Influence of environmental factors on mutagenesis. Mutations. Classification. Mechanism of mutations. Mutagenic factors. Practical application of mutations Environmental factors causing mutations

Factors causing mutations. Factors that cause (induce) mutations can be a wide variety of environmental influences: temperature, ultraviolet radiation, radiation (both natural and artificial), the effects of various chemical compounds - mutagens. Mutagens are agents of the external environment that cause certain changes in the genotype - mutation, and the process of formation of mutations itself - mutagenesis.

Radioactive mutagenesis began to be studied in the 20s of our century. In 1925, Soviet scientists G.S. Filippov and G.A. Nadson, for the first time in the history of genetics, used X-rays to obtain mutations in yeast. A year later, the American researcher G. Meller (later twice a Nobel Prize winner), who worked for a long time in Moscow at the institute headed by N.K. Koltsov, used the same mutagen on Drosophila.

Chemical mutagenesis was first purposefully studied by N.K. Koltsov’s collaborator V.V. Sakharov in 1931 on Drosophila when its eggs were exposed to iodine, and later by M.E. Lobashov.

Chemical mutagens include a wide variety of substances (alkylating compounds, hydrogen peroxide, aldehydes and ketones, nitric acid and its analogues, various antimetabolites, salts of heavy metals, dyes with basic properties, aromatic substances), insecticides (from the Latin insecta - insects , cida - killer), herbicides (then lat. herba - grass), drugs, alcohol, nicotine, some medicinal substances and many others.

Genetically active factors can be divided into 3 categories: physical, chemical and biological.

Physical factors. These include various types of ionizing radiation and ultraviolet radiation. A study of the effect of radiation on the mutation process showed that in this case there is no threshold dose, and even the smallest doses increase the likelihood of mutations occurring in the population. An increase in the frequency of mutations is dangerous not so much in an individual sense, but from the point of view of increasing the genetic load of the population. For example, irradiation of one of the spouses with a dose within the range of doubling the frequency of mutations (1.0 - 1.5 Gy) slightly increases the risk of having a sick child (from a level of 4 - 5% to a level of 5 - 6%). If the population of an entire region receives the same dose, the number of hereditary diseases in the population will double in a generation.

Chemical factors. The chemicalization of agriculture and other areas of human activity, the development of the chemical industry led to the synthesis of a huge flow of substances (totaling from 3.5 to 4.3 million), including those that had never existed in the biosphere for millions of years of previous evolution. This means, first of all, the indegradability and thus long-term preservation of foreign substances entering the environment.

What was initially taken as an achievement in the fight against pests later turned into a complex problem. Widely used in the 40s - 60s insecticide DDT, which belongs to the class of chlorinated hydrocarbons, led to its spread throughout the globe, right up to the ice of Antarctica.

Most pesticides are highly resistant to chemical and biological degradation and have a high level of toxicity. anthropogenetics chromosomal inheritance anomaly

Biological factors. Along with physical and chemical mutagens, some factors of biological nature also have genetic activity. The mechanisms of the mutagenic effect of these factors have been studied in the least detail. At the end of the 30s, S. and M. Gershenzon began research on mutagenesis in Drosophila under the influence of exogenous DNA and viruses. Since then, the mutagenic effect of many viral infections in humans has been established. Chromosome aberrations in somatic cells cause smallpox, measles, chickenpox, mumps, influenza, hepatitis viruses and etc.

Mutation- this is an abrupt, sustainable change in genetic material under the influence of external or internal environmental factors, transmitted by inheritance.

Properties of mutations:

▪ arise suddenly;

▪ are inherited;

▪ non-directional;

▪ may occur repeatedly.

The process of mutation formation is called mutagenesis, and the factors causing them are mutagens. Mutagens initially affect the genetic material of an individual, as a result of which the phenotype may change. These can be exomutagens (environmental factors) and endomutagens (metabolic products of the body itself).

Mutagenic factors are divided into physical, chemical and biological.

Physical mutagens include various types of radiation (mainly ionizing - alpha, beta and gamma rays, ultraviolet rays), temperature, humidity, etc. Their mechanisms of action: 1) disruption of the structure of genes and chromosomes; 2) the formation of free radicals that enter into chemical interaction with DNA; 3) destruction of the filaments of the achromatin spindle; 4) the formation of dimers - the connection between themselves ("cross-linking") of neighboring pyrimidine bases of one DNA chain (usually T-T).

Chemical mutagens include: natural organic and inorganic substances (nitrites, nitrates, alkaloids, hormones, enzymes, etc.); products of industrial processing of natural compounds (coal, oil); synthetic substances not previously found in nature (pesticides, insecticides, food preservatives, detergents, deodorants); medications that can provoke congenital malformations (immunosuppressants, some antibiotics, narcotic substances, synthetic corticosteroids, etc.). Chemical mutagens have great penetrating power, cause predominantly gene mutations and act during the period of DNA replication. The mechanism of their action: 1) deamination and alkylation of nucleotides; 2) replacement of nitrogenous bases with their analogues; 3) inhibition of the synthesis of nucleic acid precursors, etc.

Supermutagens are factors (usually of a chemical nature) that increase the frequency of mutations hundreds to tens of thousands of times (for example, colchicine, ethyleneimine, mustard gas). They are used to obtain induced mutations in breeding.

