Environmental factors that cause mutations are called. Mutation factors

Under natural conditions, a mutation appears under the influence of external and internal environmental factors and is designated by the term “natural (or spontaneous) mutations.”

The cause of gene, or so-called point, mutations is the replacement of one nitrogenous base in the DNA molecule. to another, the loss, insertion, or rearrangement of nitrogenous bases in a DNA molecule. It follows that when a gene mutates, a person can develop pathological conditions, the pathogenesis of which is different.

The factors causing mutations at the gene level were influenced by the environment (gout, some forms of diabetes). Such diseases more often occur with constant exposure to unfavorable or harmful environmental factors (diet disorders, etc.). A gene mutation can lead to a disruption in the synthesis of proteins that perform plastic functions. The probable cause of such diseases is Ehlers-Danlos syndrome. Diseases based on insufficient mechanisms for restoring altered DNA molecules are being studied.

A gene mutation can lead to the development of immunodeficiency diseases (thymic aplasia combined with agammaglobulinemia). The reason for the abnormal structure of hemoglobin is the replacement of a glutamic acid residue in the molecule with a valine residue. A number of mutations of genes that control the synthesis of blood clotting factors are known. Gene mutations can cause disruption of the transport of various compounds across cell membranes. They are associated with dysfunction of membrane mechanisms and with defects in some systems.

If a mutation at the gene level occurs under the influence of various physical, chemical, biological factors, then this is called mutagenesis. The basis of mutation is primary damage in the DNA molecule.

Mutagens

Mutagens (from the Greek γεννάω - I give birth) are chemical and physical factors that cause hereditary changes - mutations. Artificial mutations were first obtained in 1925 by G. A. Nadsen and G. S. Filippov in yeast by the action of radium radiation; in 1927, G. Möller obtained mutations in Drosophila by exposure to X-rays. The ability of chemical substances to cause mutations (by the effect of iodine on Drosophila) was discovered by I. A. Rapoport. In flies that developed from these larvae, the frequency of mutations was several times higher than in control insects.

Classification

Mutagens can be various factors that cause changes in the structure of genes, the structure and number of chromosomes. Based on their origin, mutagens are classified into endogenous, formed during the life of the body, and exogenous - all other factors, including environmental conditions.

Based on the nature of their occurrence, mutagens are classified into physical, chemical and biological:

1. Physical mutagens

Ionizing radiation;
radioactive decay;
ultraviolet radiation;
simulated radio emission and electromagnetic fields;
excessively high or low temperature.

2. Chemical mutagens

Oxidizing agents and reducing agents (nitrates, nitrites, reactive oxygen species);
alkylating agents (eg iodoacetamide);
pesticides (eg herbicides, fungicides);
some food additives (for example, aromatic hydrocarbons, cyclamates);
petroleum products;
organic solvents;
medications (for example, cytostatics, mercury preparations, immunosuppressants).
A number of viruses can also be classified as chemical mutagens (the mutagenic factor of viruses is their nucleic acids - DNA or RNA)

3. Biological mutagens

Specific DNA sequences are transposons;
some viruses (measles, rubella, influenza virus);
metabolic products (lipid oxidation products);
antigens of some microorganisms.

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The information that DNA carries is not something absolutely stable. If it were so, then the range of reactions of related microorganisms to external influences would be constant, which means that a sudden change in environmental conditions for microorganisms with a “frozen” genotype would lead to the extinction of the species. Real genome instability is caused by mutations, the exchange of genetic information between donor and recipient.

The term “mutation” was proposed by de Vries as the concept of “an abrupt change in a hereditary character” when studying heredity in plants. Beijerinck later extended this concept to bacteria. Mutation is a change in the primary structure of the DIC, manifested by a hereditarily fixed loss or change of any characteristic or group of characteristics. Mutations are divided according to their origin, the nature of changes in DNA structure, phenotypic consequences for the mutant cell, etc. Factors that cause mutations are known as mutagens.

They are usually of a physical or chemical nature. Based on their origin, mutations are divided into induced, that is, caused artificially, and spontaneous (“wild”, occurring in a bacterial population without visible outside interference).

Spontaneous mutations. Back mutations (reversions).

Spontaneous mutations are caused by replication errors, incorrect formation of complementary base pairs, or structural distortions of DNA under the influence of natural mutagens. Spontaneous mutations can cause beneficial and unfavorable genetic changes. The approximate level of spontaneous mutation is one mutation for every 106-107 cells. The numerical proportion of mutants in the cell population is different for different traits and can vary from 10-4 to 10-11.

