione peroxidase, catalase, vitamin C, A,α-tocopherol, β-carotene, E, melatonin, etc.).
4. Increased activity of enzyme systems that neutralize mutagens, carcinogens and other genotoxic compounds. The universal mechanism of inactivation of xenobiotics is provided by microsomal liver enzymes, which metabolize up to 75% of all drugs.
5. Antimutagens that reduce DNA repair and replication errors,
activation and correction of repair (reparatives) . To reparations
Antimutagens found in certain foods (such as corn, cottonseed, sunflower, soybean, and other vegetable oils) include:
– vanillin, cyanamaldehyde and other aldehydes formed during the oxidation of saturated fatty acids. These substances stimulate genetic recombination, temporarily inhibit cell division, increasing the DNA repair time;
– cobalt salts that increase the efficiency of error-free DNA repair (contained in sufficient quantities in onions, cabbage, tomatoes, lettuce, potatoes, blackcurrants and pears).
6. Antimutagens with an unknown mechanism of action.In recent years, polyfunctionality has been established for some antimutagens (the phenolic component of green tea - epigallocatechinhalate, isocyanates from cruciferous vegetables - sulforane and phenol isocyanate, etc.). Antimutagens act as free radical scavengers, inhibit the synthesis of metabolic activation of xenobiotics and stimulate their detoxification, modulate DNA repair, affect transcription factors and signaling pathways involved in apoptosis and cell cycle regulation, and suppress inflammation and angiogenesis.
Thus, the main antimutagens include:
1) compounds that neutralize the mutagen before it reacts with the molecule
2) substances that remove damage to the DNA molecule caused by a mutagen or increase its resistance to a mutagen;
3) compounds that prevent the transformation of indirect mutagens into true mutagens in the body.
GENE DISEASES
Genetic diseases are a group of diseases that are heterogeneous in clinical manifestations and are caused by mutations at the gene level. The basis for combining them into one group is the etiological genetic characteristics and, accordingly, the patterns of inheritance in families and populations.
Etiology of gene diseases
The causes of gene diseases are gene mutations that can affect structural, transport and embryonic proteins, as well as enzymes.
Gene mutations are molecular changes in the structure of DNA. They are due to a change in the chemical structure of the gene, namely the specific
Variability- this is a general property of living systems associated with changes in the phenotype and genotype that occur under the influence of the external environment or as a result of changes in hereditary material. Distinguish between non-hereditary and hereditary variability.
Non-hereditary variability. Non-hereditary, or group (defined), or modification variability- these are changes in the phenotype under the influence of environmental conditions. Modification variability does not affect the genotype of individuals. The genotype, while remaining unchanged, determines the limits within which the phenotype can change. These limits, i.e. opportunities for the phenotypic manifestation of a trait are called reaction rate and inherited. The reaction norm sets the boundaries within which a particular feature can change. Different signs have a different reaction rate - wide or narrow. So, for example, such signs as blood type, eye color do not change. The shape of the mammalian eye changes insignificantly and has a narrow reaction rate. The milk yield of cows can vary over a fairly wide range depending on the conditions of the breed. Other quantitative characteristics may also have a wide reaction rate - growth, leaf size, number of grains per cob, etc. The wider the reaction rate, the more opportunities an individual has to adapt to environmental conditions. That is why there are more individuals with an average expression of a trait than individuals with its extreme expressions. This is well illustrated by such an example as the number of dwarfs and giants in humans. There are few of them, while there are thousands of times more people with a height in the range of 160-180 cm.
The phenotypic manifestations of a trait are influenced by the cumulative interaction of genes and environmental conditions. Modification changes are not inherited, but they do not necessarily have a group character and do not always appear in all individuals of a species under the same environmental conditions. Modifications ensure that the individual is adapted to these conditions.
hereditary variability(combinative, mutational, indeterminate).