Antimutagens significantly reduce the frequency of mutations. These include about 200 natural and synthetic compounds: some amino acids (histidine, methionine, etc.); vitamins (tocopherol, ascorbic acid, carotene, etc.); pharmacological agents (interferon, antioxidants, oxypyridines, etc.); food products (certain types of beans, black pepper, cabbage, apple extract).

A number of antimutagens are used as radioprotectors.

Mutagenic factors – factors causing mutation.

Factors of physical, chemical and biological nature have a mutagenic effect.

Chemical substances that cause mutations include organic and inorganic substances, such as acids, alkalis, peroxides, metal salts, formaldehyde, pesticides, defoliants, herbicides, colchicine, etc.

The action of chemical factors: enhance mutation processes, cause point mutations that induce chromosomal rearrangements, and cause disruption of DNA replication. Some mutagens can cause disruption of meiosis, which leads to chromosome non-disjunction.

Physical factors: ionizing radiation, radioactive decay, ultraviolet radiation, electromagnetic radiation, extreme heat and cold.

The action of physical factors: X-ray radiation, having a high penetrating ability, causes the formation of free radicals of water, which break down nucleic acids, causing gene and chromosomal rearrangements. Ultraviolet radiation leads to the formation of thymidine dimers, which cause disruption of DNA replication.

Biological factors: viruses (measles, rubella, influenza), metabolic products (lipid oxidation products), microorganism antigens./

The action of biological factors: they increase the rate of cell mutations by suppressing the activity of repair systems.

3. Gene and chromosomal mutations, their characteristics.

Gene (point) mutations- these are changes in the number and/or sequence of nucleotides in the DNA structure (insertions, deletions, movements, substitutions of nucleotides) within individual genes, leading to a change in the quantity or quality of the corresponding protein products. Base substitutions lead to the appearance of three types of mutant codons: with a changed meaning (missense mutations), with an unchanged meaning (neutral mutations) and meaningless or stop codons (nonsense mutations).

There are three groups of such changes. Mutations of the first group consist of replacing some bases with others (about 20% of spontaneously occurring gene changes). The second group of mutations is caused by a shift in the reading frame that occurs when the number of nucleotide pairs in the gene changes. The third group is mutations associated with a change in the order of nucleotide sequences within a gene.

Mutations by type of replacement of nitrogenous bases occur due to the following reasons. Firstly, a change in the structure of a base already included in the DNA helix can occur accidentally or under the influence of chemical agents. If such an altered form of the base remains undetected by repair enzymes, then during the next replication cycle it can attach another nucleotide to itself.

Another reason for base substitution may be the erroneous inclusion in the synthesized DNA chain of a nucleotide carrying a chemically altered form of the base or its analogue. Thus, a change in DNA structure by base substitution occurs before or during replication, initially in one polynucleotide chain. If such changes are not corrected during repair, then during subsequent replication they become the property of both DNA strands. The consequence of replacing one pair of complementary nucleotides with another is the formation of a new triplet in the DNA nucleotide sequence, different from the previous one. In this case, the new triplet can encode the same amino acid (a “synonym” triplet), another amino acid, or not encode any amino acid (a nonsense triplet). In the first case, no changes occur, in the second, the structure and properties of the corresponding protein change. Depending on the nature and location of the replacement that occurs, the specific properties of the protein change to varying degrees, in some cases significantly. It is known that replacing nucleotides in one triplet leads to the formation of synonymous triplets in 25% of cases, meaningless triplets in 2-3%, and true gene mutations in 75-70% of cases.

Chromosomal mutations(or aberrations) – changes in the structure of chromosomes. At the chromosomal level of organization, the hereditary material has all the characteristics of the substrate of heredity and variability, including the ability to acquire changes that can be transmitted to a new generation. Under the influence of various influences, the physicochemical and morphological structure of chromosomes can change. Changes in the structure of chromosomes, as a rule, are based on an initial violation of its integrity - breaks, which are accompanied by various rearrangements, called chromosomal mutations or aberrations. Chromosome breaks occur naturally during crossing over, when they are accompanied by the exchange of corresponding sections between homologous chromosomes. Crossing-over disruption, in which chromosomes exchange unequal genetic material, leads to the appearance of new linkage groups, where individual sections fall out - deletion - or double - duplication. With such rearrangements, the number of genes in the linkage group changes. Chromosome breaks can also occur under the influence of various external factors, most often physical (for example, ionizing radiation), certain chemical compounds, and viruses. Violation of the integrity of chromosomes can be accompanied by a rotation of its section located between the breaks by 180° - inversion. A fragment of a chromosome separated from it during a break can attach to another chromosome - translocation. Often, two damaged non-homologous chromosomes mutually exchange detached sections - reciprocal translocation. It is possible to attach a fragment to its own chromosome, but in another place - transposition. A special category of chromosomal mutations are aberrations associated with the fusion or separation of chromosomes, when two non-homologous structures combine into one - Robertsonian translocation, or one chromosome forms two independent chromosomes. With such mutations, not only the morphology of chromosomes changes, but also their number in the karyotype changes. The latter can be considered a genomic mutation. The cause of genomic mutations can also be a disruption of the processes occurring in meiosis. Violation of the divergence of bivalents in anaphase leads to the appearance of gametes with different numbers of chromosomes. Fertilization of such gametes by normal germ cells leads to a change in the total number of chromosomes in the karyotype due to a decrease (monosomy) or increase (trisomy) in the number of individual chromosomes. Such violations of the genome structure are called aneuploidy. If the mechanism of distribution of homologous chromosomes is damaged, the cell remains undivided, and then diploid gametes are formed. Fertilization of such gametes leads to the formation of triploid zygotes, that is, an increase in the number of sets of chromosomes occurs - polyploidy. Any mutational changes in the hereditary material of gametes - generative mutations - become the property of the next generation if such gametes are involved in fertilization.