For a specific gene, the mutation frequency is about 10-5, and for a certain pair of nucleotides it is 10-8. For example, if a million bacteria are inoculated onto a medium containing an antibiotic, one colony can be expected to survive as a result of spontaneous mutation.

Although the rate of mutation in a bacterial population for individual cells seems insignificant, we must remember that the bacterial population is huge and multiplies quickly. Therefore, the mutation rate from the point of view of the entire population is quite significant. In addition, mutants that appear spontaneously and are resistant to any antibiotic have an advantage during reproduction compared to the “wild” type of bacteria and quickly form a stable population.

Back mutations (reversions) return a spontaneously mutated cell to its original genetic state. They are observed with a frequency of one cell in 107-108 (that is, at least 10 times less often than direct spontaneous mutations).

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 (the formation of organisms or cells whose genome is represented by more than two (3n, 4n, 6n, etc.) sets of chromosomes) and aneuploidy (heteroploidy) - a change in the number of chromosomes that is not a multiple of the haploid set (see Inge- Vechtomov, 1989). 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 by a multiple of n.

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 entire chromosomes, the so-called Robertsonian translocation, which is a transitional variant from a chromosomal mutation to a genomic one).

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 under the influence of a mutation, they speak of point mutations. Since DNA contains only two types of nitrogenous bases - purines and pyrimidines, all point mutations with base substitutions are divided into two classes: transitions (replacement of a purine with a purine or a pyrimidine with a pyrimidine) and transversions (replacement of a purine with a pyrimidine or vice versa). There are four possible genetic consequences of point mutations: 1) preservation of the meaning of the codon due to the degeneracy of the genetic code (synonymous nucleotide substitution), 2) change in the meaning of the codon, leading to the replacement of an amino acid in the corresponding place of the polypeptide chain (missense mutation), 3) formation of a meaningless codon with premature termination (nonsense mutation). There are three meaningless codons in the genetic code: amber - UAG, ocher - UAA and opal - UGA (in accordance with this, mutations leading to the formation of meaningless triplets are also named - for example, amber mutation), 4) reverse substitution (stop codon to sense codon).

Based on their effect on gene expression, mutations are divided into two categories: mutations of the base pair substitution type and the frameshift type. The latter are deletions or insertions of nucleotides, the number of which is not a multiple of three, which is associated with the triplet nature of the genetic code.

A primary mutation is sometimes called a direct mutation, and a mutation that restores the original structure of a gene is called a reverse mutation, or reversion. A return to the original phenotype in a mutant organism due to restoration of the function of the mutant gene often occurs not due to true reversion, but due to a mutation in another part of the same gene or even another non-allelic gene. In this case, the recurrent mutation is called a suppressor mutation. The genetic mechanisms due to which the mutant phenotype is suppressed are very diverse.

Mutagens (from mutation and other Greek γεννάω - I give birth) are chemical and physical factors that cause hereditary changes - mutations. Artificial mutations were first obtained in 1925 by G. A. Nadsen and G. S. Filippov in yeast by the action of radium radiation; in 1927, G. Möller obtained mutations in Drosophila by exposure to X-rays. The ability of chemical substances to cause mutations (by the action of iodine on Drosophila) was discovered by I. A. Rapoport. In flies that developed from these larvae, the frequency of mutations was several times higher than in control insects.

Based on the nature of their occurrence, mutagens are classified into physical, chemical and biological:

Physical mutagens

ionizing radiation;

radioactive decay;

ultraviolet radiation;

simulated radio emission and electromagnetic fields;

excessively high or low temperature.

Chemical mutagens

oxidizing agents and reducing agents (nitrates, nitrites, reactive oxygen species);

alkylating agents (eg iodoacetamide);

pesticides (eg herbicides, fungicides);

some food additives (for example, aromatic hydrocarbons, cyclamates);

petroleum products;

organic solvents;

medications (for example, cytostatics, mercury preparations, immunosuppressants).

A number of viruses can also be classified as chemical mutagens (the mutagenic factor of viruses is their nucleic acids - DNA or RNA).

Biological mutagens

specific DNA sequences - transposons;

some viruses (measles, rubella, influenza virus);

metabolic products (lipid oxidation products);

antigens of some microorganisms.

The development of genetics, which discovered methods for obtaining hereditarily modified forms of microorganisms, has expanded the possibilities of using microorganisms in agriculture, industrial production, and medicine. The main method is the induced production of mutants by the effects of mutagens (radiation, chemicals) on wild, naturally occurring cultures of microorganisms. This method makes it possible to create mutants that produce tens and hundreds of times more valuable products (antibiotics, enzymes, vitamins, amino acids, etc.).