Combination variability occurs during the sexual process as a result of new combinations of genes that occur during fertilization, crossing over, conjugation, i.e. in processes accompanied by recombinations (redistribution and new combinations) of genes. As a result of combinative variability, organisms arise that differ from their parents in genotypes and phenotypes. Some combinative changes can be detrimental to an individual. For the species, combinative changes are, in general, useful, because. lead to genotypic and phenotypic diversity. This contributes to the survival of species and their evolutionary progress.
Mutational variability associated with changes in the sequence of nucleotides in DNA molecules, deletions and insertions of large sections in DNA molecules, changes in the number of DNA molecules (chromosomes). Such changes are called mutations. Mutations are inherited.
Mutations include:
– genetic- causing changes in the sequence of DNA nucleotides in a particular gene, and therefore in the mRNA and protein encoded by this gene. Gene mutations are both dominant and recessive. They can lead to the appearance of signs that support or depress the vital activity of the organism;
– generative mutations affect germ cells and are transmitted during sexual reproduction;
– somatic mutations do not affect germ cells and are not inherited in animals, while in plants they are inherited during vegetative reproduction;
– genomic mutations (polyploidy and heteroploidy) are associated with a change in the number of chromosomes in the cell karyotype;
– chromosomal mutations are associated with rearrangements in the structure of chromosomes, a change in the position of their sections resulting from breaks, loss of individual sections, etc.
The most common gene mutations, as a result of which there is a change, loss or insertion of DNA nucleotides in the gene. Mutant genes transmit different information to the site of protein synthesis, and this, in turn, leads to the synthesis of other proteins and the emergence of new traits. Mutations can occur under the influence of radiation, ultraviolet radiation, various chemical agents. Not all mutations are effective. Some of them are corrected during DNA repair. Phenotypically, mutations are manifested if they did not lead to the death of the organism. Most gene mutations are recessive. Of evolutionary importance are phenotypically manifested mutations that provided individuals with either advantages in the struggle for existence, or vice versa, which caused their death under the pressure of natural selection.
The mutation process increases the genetic diversity of populations, which creates the prerequisites for the evolutionary process.
The frequency of mutations can be increased artificially, which is used for scientific and practical purposes.
EXAMPLES OF TASKS
Part A
A1. Modification variability is understood as
1) phenotypic variability
2) genotypic variability
3) reaction rate
4) any changes in the feature
A2. Indicate the trait with the widest reaction rate
1) the shape of the wings of a swallow
2) the shape of an eagle's beak
3) hare molting time
4) the amount of wool in a sheep
A3. Specify the correct statement
1) environmental factors do not affect the genotype of an individual
2) it is not the phenotype that is inherited, but the ability to manifest it
3) modification changes are always inherited
4) modification changes are harmful
A4. Give an example of a genomic mutation
1) the occurrence of sickle cell anemia
2) the appearance of triploid potato forms
3) the creation of a tailless dog breed
4) the birth of an albino tiger
A5. With a change in the sequence of DNA nucleotides in a gene,
1) gene mutations
2) chromosomal mutations
3) genomic mutations
4) combinative rearrangements
A6. A sharp increase in the percentage of heterozygotes in a population of cockroaches can lead to:
1) an increase in the number of gene mutations
2) the formation of diploid gametes in a number of individuals
3) chromosomal rearrangements in some members of the population
4) change in ambient temperature
A7. The accelerated skin aging of rural residents compared to urban ones is an example
1) mutational variability
2) combination variability
3) gene mutations under the influence of ultraviolet radiation
4) modification variability
A8. The main cause of chromosomal mutation can be
1) replacement of a nucleotide in a gene
2) change in ambient temperature
3) violation of meiotic processes
4) insertion of a nucleotide into a gene
Part B
IN 1. What examples illustrate modification variability
1) human tan
2) birthmark on the skin
3) the density of the coat of a rabbit of the same breed
4) increase in milk yield in cows
5) six-fingered in humans
6) hemophilia
IN 2. Specify events related to mutations
1) a multiple increase in the number of chromosomes
2) changing the undercoat of a hare in winter
3) amino acid replacement in a protein molecule
4) the appearance of an albino in the family
5) growth of the root system of a cactus
6) the formation of cysts in protozoa
VZ. Match the feature that characterizes variability with its type
Part C
C1. What are the ways to achieve an artificial increase in the frequency of mutations and why should this be done?