There are many inherited metabolic diseases. Examples include disorders of porphyrin metabolism (Gunther's disease, erythropoietic protoporphyria, coproporphyria, etc.). These are diseases that manifest themselves after exposure to UV rays by damage to the skin and deeper tissues, an increased content of proporphins and coproporphyrins in erythrocytes. Manifest among brothers and sisters of the same generation.

Based on the reasons for their occurrence, spontaneous and induced mutations are distinguished.

Spontaneous (spontaneous) mutations occur for no apparent reason. These mutations are sometimes considered three P errors: processes DNA replication, repair and recombination . This means that the process of occurrence of new mutations is under the genetic control of the body. For example, mutations are known that increase or decrease the frequency of other mutations; therefore, there are mutator genes and antimutator genes.

At the same time, the frequency of spontaneous mutations also depends on the state of the cell (organism). For example, under stress conditions the frequency of mutations may increase.

Induced mutations arise under the influence mutagens .

Mutagens are a variety of factors that increase the frequency of mutations.

For the first time, induced mutations were obtained by domestic geneticists G.A. Nadson and G.S. Filippov in 1925 when irradiating yeast with radium radiation.

There are several classes of mutagens:

– Physical mutagens: ionizing radiation, thermal radiation, ultraviolet radiation.

– Chemical mutagens: nitrogen base analogues (e.g. 5-bromouracil), aldehydes, nitrites, methylating agents, hydroxylamine, heavy metal ions, some drugs and plant protection products.

– Biological mutagens: pure DNA, viruses, antiviral vaccines.

– Automutagens– intermediate metabolic products (intermediates). For example, ethyl alcohol itself is not a mutagen. However, in the human body it is oxidized to acetaldehyde, and this substance is already a mutagen.

Question No. 21.

(Chromosomal mutations, their classification: deletions and duplications, inversions, translocations. Causes and mechanisms occurrence. Significance in the development of human pathological conditions)

With chromosomal Mutations cause major rearrangements in the structure of individual chromosomes. In this case, there is a loss (deletion) or doubling of a part (duplication) of the genetic material of one or more chromosomes, a change in the orientation of chromosome segments in individual chromosomes (inversion), as well as a transfer of part of the genetic material from one chromosome to another (translocation) (an extreme case - unification of whole chromosomes

Changes in the structure of a chromosome, as a rule, are based on an initial violation of its integrity - breaks, which are accompanied by various rearrangements called chromosomal mutations.

Chromosome breaks occur naturally during crossing over, when they are accompanied by the exchange of corresponding sections between homologues. Crossing-over disruption, in which chromosomes exchange unequal genetic material, leads to the emergence of new linkage groups, where individual sections drop out - division - or double - duplications. With such rearrangements, the number of genes in the linkage group changes.

Chromosome breaks can also occur under the influence of various mutagenic factors, mainly physical (ionizing and other types of radiation), certain chemical compounds, and viruses.

Violation of the integrity of a chromosome can be accompanied by a rotation of its section located between two breaks by 180° - inversion. Depending on whether a given region includes the centromere region or not, they distinguish pericentric And paracentric inversions.

A chromosome fragment separated from it during breakage can be lost by the cell during the next mitosis if it does not have a centromere. More often, such a fragment is attached to one of the chromosomes - translocation. It is possible to attach a fragment to its own chromosome, but in a new place - transposition. Thus, various types of inversions and translocations are characterized by changes in gene localization.

Thus, changes in chromosomal organization, which most often have an adverse effect on the viability of the cell and organism, with a certain probability can be promising, inherited in a number of generations of cells and organisms and create the prerequisites for the evolution of the chromosomal organization of hereditary material.

Question No. 22.

(Genomic mutations: classification, causes, mechanisms. Role in the occurrence of chromosomal syndromes. Antimutation mechanisms).

Genomic: - polyploidization a change in the number of chromosomes that is not a multiple of the haploid set. Depending on the origin of chromosome sets among polyploids, a distinction is made between allopolyploids, which have chromosome sets obtained by hybridization from different species, and autopolyploids, in which the number of chromosome sets of their own genome increases

Genomic mutations include haploidy, polyploidy and aneuploidy.

Aneuploidy is a change in the number of individual chromosomes - the absence (monosomy) or the presence of additional (trisomy, tetrasomy, generally polysomy) chromosomes, i.e. unbalanced chromosome set. Cells with an altered number of chromosomes appear as a result of disturbances in the process of mitosis or meiosis, and therefore they distinguish between mitotic and meiotic.

Causes of mutations

Mutations are divided into spontaneous and induced. Spontaneous mutations occur spontaneously throughout the life of an organism under normal environmental conditions with a frequency of approximately one nucleotide per cell generation.

Induced mutations are heritable changes in the genome that arise as a result of certain mutagenic effects in artificial (experimental) conditions or under adverse environmental influences.