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 based on 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.

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

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 the autosomes of 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 that cause mutations are called mutagenic factors (mutagens) and are divided into:

1. Physical;2. Chemical;3. Biological.

To physical mutagenic factors include various types of radiation, temperature, humidity, etc. The most powerful mutagenic effect is exerted by ionizing radiation - x-rays, α-, β-, γ-rays. They have great penetrating power.

When they act on the body they cause:

a) ionization of tissues - the formation of free radicals (OH) or (H) from water located in tissues. These ions enter into a chemical interaction with DNA, break down nucleic acid and other organic substances;

b) ultraviolet radiation is characterized by lower energy, penetrates only through the superficial layers of the skin and does not cause ionization of tissues, but leads to the formation of dimers (chemical bonds between two pyrimidine bases of the same chain, often T-T). The presence of dimers in DNA leads to errors during its replication and disrupts the reading of genetic information;

c) rupture of spindle filaments;

d) disruption of the structure of genes and chromosomes, i.e. formation of gene and chromosomal mutations.

Chemical mutagens include:

Natural organic and inorganic substances (nitrites, nitrates, alkaloids, hormones, enzymes, etc.);

Synthetic substances not previously found in nature (pesticides, insecticides, food preservatives, medicinal substances).

Products of industrial processing of natural compounds - coal, oil.

Mechanisms of their action :

a) deamination - the removal of an amino group from an amino acid molecule;

b) suppression of nucleic acid synthesis;

c) replacement of nitrogenous bases with their analogues.

Chemical mutagens cause predominantly gene mutations and act during DNA replication.

Biological mutagens include:

Viruses (influenza, rubella, measles)

Mechanisms of their action:

a) viruses integrate their DNA into the DNA of host cells.

Biological mutagens cause gene and chromosomal mutations.

Classification of mutations

The following main types of mutations are distinguished:

1. According to the method of occurrence they are divided into spontaneous and induced.

Spontaneous– occur under the influence of natural mutagenic environmental factors without human intervention. They arise under the conditions of the natural radioactive background of the Earth in the form of cosmic radiation and radioactive elements on the surface of the earth.

Induced mutations are caused artificially by exposure to certain mutagenic factors.

2. By mutated cells mutations are divided into generative and somatic.

Generative- occur in germ cells and are inherited through sexual reproduction.

Somatic– occur in somatic cells and are transmitted only to those cells that arise from this somatic cell. They are not inherited.

3. By effect on the body:

Negative mutations are lethal (incompatible with life); semi-lethal (reducing the viability of the organism); neutral (not affecting vital processes); positive (increasing vitality). Positive mutations occur rarely, but are of great importance for progressive evolution.

4. By changes in genetic material mutations are divided into genomic, chromosomal and gene mutations.

Genomic mutations- These are mutations caused by changes in the number of chromosomes. Extra homologous chromosomes may appear. In the chromosome set, instead of two homologous chromosomes, there are three - this is trisomy. In the case of monosomy, there is a loss of one chromosome from a pair. With polyploidy, there is a multiple of the haploid increase in the number of chromosomes. Another variant of genomic mutation is haploidy, in which only one chromosome from each pair remains.

Chromosomal mutations are associated with disruption of chromosome structure. Such mutations include losses of chromosome sections (deletions), additions of sections (duplication) and rotation of a chromosome section by 180° (inversion).

Genetic mutations in which changes occur at the level of individual genes, i.e. sections of the DNA molecule. This may be the loss of nucleotides, the replacement of one base with another, the rearrangement of nucleotides, or the addition of new ones.

Ministry of Education and Science of the Russian Federation

Federal Agency for Education

GOUVPO

"Khabarovsk State Academy of Economics and Law"

Department of General Economic Disciplines.

Faculty: Auditor

Abstract on the topic:

Mutations. Influence of environmental factors on mutagenesis.

Completed by a student of the group: BUK-82 Vyazkova Ekaterina Andreevna

Checked by the teacher: Arzumanyan Elena Vladimirovna

Khabarovsk 2008
1.

1.Introduction…………………………………………………………………….…..2

2. A little history…………………………………………………………… ….3

3. Factors influencing mutation………………………………………………………........ ..4

5. Consequences of mutations………………………………………………………. 9

6. Conclusion……….……………….………………… ………………………...10

7. References……………………………………………………………11

1. Introduction.

Each new generation of plants and animals is very similar to its parents: when two Siamese cats are crossed, only Siamese kittens are produced, and not kittens of any other breed. This tendency of living organisms to resemble their parents is called heredity. Although the similarity between parents and offspring is great, it is usually not absolute. Most traits are strongly influenced by the conditions in which an individual grows and develops.