C2. Find errors in the given text. Fix them. Indicate the numbers of sentences in which errors were made. Explain them.
1. Modification variability is accompanied by genotypic changes. 2. Examples of modification are hair lightening after long exposure to the sun, increasing the milk yield of cows while improving feeding. 3. Information about modification changes is contained in genes. 4. All modification changes are inherited. 5. The manifestation of modification changes is influenced by environmental factors. 6. All signs of one organism are characterized by the same reaction rate, i.e. the limits of their variability.
The harmful effects of mutagens, alcohol, drugs, nicotine on the genetic apparatus of the cell. Protection of the environment from pollution by mutagens. Identification of sources of mutagens in the environment (indirectly) and assessment of the possible consequences of their influence on one's own body. Human hereditary diseases, their causes, prevention
The main terms and concepts tested in the examination paper: biochemical method, twin method, hemophilia, heteroploidy, color blindness, mutagens, mutagenesis, polyploidy.
Non-hereditary (phenotypic) variability - this is a type of variability that reflects changes in the phenotype under the influence of environmental conditions that do not affect the genotype. The degree of its severity can be determined by the genotype. Phenotypic differences in genetically identical individuals arising from the influence of environmental factors are called modifications . There are age, seasonal and ecological modifications. They are reduced to a change in the degree of expression of the trait. Violations of the structure of the genotype do not occur with them.
Age (ontogenetic) modifications are expressed in the form of a constant change of signs in the process of development of an individual. In humans, in the process of development, modifications of morphophysiological and mental signs are observed. For example, a child will not be able to develop properly both physically and intellectually if in early childhood he is not influenced by normal external and social factors. A child's long stay in a socially disadvantaged environment can cause an irreversible defect in his intellect.
Ontogenetic variability, like ontogeny itself, is determined by the genotype, where the development program of the individual is encoded. However, the features of the formation of the phenotype in ontogeny are due to the interaction of the genotype and the environment. Under the influence of unusual external factors, deviations in the formation of a normal phenotype may occur.
Seasonal modifications individuals or entire populations are manifested in the form of a genetically determined change in traits (for example, a change in coat color, the appearance of a down in animals), which occurs as a result of seasonal changes in climatic conditions. For example, at high temperatures, a rabbit develops a white coat color, and at low temperatures, a dark one. In Siamese cats, depending on the season, the fawn color of the coat changes to dark fawn and even brown.
Environmental modifications are adaptive changes in the phenotype in response to changing environmental conditions. Ecological modifications are phenotypically manifested in a change in the degree of expression of a trait. They can appear in the early stages of development and persist throughout the life of the individual. Examples include large and small plant specimens grown in soils containing varying amounts of nutrients; undersized and weakly viable individuals in animals that develop in poor conditions and do not receive enough nutrients necessary for life; the number of petals in the flowers of the liverwort, popovnik, buttercup, the number of flowers in the inflorescence of plants, etc.
Ecological modifications affect quantitative (the number of petals in a flower, offspring in animals, the mass of animals) and qualitative (human skin color under the influence of ultraviolet rays).
Ecological modifications are reversible and with the change of generations, subject to changes in the external environment, they may not appear. For example, the offspring of low-growing plants on well-fertilized soils will be of normal height; a person with crooked legs due to rickets has quite normal offspring. If, in a number of generations, the conditions do not change, the degree of expression of the trait in the offspring is preserved, then it is taken as a persistent hereditary trait (long-term modifications). When the conditions of development change, long-term modifications are not inherited. It was assumed that from well-trained animals, offspring are obtained with better “acting” data than from untrained ones. The offspring of trained animals is indeed easier to educate, but this is explained by the fact that it inherits not the skills acquired by the parent individuals, but the ability to train, due to the inherited type of nervous activity.