Mutations appear constantly during processes occurring in a living cell. The main processes leading to the occurrence of mutations are DNA replication, DNA repair disorders and genetic recombination.

Relationship between mutations and DNA replication

Many spontaneous chemical changes in nucleotides lead to mutations that occur during replication. For example, due to the deamination of cytosine opposite it, uracil can be included in the DNA chain (a U-G pair is formed instead of the canonical C-G pair). During DNA replication opposite uracil, adenine is included in the new chain, a U-A pair is formed, and during the next replication it is replaced by a T-A pair, that is, a transition occurs (a point replacement of a pyrimidine with another pyrimidine or a purine with another purine).

Relationship between mutations and DNA recombination

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

Relationship between mutations and DNA repair

Spontaneous DNA damage is quite common and occurs in every cell. To eliminate the consequences of such damage, there are special repair mechanisms (for example, an erroneous section of DNA is cut out and the original one is restored at this place). Mutations occur only when the repair mechanism for some reason does not work or cannot cope with the elimination of damage. Mutations that occur in genes encoding proteins responsible for repair can lead to a multiple increase (mutator effect) or decrease (antimutator effect) in the frequency of mutation of other genes. Thus, mutations in the genes of many enzymes of the excision repair system lead to a sharp increase in the frequency of somatic mutations in humans, and this, in turn, leads to the development of xeroderma pigmentosum and malignant tumors of the integument.

Mutation classifications

There are several classifications of mutations according to various criteria. Möller proposed dividing mutations according to the nature of the change in the functioning of the gene into hypomorphic (the altered alleles act in the same direction as the wild-type alleles; only less protein product is synthesized), amorphous (the mutation looks like a complete loss of gene function, for example, the white mutation in Drosophila ), antimorphic (the mutant trait changes, for example, the color of the corn grain changes from purple to brown) and neomorphic.

Modern educational literature also uses a more formal classification based on the nature of changes in the structure of individual genes, chromosomes and the genome as a whole. Within this classification, the following types of mutations are distinguished:

genomic;

chromosomal;

Genomic: - polyploidization, a change in the number of chromosomes that is not a multiple of the haploid set. Depending on the origin of chromosome sets among polyploids, a distinction is made between allopolyploids, which have chromosome sets obtained by hybridization from different species, and autopolyploids, in which the number of chromosome sets of their own genome increases

With chromosomal mutations, major rearrangements in the structure of individual chromosomes occur. In this case, there is a loss (deletion) or doubling of a part (duplication) of the genetic material of one or more chromosomes, a change in the orientation of chromosome segments in individual chromosomes (inversion), as well as a transfer of part of the genetic material from one chromosome to another (translocation) (an extreme case - unification of whole chromosomes.

At the gene level, changes in the primary DNA structure of genes under the influence of mutations are less significant than with chromosomal mutations, but gene mutations are more common. As a result of gene mutations, substitutions, deletions and insertions of one or more nucleotides, translocations, duplications and inversions of various parts of the gene occur. In the case when only one nucleotide changes due to a mutation, they speak of point mutations

Antimutational mechanisms ensure the detection, elimination or suppression of oncogene activity. Antimutational mechanisms are realized with the participation of tumor suppressors and DNA repair systems.

Question No. 23.

(Human as an object of genetic research. Cytogenetic method: its significance for the diagnosis of chromosomal syndromes. Rules for compiling idiograms of healthy people. Idiograms for chromosomal syndromes (autosomal and gonosomal). Examples)

Man as an object of genetic research. Anthropogenetics, its place in the system of human sciences, the main genetic markers of ethnogenetics. Hereditary diseases, as part of the general hereditary variability of a person.

Man, as an object of genetic research, is complex:

The hybridological method cannot be adopted.

Slow generation change.

Small number of children.

Large number of chromosomes

Human genetics is a special branch of genetics that studies the characteristics of the inheritance of traits in humans, hereditary diseases (medical genetics), and the genetic structure of human populations. Human genetics is the theoretical basis of modern medicine and modern healthcare.

It is now firmly established that the laws of genetics are universal.

However, since a person is not only a biological, but also a social being, human genetics differs from the genetics of most organisms in a number of features:

– hybridological analysis (crossing method) is not applicable to study human inheritance; therefore, specific methods are used for genetic analysis: genealogical (method of pedigree analysis), twin, as well as cytogenetic, biochemical, population and some other methods;

– humans are characterized by social characteristics that are not found in other organisms, for example, temperament, complex communication systems based on speech, as well as mathematical, visual, musical and other abilities;

– thanks to public support, the survival and existence of people with obvious deviations from the norm is possible (in the wild, such organisms are not viable).

Human genetics studies the characteristics of the inheritance of traits in humans, hereditary diseases (medical genetics), and the genetic structure of human populations. Human genetics is the theoretical basis of modern medicine and modern healthcare. Several thousand actual genetic diseases are known, which are almost 100% dependent on the genotype of the individual. The most terrible of them include: acid fibrosis of the pancreas, phenylketonuria, galactosemia, various forms of cretinism, hemoglobinopathies, as well as Down, Turner, and Klinefelter syndromes. In addition, there are diseases that depend on both the genotype and the environment: coronary disease, diabetes mellitus, rheumatoid diseases, gastric and duodenal ulcers, many oncological diseases, schizophrenia and other mental diseases.