The branch of biology concerned with the phenomena of heredity and the study of the laws governing the similarities and differences between related organisms is called genetics.

The growth of every plant or animal occurs as a result of the division and increase in size of the cells that make up the body. This cell division, which is an extremely orderly process, is called mitosis.

Examining a dividing cell in a microscope after appropriate fixation and staining, you can see elongated dark-colored bodies called chromosomes in its nucleus. Each chromosome contains numerous hereditary factors, each of which is somehow different from all the others. These hereditary units are called genes; each gene controls the inheritance of one or more traits. Although genes are remarkably stable and are passed on to subsequent generations with great precision, they undergo changes from time to time, called mutations. After the gene

mutated into a new form, this new form turns out to be stable and is usually no more prone to new changes than the original gene.

2. A little history.

Rock paintings made many millennia ago in Australia, which depict conjoined twins, can perhaps be considered the very first evidence that has reached us of human interest in congenital deformities. Time has preserved very little such ancient evidence, they are isolated. In Babylonian cuneiform, which is at least four thousand years old, a total of 62 types of congenital human development defects are listed and described.

It is likely that the thousand-year-old myths and legends about mermaids, centaurs, sphinxes, harpies, fauns, the Cyclops, and the two-faced Janus are also caused by human interest in deformities. Some vices actually have a certain resemblance to such monsters, and human imagination has completed their image.

There were not so many reasons for the appearance of freaks, as it was believed in ancient times - copulation with the devil, intervention of supernatural forces, unfavorable astral influences, etc. And people still use horoscopes as messengers of astral phenomena.

In Babylon, and in ancient Greece, and in Rome, the birth of freaks was usually interpreted as an unfavorable omen: it was seen as a warning from above, for example, about impending severe trials. Sometimes, however, in this way the gods communicated the need to make one decision or another. It is known that at the end of the 4th century the birth of a two-headed child was perceived as the gods’ approval of the idea of dividing the Roman Empire into western and eastern parts.

In later times, attitudes towards freaks were not the same everywhere. Thus, the Inquisition in such cases inflicted severe punishment on both the child and his mother, thereby strictly intersecting the machinations of the devil. However, in countries where the Inquisition was not so active or did not exist at all, ugly people

They were often credited with special magical powers, the ability of divination, guessing fate by the stars, and the like. And here the relationship with otherworldly forces played its positive role: it was they who provided their “relative” with these special qualities. It is possible that mercy towards holy fools in Rus' was to some extent explained by precisely such views.

3. Factors influencing mutation.

Mutations that appear in natural conditions under the influence of the external environment are designated by the term “spontaneous mutations.”

Exposure to a variety of environmental factors, including radiation and a number of chemical compounds, leads to an increase in the frequency of mutations. In 1927, the American geneticist and later Nobel Prize winner Heinrich Möller first showed that X-ray irradiation leads to a significant increase in the frequency of mutations in Drosophila. This work marked the beginning of a new direction in biology - radiation genetics. Thanks to numerous works carried out over the past decades, we now know that when elementary particles (Y-quanta, electrons, protons and neutrons) enter the nucleus, water molecules are ionized, which, in turn, disrupt the chemical structure of DNA. DNA breaks occur in these places, which leads to additional radiation-induced mutations.

A large amount of information on the effects of radiation on humans was obtained by studying the consequences of the bombing of Hiroshima and Nagasaki and the Chernobyl accident.

The first large-scale study of the genetic effects of radiation on humans was carried out by American and Japanese researchers in Hiroshima and Nagasaki. This work began in 1946, that is, almost immediately after the surrender of Japan. The explosions of atomic bombs in Hiroshima and Nagasaki led to the immediate death of tens of thousands of people and massive radiation exposure of survivors. At that time, the effects of radiation were practically unknown, so the American government decided to conduct a comprehensive study of the consequences of the explosions on the population of the two cities. Then, by chance, medical lieutenant James Neal served in the American army, who before the war was actively involved in genetic research on Drosophila. He was entrusted with the scientific supervision of these works, which immediately acquired a pronounced genetic orientation.

Diseases based on insufficient mechanisms for restoring altered DNA molecules are being studied.

A number of mutations of genes that control the synthesis of blood clotting factors are known.

Gene mutations can cause disruption of the transport of various compounds across cell membranes. They are associated with dysfunction of membrane mechanisms and with defects in some systems.

If a mutation at the gene level occurs under the influence of various physical, chemical, biological factors, then this is called mutagenesis.

The basis of the mutation is primary damage in the D.N.K. molecule.