In most cases, modifications are adequate character, i.e. the degree of manifestation of the symptom is directly dependent on the type and duration of the action of a particular factor. Thus, improving the maintenance of livestock contributes to an increase in the live weight of animals, fertility, milk yield and fat content of milk. Modifications are worn adaptive, adaptive character. This means that in response to changing environmental conditions, an individual exhibits such phenotypic changes that contribute to its survival. An example is the content of erythrocytes and hemoglobin in persons who find themselves high above sea level. But, it is not the modifications themselves that are adaptive, but the body's ability to change depending on environmental conditions.
One of the main properties of modifications is their mass character. It is due to the fact that the same factor causes approximately the same change in individuals that are genotypically similar.
Modification variability is caused by external factors, but its limit and the degree of expression of the trait are controlled by the genotype. So, identical twins are phenotypically similar and even react in the same way to different conditions (for example, they most often suffer the same diseases). But the environment significantly affects the formation of signs. For example, identical twins show freckles to varying degrees in different climates. In animals, a sharp deterioration in the diet can lead to weight loss in some and death in others. In a person with equally enhanced nutrition, a hypersthenic will sharply increase in body weight, to a lesser extent - a normasthenic, while the mass of an asthenic may not change at all. This indicates that the genotype controls not only the ability of the organism to change, but also its limits. The modification limit is called reaction rate . It is the reaction rate, and not the modifications themselves, that is inherited, i.e. the ability to develop one or another trait is inherited. The reaction rate is a specific quantitative and qualitative characteristic of the genotype, i.e. a certain combination of genes in the genotype and the nature of their interaction. Gene combinations and interactions include:
polygenic determination of traits, when some of the polygenes that control the development of a quantitative trait, depending on the conditions, can move from a heterochromatic state to a euchromatic state and vice versa (the limit of modification in this case is determined by the number of polygenes in the genotype);
change of dominance in heterozygotes when external conditions change;
various types of interaction of non-allelic genes;
mutation expressivity.
Distinguish signs from wide(weight, yield, etc.), narrow(e.g. percentage of fat in milk, number of chicks in birds, blood proteins in humans) and unambiguous reaction norm(most qualitative features: animal color, human hair and eye color, etc.).
Sometimes individuals of a particular species are exposed to such harmful factors that it has not encountered in the process of evolution, and their toxicity is so great that it excludes the possibility of modification variability of the organism, determined by the reaction rate. Such agents may be lethal or limited to inducing developmental malformations. Deformities, or anomalies, of development are called morphoses. Morophoses - these are various violations of morphogenesis processes during the period of morphogenesis, leading to a sharp change in morphological, biochemical, physiological signs and properties of the organism. Examples of morphoses are defects in the development of wings and limbs in insects, deformities of the shell in mollusks, and deformities in the physical structure of mammals. An example of morphoses in humans is the birth of children without limbs, with intestinal obstruction, a tumor of the upper lip, which took on the character of an almost epidemic in 1961 in Germany and some countries of Western Europe and America. The reason for the deformities was that mothers in the first three months of pregnancy took thalidomide as a sedative drug. A number of other substances (teratogens, or morphogens) are known to cause deformities in human development. These include quinine, the hallucinogen LSD, drugs, and alcohol. Morphoses are new reactions of the body to unusual harmful environmental factors that do not have a historical basis. Phenotypically, they differ sharply from modifications: if modification is a change in the degree of expression of a trait, then morphosis- this is a sharply changed, often qualitatively new sign.