The tasks of medical genetics are to timely identify carriers of these diseases among parents, identify sick children and develop recommendations for their treatment. Genetic and medical consultations and prenatal diagnosis (that is, detection of diseases in the early stages of the body’s development) play a major role in the prevention of genetically determined diseases.

There are special sections of applied human genetics (environmental genetics, pharmacogenetics, genetic toxicology) that study the genetic basis of healthcare. When developing drugs, when studying the body’s response to the effects of adverse factors, it is necessary to take into account both the individual characteristics of people and the characteristics of human populations.

Hereditary diseases are diseases caused by disturbances in the genetic (hereditary) apparatus of germ cells. Hereditary diseases are caused by mutations (see Variability) that arise in the chromosomal apparatus of the germ cell of one of the parents or in more distant ancestors

Question No. 24.

(Biochemical method for studying human genetics; its significance for the diagnosis of hereditary metabolic diseases. The role of transcriptional, post-transcriptional and post-translational modifications in the regulation of cellular metabolism. Examples).

In contrast to the cytogenetic method, which makes it possible to study the structure of chromosomes and karyotype normally and to diagnose hereditary diseases associated with changes in their number and disruption of organization, hereditary diseases caused by gene mutations, as well as polymorphism in normal primary gene products, are studied using biochemical methods.

Enzyme defects are determined by determining the content of metabolic products in the blood and urine that are the result of the functioning of this protein. Deficiency of the final product, accompanied by the accumulation of intermediate and by-products of impaired metabolism, indicates an enzyme defect or deficiency in the body.

Biochemical diagnosis of hereditary metabolic disorders is carried out in two stages.

At the first stage, presumptive cases of diseases are selected, at the second, the diagnosis of the disease is clarified using more accurate and complex methods. The use of biochemical studies to diagnose diseases in the prenatal period or immediately after birth makes it possible to timely identify pathology and begin specific medical measures, as, for example, in the case of phenylketonuria.

To determine the content of intermediate, by-products and final metabolic products in the blood, urine or amniotic fluid, in addition to qualitative reactions with specific reagents for certain substances, chromatographic methods for studying amino acids and other compounds are used.

Transcription factors are proteins that interact with certain regulatory sites and speed up or slow down the transcription process. The ratio of informative and non-informative parts in eukaryotic transcriptons is on average 1:9 (in prokaryotes it is 9:1). Neighboring transcriptons can be separated from each other by non-transcribed DNA regions. The division of DNA into many transcriptons allows for individual reading (transcription) of different genes with different activities.

In each transcriptone, only one of the two DNA strands is transcribed, which is called the template strand, the second, complementary to it, is called the coding strand. The synthesis of the RNA chain proceeds from the 5" to the 3" end, while the template DNA strand is always antiparallel to the synthesized nucleic acid

Post-transcriptional modifications of the primary tRNA transcript (tRNA processing)

The primary transcript tRNA contains about 100 nucleotides, and after processing - 70-90 nucleotide residues. Posttranscriptional modifications of primary tRNA transcripts occur with the participation of RNases (ribonucleases). Thus, the formation of the 3" end of tRNA is catalyzed by RNase, which is a 3" exonuclease that “cuts off” one nucleotide at a time until it reaches the sequence -CCA, which is the same for all tRNAs. For some tRNAs, the formation of the -CCA sequence at the 3" end (acceptor end) occurs as a result of the sequential addition of these three nucleotides. Pre-tRNA contains only one intron, consisting of 14-16 nucleotides. Removal of the intron and splicing lead to the formation of a structure called "anticodon" - a triplet of nucleotides that ensures the interaction of tRNA with the complementary codon of mRNA during protein synthesis

Post-transcriptional modifications (processing) of primary transcript RNA. Ribosome formation

Human cells contain about a hundred copies of the rRNA gene, localized in groups on five chromosomes. rRNA genes are transcribed by RNA polymerase I to produce identical transcripts. Primary transcripts are about 13,000 nucleotide residues in length (45S rRNA). Before leaving the nucleus as part of the ribosomal particle, the 45 S rRNA molecule undergoes processing, resulting in the formation of 28S rRNA (about 5000 nucleotides), 18S rRNA (about 2000 nucleotides) and 5.88 rRNA (about 160 nucleotides), which are components ribosomes (Fig. 4-35). The rest of the transcript is destroyed in the nucleus.

Question No. 25.

(Genealogical method of human genetics. Basic rules for compiling and analyzing pedigree charts (using the example of one’s own family pedigree chart). The significance of the method in the study of patterns of inheritance of traits).

This method is based on the compilation and analysis of pedigrees. This method has been widely used from ancient times to the present day in horse breeding, selection of valuable lines of cattle and pigs, in obtaining purebred dogs, as well as in breeding new breeds of fur-bearing animals. Human genealogies have been compiled over many centuries regarding the reigning families of Europe and Asia.

When compiling pedigrees, the starting point is the person - the proband, whose pedigree is being studied. Usually this is either a patient or a carrier of a certain trait, the inheritance of which needs to be studied. When compiling pedigree tables, the symbols proposed by G. Just in 1931 are used (Fig. 6.24). Generations are designated by Roman numerals, individuals in a given generation are designated by ar

Conventions when compiling pedigrees (according to G. Just)

Using the genealogical method, the hereditary nature of the trait under study can be established, as well as the type of its inheritance (autosomal dominant, autosomal recessive, X-linked dominant or recessive, Y-linked). When analyzing pedigrees for several characteristics, the linked nature of their inheritance can be revealed, which is used in the compilation of chromosomal maps. This method allows you to study the intensity of the mutation process, assess the expressivity and penetrance of the allele. It is widely used in medical genetic counseling to predict offspring. However, it should be noted that genealogical analysis becomes significantly more complicated when families have few children.