Mutations (from the Latin mutatio - change, change), occurring naturally or artificially caused changes in the hereditary properties of an organism as a result of rearrangements and disturbances in its genetic material - chromosomes and genes. Mutations are the basis of hereditary variability in living nature.

Mutations can be caused by the action of external factors of a physical, chemical or biological nature - these are induced mutations or induced mutagenesis.

Newly occurring mutations are called new mutations or de novo mutations. These include, for example, mutations that underlie a number of autosomal dominant diseases, such as achondroplasia (10% of cases

belong to familial forms), Recklinghausen's neurofibromatosis, type I (50-70% familial forms), Alzheimer's disease, Huntington's chorea.

Mutations that go from the normal state of a gene (trait) to a pathological state are called direct.

Mutations that move from a pathological state of a gene (trait) to a normal state are called reverse.

Mutations in somatic cells are called somatic. They form pathological cell clones (a set of pathological cells) and in the case of the simultaneous presence of normal and pathological cells in the body, they lead to cellular mosaicism, for example, in Albright's hereditary osteodystrophy, the expressiveness of the disease depends on the number of abnormal cells.

Somatic mutations can be either familial or sporadic (non-familial) forms. They underlie malignant neoplasms and premature aging processes.

Mutations in germ cells are called germinal. They are less common than somatic mutations, underlie all hereditary and some congenital diseases and are passed on from generation to generation.

Germline mutations can be familial or sporadic and are inherited as a predisposition to cancer, such as retinoblastoma and Leigh-Fromeny syndrome.

4. General patterns of mutagenesis

Mutagenesis is the process of occurrence of hereditary changes - mutations - in the body. The basis of mutagenesis is changes in nucleic acid molecules that store and transmit hereditary information.

Mutations do not occur instantly. First, under the influence of mutagens, a premutational state of the cell occurs. Various repair systems strive to eliminate this condition, and then the mutation does not occur. The basis of repair systems is made up of various enzymes encoded in the genotype of the cell (organism). Thus, mutagenesis is under the genetic control of the cell; This is not a physico-chemical, but a biological process.

For example, enzyme repair systems cut out a damaged section of DNA if only one strand is damaged (this operation is performed by endonuclease enzymes), then a section of DNA complementary to the remaining strand is completed again (this operation is performed by DNA polymerases), then the restored section is stitched to the ends threads remaining after cutting out the damaged area (this operation is performed by ligases).

There are also more subtle reparation mechanisms. For example, when a nitrogenous base is lost in a nucleotide, its direct incorporation occurs (this applies to adenine and guanine); the methyl group can simply be split off; single-strand breaks are sutured. In some cases, more complex, little-studied repair systems operate, for example, when both strands of DNA are damaged.

However, if there is a large number of DNA damages, they can become irreversible. This is due to the fact that: firstly, the repair systems may simply not have time to correct the damage, and secondly, the enzymes of the repair systems themselves may be damaged, irreversible DNA damage leads to the appearance of mutations - permanent changes in hereditary information.

Currently, a wide variety of mutagens are known. Let's consider the mechanism of action of some of them.

5. Consequences of mutations.

Approximately one percent of all newborns are born with chromosomal or gene abnormalities. There is no exact data on how many pregnancies are terminated before term due to these anomalies. The vast majority of children born with anomalies of the hereditary apparatus also have numerous structural defects - deformities. In general, the damage to human health from genetic disorders is unlikely to be much less than from cardiovascular diseases.

Every year, millions of deformed children are born all over the world, tens and hundreds of thousands of them are viable. About two thousand years ago, Plutarch wrote in his essay “On Curiosity”: “...And in Rome there are people who do not value paintings or statues at all... But they only spin around the square where freaks are exhibited, gawking at the legless , crooked hands,

three-eyed, bird-eyed and looking out to see if somewhere a mixture of two breeds had been born - a monstrous freak ... "

Now scientists of teratology are dealing with these problems. Teratology is a science that studies the causes of origin, mechanisms of formation and manifestation of congenital malformations.

6. Conclusion.

Our common home is in danger. Scientists came to this opinion in the middle of the 20th century, convinced that technological progress is fraught with destructive power. A tangible danger threatens nature and its treasury - the gene pools that create an amazing diversity of living forms and fuel the further development of our unique world. Pollution of the biosphere not only tests the compensatory capabilities of nature, but also affects human health and can already cause damage to future generations.

4. General patterns of mutagenesis…………………………………………..8
5. Consequences of mutations……………………………………………………….9
6. Conclusion……….……………….…………………………………………...10
7. References……………………………………………………………11