Morphosis occurs when harmful agents (morphogens) influence the early processes of embryonic development. Embryogenesis is divided into a number of stages, during which the differentiation and growth of certain organs and tissues is carried out. The development of a trait begins with a short period, called "critical". During this period, the body is characterized by high sensitivity and a decrease in reparative (restorative) capabilities. In the case of exposure to morphogens during critical periods, the usual path of development of the primordium changes, since this is accompanied by induced repression of the genes responsible for its formation. The development of this or that organ, as it were, jumps from one path to another. This leads to deviations from the normal development of the phenotype and to the formation of deformities. Embryogenesis disorders are sometimes of a specific nature, since their phenotypic expression depends on the stage of development of the organism at the time of exposure. A variety of toxic agents can cause the same or similar anomalies if the organism is affected at a strictly defined period of development, when the sensitivity of the corresponding tissues and organs is increased. Some morphogens (chemical substances), due to their structural features, can cause specific morphoses as a result of selective action in a particular period of development.
Morphoses are not adaptive in nature, since the reaction of the body to the factors indicating them is usually inadequate. The frequency of induced morphoses and the sensitivity of organisms to harmful agents-morphogens is controlled by the genotype and is different in different individuals of the same species.
Morphoses are often phenotypically similar to mutations and in such cases are called phenocopies. The mechanisms of the occurrence of mutations and phenocopies are different: a mutation is a consequence of a change in the structure of a gene, and a phenocopy is the result of a violation of the implementation of hereditary information. Phenocopies can also occur due to the suppression of the function of certain genes. Unlike mutations, they are not inherited.
Biology [A complete guide to preparing for the exam] Lerner Georgy Isaakovich
3.6.1. Variability, its types and biological significance
Variability- this is a general property of living systems associated with changes in the phenotype and genotype that occur under the influence of the external environment or as a result of changes in hereditary material. Distinguish between non-hereditary and hereditary variability.
Non-hereditary variability . Non-hereditary, or group (defined), or modification variability- these are changes in the phenotype under the influence of environmental conditions. Modification variability does not affect the genotype of individuals. The genotype, while remaining unchanged, determines the limits within which the phenotype can change. These limits, i.e. opportunities for the phenotypic manifestation of a trait are called reaction rate and inherited. The reaction norm sets the boundaries within which a particular feature can change. Different signs have a different reaction rate - wide or narrow. So, for example, such signs as blood type, eye color do not change. The shape of the mammalian eye changes insignificantly and has a narrow reaction rate. The milk yield of cows can vary over a fairly wide range depending on the conditions of the breed. Other quantitative characteristics may also have a wide reaction rate - growth, leaf size, number of grains per cob, etc. The wider the reaction rate, the more opportunities an individual has to adapt to environmental conditions. That is why there are more individuals with an average expression of a trait than individuals with its extreme expressions. This is well illustrated by such an example as the number of dwarfs and giants in humans. There are few of them, while there are thousands of times more people with a height in the range of 160-180 cm.
The phenotypic manifestations of a trait are influenced by the cumulative interaction of genes and environmental conditions. Modification changes are not inherited, but they do not necessarily have a group character and do not always appear in all individuals of a species under the same environmental conditions. Modifications ensure that the individual is adapted to these conditions.
hereditary variability (combinative, mutational, indeterminate).
Combination variability occurs during the sexual process as a result of new combinations of genes that occur during fertilization, crossing over, conjugation, i.e. in processes accompanied by recombinations (redistribution and new combinations) of genes. As a result of combinative variability, organisms arise that differ from their parents in genotypes and phenotypes. Some combinative changes can be detrimental to an individual. For the species, combinative changes are, in general, useful, because. lead to genotypic and phenotypic diversity. This contributes to the survival of species and their evolutionary progress.
Mutational variability associated with changes in the sequence of nucleotides in DNA molecules, deletions and insertions of large sections in DNA molecules, changes in the number of DNA molecules (chromosomes). Such changes are called mutations. Mutations are inherited.