Pedigrees with autosomal dominant inheritance. The autosomal type of inheritance is generally characterized by an equal probability of occurrence of this trait in both men and women. This is due to the same double dose of genes located in autosomes in all representatives of the species and received from both parents, and the dependence of the developing trait on the nature of the interaction of allelic genes.

If a trait is analyzed that does not affect the viability of the organism, then carriers of the dominant trait can be both homo- and heterozygotes. In the case of dominant inheritance of some pathological trait (disease), homozygotes, as a rule, are not viable, and carriers of this trait are heterozygotes.

Thus, with autosomal dominant inheritance, the trait can occur equally in men and women and can be traced when there is a sufficient number of offspring in each vertical generation. The first description of a pedigree with an autosomal dominant type of inheritance of an anomaly in humans was given in 1905. It traces the transmission of brachydactyly (short-fingered feet) over a number of generations.

Pedigrees with autosomal recessive inheritance. Recessive traits appear phenotypically only in homozygotes for recessive alleles. These traits are usually found in the offspring of phenotypically normal parents who are carriers of recessive alleles. The probability of the appearance of recessive offspring in this case is 25%. If one of the parents has a recessive trait, then the likelihood of its manifestation in the offspring will depend on the genotype of the other parent. With recessive parents, all offspring will inherit the corresponding recessive trait.

It is typical for pedigrees with an autosomal recessive type of inheritance that the trait does not appear in every generation. Most often, recessive offspring appear in parents with a dominant trait, and the likelihood of such offspring increases in closely related marriages, where both parents may be carriers of the same recessive allele received from a common ancestor. An example of autosomal recessive inheritance is the pedigree of a family with pseudohypertrophic progressive myopathy, in which consanguineous marriages are common.

Pedigrees with dominant X-linked inheritance of the trait. Genes located on the X chromosome and not having alleles on the Y chromosome are present in the genotypes of men and women in different doses. A woman receives her two X chromosomes and corresponding genes from both her father and mother, while a man inherits his only X chromosome only from his mother. The development of the corresponding trait in men is determined by the only allele present in his genotype, while in women it is the result of the interaction of two allelic genes. In this regard, traits inherited in an X-linked manner occur in a population with different probabilities in males and females.

With dominant X-linked inheritance, the trait is more common in women due to the greater possibility of them receiving the corresponding allele either from the father or from the mother. Men can only inherit this trait from their mother. Women with a dominant trait pass it on equally to daughters and sons, while men pass it on only to daughters. Sons never inherit a dominant X-linked trait from their fathers.

An example of this type of inheritance is a pedigree described in 1925 with keratosis pilaris, a skin disease accompanied by loss of eyelashes, eyebrows, and scalp hair.

Pedigrees for recessive X-linked inheritance of traits. A characteristic feature of pedigrees with this type of inheritance is the predominant manifestation of the trait in hemizygous men, who inherit it from mothers with a dominant phenotype who are carriers of a recessive allele. As a rule, the trait is inherited by men through generations from maternal grandfather to grandson. In women, it manifests itself only in a homozygous state, the likelihood of which increases with closely related marriages.

The most famous example of recessive X-linked inheritance is hemophilia. Another example of inheritance according to this type is color blindness - a certain form of color vision impairment.

Pedigrees with Y-linked inheritance. The presence of the Y chromosome only in males explains the characteristics of the Y-linked, or holandric, inheritance of the trait, which is found only in men and is transmitted through the male line from generation to generation from father to son.

One trait for which Y-linked inheritance in humans is still debated is pinna hypertrichosis, or the presence of hair on the outer edge of the pinna.

Question No. 26.

(Methods of human genetics: population-statistical; dermatoglyphic (using the example of analysis of one’s own dermatoglyph), genetics of somatic cells, DNA study; their role in the study of human hereditary pathology).

Using the population statistical method, hereditary characteristics are studied in large groups of the population, in one or several generations. An essential point when using this method is the statistical processing of the data obtained. Using this method, you can calculate the frequency of occurrence of various gene alleles and different genotypes for these alleles in a population, and find out the distribution of various hereditary traits, including diseases, in it. It allows you to study the mutation process, the role of heredity and environment in the formation of human phenotypic polymorphism according to normal characteristics, as well as in the occurrence of diseases, especially with a hereditary predisposition. This method is also used to clarify the significance of genetic factors in anthropogenesis, in particular in race formation.

When statistically processing material obtained from examining a population group based on a trait of interest to the researcher, the basis for elucidating the genetic structure of the population is the Hardy-Weinberg law of genetic equilibrium. It reflects a pattern according to which, under certain conditions, the ratio of gene alleles and genotypes in the gene pool of a population remains unchanged over a number of generations of this population. Based on this law, having data on the frequency of occurrence in a population of a recessive phenotype that has a homozygous genotype (aa), it is possible to calculate the frequency of occurrence of the specified allele (a) in the gene pool of a given generation. By extending this information to the next generations, it is possible to predict the frequency of occurrence of people with a recessive trait, as well as heterozygous carriers of a recessive allele.

The mathematical expression of the Hardy-Weinberg law is the formula (pA + qa)2, where p and q are the frequencies of alleles A and a of the corresponding gene. Expanding this formula makes it possible to calculate the frequency of occurrence of people with different genotypes and, first of all, heterozygotes - carriers of the hidden recessive allele: p2AA + 2pqAa + q2aa. For example, albinism is caused by the absence of an enzyme involved in the formation of the melanin pigment and is an inherited recessive trait. The frequency of occurrence in the population of albinos (aa) is 1:20,000. Therefore, q2 = 1/20,000, then q = 1/141, up = 140/141. In accordance with the formula of the Hardy-Weinberg law, the frequency of occurrence of heterozygotes = 2pq, i.e. corresponds to 2 x (1/141) x (140/141) = 280/20000 = 1/70. This means that in this population, heterozygous carriers of the albinism allele occur with a frequency of one in 70 people.

Analysis of the frequencies of occurrence of different traits in a population, if they comply with the Hardy-Weinberg law, allows us to assert that the traits are caused by different alleles of one gene. In the event that a gene in the gene pool of a population is represented by several alleles, for example, the ABO blood group gene, the ratio of different genotypes is expressed formula (pIA + qIB + rI0) 2.

Currently, the hereditary nature of skin patterns has been established, although the nature of inheritance has not been fully clarified. This trait is probably inherited in a polygenic manner. The nature of the finger and palm patterns of the body is greatly influenced by the mother through the mechanism of cytoplasmic heredity.

Dermatoglyphic studies are important in identifying zygosity of twins. It is believed that if out of 10 pairs of homologous fingers at least 7 have similar patterns, this indicates identicalness. The similarity of the patterns of only 4-5 fingers indicates that the twins are fraternal.

A study of people with chromosomal diseases revealed specific changes in them not only in the patterns of the fingers and palms, but also in the nature of the main flexion grooves on the skin of the palms. Characteristic changes in these indicators are observed in Down disease, Klinefelter, Shereshevsky-Turner syndromes, which allows the use of dermatoglyphics and palmoscopy methods in the diagnosis of these diseases. Specific dermatoglyphic changes are also detected in some chromosomal aberrations, for example, in the “cry of the cat” syndrome. Dermatoglyphic changes in gene diseases have been less studied. However, specific deviations of these indicators have been described in schizophrenia, myasthenia gravis, and lymphoid leukemia.

These methods are also used to establish paternity. They are described in more detail in specialized literature.

Question No. 27.

(The concept of hereditary diseases: monogenic, chromosomal and multifactorial human diseases, the mechanism of their occurrence and manifestations. Examples).

Monogenic This type of inheritance is called when a hereditary trait is controlled by a single gene.

Monogenic diseases are divided according to the type of inheritance:
autosomal dominant (that is, if at least one of the parents is sick, then the child will also be sick), for example
- Marfan syndrome, neurofibromatosis, achondroplasia
– autosomal recessive (a child can get sick if both parents are carriers of this disease, or one parent is sick, and the other is a carrier of gene mutations that cause it
disease)
– cystic fibrosis, spinal myoatrophy.
Close attention to this group of diseases is also due to the fact that, as it turns out, their number is much higher than previously thought. All diseases have completely different prevalence, which can vary depending on both geography and nationality, for example, Huntington's chorea occurs in 1 in 20,000 Europeans and is almost never found in Japan, Tay-Sachs disease is characteristic of Ashkenazi Jews and is extremely rare in other peoples.
In Russia, the most common monogenically inherited diseases are cystic fibrosis (1/12000 newborns), myoatrophy group (1/10000 newborns), hemophilia A (1/5000 newborn boys).
Of course, many monogenic diseases have been identified for a long time and are well known to medical geneticists.

To chromosomal These include diseases caused by genomic mutations or structural changes in individual chromosomes. Chromosomal diseases arise as a result of mutations in the germ cells of one of the parents. No more than 3-5% of them are passed on from generation to generation. Chromosomal abnormalities account for approximately 50% of spontaneous abortions and 7% of all stillbirths.

All chromosomal diseases are usually divided into two groups: abnormalities in the number of chromosomes and disturbances in the structure of chromosomes.

Diseases caused by a violation of the number of autosomes (non-sex) chromosomes

Down syndrome - trisomy on chromosome 21, signs include: dementia, growth retardation, characteristic appearance, changes in dermatoglyphics;

Patau syndrome - trisomy on chromosome 13, characterized by multiple malformations, idiocy, often - polydactyly, structural abnormalities of the genital organs, deafness; almost all patients do not live to see one year;

Edwards syndrome - trisomy on chromosome 18, the lower jaw and mouth opening are small, the palpebral fissures are narrow and short, the ears are deformed; 60% of children die before the age of 3 months, only 10% survive to one year, the main cause is respiratory arrest and disruption of the heart.