Mutations include:
– genetic- causing changes in the sequence of DNA nucleotides in a particular gene, and therefore in the mRNA and protein encoded by this gene. Gene mutations are both dominant and recessive. They can lead to the appearance of signs that support or depress the vital activity of the organism;
– generative mutations affect germ cells and are transmitted during sexual reproduction;
– somatic mutations do not affect germ cells and are not inherited in animals, while in plants they are inherited during vegetative reproduction;
– genomic mutations (polyploidy and heteroploidy) are associated with a change in the number of chromosomes in the cell karyotype;
– chromosomal mutations are associated with rearrangements in the structure of chromosomes, a change in the position of their sections resulting from breaks, loss of individual sections, etc.
The most common gene mutations, as a result of which there is a change, loss or insertion of DNA nucleotides in the gene. Mutant genes transmit different information to the site of protein synthesis, and this, in turn, leads to the synthesis of other proteins and the emergence of new traits. Mutations can occur under the influence of radiation, ultraviolet radiation, various chemical agents. Not all mutations are effective. Some of them are corrected during DNA repair. Phenotypically, mutations are manifested if they did not lead to the death of the organism. Most gene mutations are recessive. Of evolutionary importance are phenotypically manifested mutations that provided individuals with either advantages in the struggle for existence, or vice versa, which caused their death under the pressure of natural selection.
The mutation process increases the genetic diversity of populations, which creates the prerequisites for the evolutionary process.
The frequency of mutations can be increased artificially, which is used for scientific and practical purposes.
EXAMPLES OF TASKS
Part BUT
A1. Modification variability is understood as
1) phenotypic variability
2) genotypic variability
3) reaction rate
4) any changes in the feature
A2. Indicate the trait with the widest reaction rate
1) the shape of the wings of a swallow
2) the shape of an eagle's beak
3) hare molting time
4) the amount of wool in a sheep
A3. Specify the correct statement
1) environmental factors do not affect the genotype of an individual
2) it is not the phenotype that is inherited, but the ability to manifest it
3) modification changes are always inherited
4) modification changes are harmful
A4. Give an example of a genomic mutation
1) the occurrence of sickle cell anemia
2) the appearance of triploid potato forms
3) the creation of a tailless dog breed
4) the birth of an albino tiger
A5. With a change in the sequence of DNA nucleotides in a gene,
1) gene mutations
2) chromosomal mutations
3) genomic mutations
4) combinative rearrangements
A6. A sharp increase in the percentage of heterozygotes in a population of cockroaches can lead to:
1) an increase in the number of gene mutations
2) the formation of diploid gametes in a number of individuals
3) chromosomal rearrangements in some members of the population
4) change in ambient temperature
A7. The accelerated skin aging of rural residents compared to urban ones is an example
1) mutational variability
2) combination variability
3) gene mutations under the influence of ultraviolet radiation
4) modification variability
A8. The main cause of chromosomal mutation can be
1) replacement of a nucleotide in a gene
2) change in ambient temperature
3) violation of meiotic processes
4) insertion of a nucleotide into a gene
Part B
IN 1. What examples illustrate modification variability
1) human tan
2) birthmark on the skin
3) the density of the coat of a rabbit of the same breed
4) increase in milk yield in cows
5) six-fingered in humans
6) hemophilia
IN 2. Specify events related to mutations
1) a multiple increase in the number of chromosomes
2) changing the undercoat of a hare in winter
3) amino acid replacement in a protein molecule
4) the appearance of an albino in the family
5) growth of the root system of a cactus
6) the formation of cysts in protozoa
VZ. Match the feature that characterizes variability with its type
Part FROM
C1. What are the ways to achieve an artificial increase in the frequency of mutations and why should this be done?
C2. Find errors in the given text. Fix them. Indicate the numbers of sentences in which errors were made. Explain them.
1. Modification variability is accompanied by genotypic changes. 2. Examples of modification are hair lightening after long exposure to the sun, increasing the milk yield of cows while improving feeding. 3. Information about modification changes is contained in genes. 4. All modification changes are inherited. 5. The manifestation of modification changes is influenced by environmental factors. 6. All signs of one organism are characterized by the same reaction rate, i.e. the limits of their variability.
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