Diseases associated with a violation of the number of sex chromosomes

Shereshevsky-Turner syndrome - the absence of one X chromosome in women (45 XO) due to a violation of the divergence of sex chromosomes; signs include short stature, sexual infantilism and infertility, various somatic disorders (micrognathia, short neck, etc.);

polysomy on the X chromosome - includes trisomy (karyotes 47, XXX), tetrasomy (48, XXXX), pentasomy (49, XXXXX), there is a slight decrease in intelligence, an increased likelihood of developing psychosis and schizophrenia with an unfavorable type of course;

Y-chromosome polysomy - like X-chromosome polysomy, includes trisomy (karyotes 47, XYY), tetrasomy (48, XYYY), pentasomy (49, XYYYY), clinical manifestations are also similar to X-chromosome polysomy;

Klinefelter syndrome - polysomy on the X- and Y-chromosomes in boys (47, XXY; 48, XXYY, etc.), signs: eunuchoid type of build, gynecomastia, weak hair growth on the face, in the armpits and on the pubis, sexual infantilism, infertility; mental development is lagging behind, but sometimes intelligence is normal.

Diseases caused by polyploidy

triploidy, tetraploidy, etc.; the reason is a disruption of the meiosis process due to mutation, as a result of which the daughter sex cell receives instead of the haploid (23) a diploid (46) set of chromosomes, that is, 69 chromosomes (in men the karyotype is 69, XYY, in women - 69, XXX); almost always lethal before birth

Multifactorial diseases, or diseases with a hereditary predisposition

The group of diseases differs from gene diseases in that they require the action of environmental factors to manifest themselves. Among them, a distinction is also made between monogenic, in which hereditary predisposition is caused by one pathologically altered gene, and polygenic. The latter are determined by many genes, which in a normal state, but with a certain interaction between themselves and with environmental factors, create a predisposition to the onset of the disease. They are called multifactorial diseases (MFDs).

Monogenic diseases with a hereditary predisposition are relatively few in number. The method of Mendelian genetic analysis is applicable to them. Considering the important role of the environment in their manifestation, they are considered as hereditarily determined pathological reactions to the action of various external factors (drugs, food additives, physical and biological agents), which are based on hereditary deficiency of certain enzymes.

Factors causing mutations. Factors that cause (induce) mutations can be a wide variety of environmental influences: temperature, ultraviolet radiation, radiation (both natural and artificial), the actions of various chemical compounds - mutagens. Mutagens are agents of the external environment that cause certain changes in the genotype - mutation, and the process of formation of mutations is called mutagenesis.

Radioactive mutagenesis began to be studied in the 20s of our century. In 1925, Soviet scientists G.S. Filippov and G.A. Nadson, for the first time in the history of genetics, used X-rays to obtain mutations in yeast. A year later, the American researcher G. Meller (later twice a Nobel Prize winner), who worked for a long time in Moscow at the institute headed by N.K. Koltsov, used the same mutagen on Drosophila.

Chemical mutagenesis was first purposefully studied by N.K. Koltsov’s collaborator V.V. Sakharov in 1931 on Drosophila when its eggs were exposed to iodine, and later by M.E. Lobashov.

Chemical mutagens include a wide variety of substances (alkylating compounds, hydrogen peroxide, aldehydes and ketones, nitric acid and its analogues, various antimetabolites, salts of heavy metals, dyes with basic properties, aromatic substances), insecticides (from the Latin insecta - insects , cida - killer), herbicides (then lat. herba - grass), drugs, alcohol, nicotine, some medicinal substances and many others.

Genetically active factors can be divided into 3 categories: physical, chemical and biological.

Physical factors. These include various types of ionizing radiation and ultraviolet radiation. A study of the effect of radiation on the mutation process showed that in this case there is no threshold dose, and even the smallest doses increase the likelihood of mutations occurring in the population. An increase in the frequency of mutations is dangerous not so much in an individual sense, but from the point of view of increasing the genetic load of the population. For example, irradiation of one of the spouses with a dose within the range of doubling the frequency of mutations (1.0 - 1.5 Gy) slightly increases the risk of having a sick child (from a level of 4 - 5% to a level of 5 - 6%). If the population of an entire region receives the same dose, the number of hereditary diseases in the population will double in a generation.

Chemical factors. The chemicalization of agriculture and other areas of human activity, the development of the chemical industry led to the synthesis of a huge flow of substances (totaling from 3.5 to 4.3 million), including those that had never existed in the biosphere for millions of years of previous evolution. This means, first of all, the indegradability and thus long-term preservation of foreign substances entering the environment. What was initially taken as an achievement in the fight against pests later turned into a complex problem. The widespread use in the 40-60s of the insecticide DDT, which belongs to the class of chlorinated hydrocarbons, led to its spread throughout the globe, right up to the ice of Antarctica.

Most pesticides are highly resistant to chemical and biological degradation and have a high level of toxicity.

Biological factors. Along with physical and chemical mutagens, some factors of biological nature also have genetic activity. The mechanisms of the mutagenic effect of these factors have been studied in the least detail. At the end of the 30s, S. and M. Gershenzon began research on mutagenesis in Drosophila under the influence of exogenous DNA and viruses. Since then, the mutagenic effect of many viral infections in humans has been established. Chromosome aberrations in somatic cells are caused by smallpox, measles, chickenpox, mumps, influenza, hepatitis viruses, etc.

More on the topic Factors causing mutations of the hereditary apparatus:

1. MUTATIONS AS A CAUSE OF CONGENITAL AND HEREDITARY DISEASES
2. PREVALENCE OF MUTATIONS ASSOCIATED WITH HEREDITARY FORMS OF BREAST CANCER AMONG RESIDENTS OF NOVOSIBIRSK