Characteristics of types of mutations. Gene mutations. Molecular mechanisms of mutagenesis. Classification of gene mutations. The significance of gene mutations for the life of an organism. What Causes Mutations

1. Determination of variability. Classification of its forms.

Variability is a general property of living organisms, which consists in changes in hereditary characteristics during ontogenesis (individual development).

The variability of organisms is divided into two large types:

1. phenotypic, not affecting the genotype and not inherited;

2. genotypic, changing the genotype and therefore transmitted by inheritance.

Genotypic variability is divided into combinative and mutational.

Mutational variability includes genomic, chromosomal and gene mutations.

Genomic mutations are divided into polyploidy and aneuploidy

Chromosomal mutations are divided into deletions, duplications, inversions, translocations

2. Phenotypic variability. Norm of reaction of genetically determined traits. Adaptive nature of modifications. Phenocopies.

Phenotypic variability (or non-hereditary, modification) is a change in the phenotypic characteristics of an organism under the influence of environmental factors, without changing the genotype.

For example: the color of the fur of the Himalayan rabbit depends on the temperature of its environment.

The reaction norm is the range of variability within which the same genotype is capable of producing different phenotypes.

1. wide norm of reaction - when the fluctuations of a characteristic occur over a wide range (for example: tanning, amount of milk).

2. narrow reaction norm - when fluctuations in the characteristic are insignificant (for example: milk fat content).

3. an unambiguous reaction norm - when the sign does not change under any conditions (for example: blood type, eye color, eye shape).

The adaptive nature of modifications lies in the fact that modification variability allows the body to adapt to changing environmental conditions. Therefore, modifications are always useful.

If during embryogenesis the body is exposed to unfavorable factors, phenotypic changes may appear that go beyond the normal reaction limits and are not adaptive in nature; they are called developmental morphoses. For example, a child is born without limbs or with a cleft lip.

Phenocopies are developmental morphoses that are very difficult to distinguish from hereditary changes (diseases).

For example: if a pregnant woman has had rubella, she may have a child with cataracts. But this pathology can also appear as a result of a mutation. In the first case we are talking about phenocopy.

The diagnosis of “phenocopy” is important for the future prognosis, since with phenocopy the genetic material does not change, that is, it remains normal.

3. Combinative variability. The importance of combinative variability in ensuring the genetic diversity of people.

Combinative variability is the emergence in descendants of new combinations of genes that their parents did not have.

Combinative variability is associated with:

with crossing over into meiotic prophase 1.

with independent divergence of homologous chromosomes into anaphase of meiosis 1.

with a random combination of gametes during fertilization.

The importance of combinative variability - provides genetic diversity of individuals within a species, which is important for natural selection and evolution.

4. Mutational variability. Basic provisions of the theory of mutations.

Hugo de Vries, a Dutch scientist, introduced the term "mutation" in 1901.

Mutation is the phenomenon of intermittent, abrupt changes in a hereditary trait.

The process of mutations occurring is called mutagenesis, and an organism that acquires new characteristics in the process of mutagenesis is called a mutant.

Basic provisions of the theory of mutations according to Hugo de Vries.

1. mutations occur suddenly without any transitions.

2. the resulting forms are quite stable.

3. mutations are qualitative changes.

4. mutations occur in different directions. they can be both beneficial and harmful.

5. The same mutations can occur repeatedly.

5. Classification of mutations.

I. By origin.

1. Spontaneous mutations. Spontaneous or natural mutations occur under normal natural conditions.

2. Induced mutations. Induced or artificial mutations occur when the body is exposed to mutagenic factors.

A. physical (ionizing radiation, UV rays, high temperature, etc.)

b. chemical (heavy metal salts, nitrous acid, free radicals, household and industrial waste, medicines).

II. By place of origin.

A. Somatic mutations arise in somatic cells and are inherited by the descendants of the cells in which they arose. They are not passed on from generation to generation.

b. Generative mutations occur in germ cells and are passed on from generation to generation.

III. According to the nature of phenotypic changes.

1. Morphological mutations, characterized by changes in the structure of an organ or the organism as a whole.

2. Physiological mutations, characterized by changes in the organ or organism as a whole.

3. Biochemical mutations associated with changes in the macromolecule.

IV. By influence on the vitality of the organism.

1. Lethal mutations in 100% of cases lead to the death of the organism due to defects incompatible with life.

2. Semi-lethal mutations lead to death in 50-90% of cases. Typically, organisms with such mutations do not survive to reproductive age.

3. Conditionally lethal mutations, under some conditions the organism dies, but under other conditions it survives (galactosemia).

4. Beneficial mutations increase the viability of the organism and are used in breeding.

V. According to the nature of changes in hereditary material.

1. Gene mutations.

2. Chromosomal mutations.

6. Gene mutations, definition. Mechanisms of occurrence of spontaneous gene mutations.

Gene mutations or point mutations are mutations that occur in genes at the nucleotide level, in which the structure of the gene changes, the mRNA molecule changes, the sequence of amino acids in the protein changes, and a trait changes in the body.

Types of gene mutations:

- missense mutations - replacing 1 nucleotide in a triplet with another will lead to the inclusion of another amino acid in the polypeptide chain of the protein, which should not normally be present, and this will lead to changes in the properties and functions of the protein.

Example: replacement of glutamic acid with valine in the hemoglobin molecule.

CTT – glutamic acid, CAT – valine

If such a mutation occurs in the gene that encodes the β chain of the hemoglobin protein, then valine is included in the β chain instead of glutamic acid → as a result of such a mutation, the properties and functions of the hemoglobin protein change and HbS appears instead of normal HbA, as a result of which a person develops sickle cell anemia (form red blood cells changes).

- nonsense mutations - replacing 1 nucleotide in a triplet with another will lead to the fact that the genetically significant triplet will turn into a stop codon, which leads to the termination of the synthesis of the polypeptide chain of the protein. Example: UAC – tyrosine. UAA – stop codon.

Mutations with a shift in the reading frame of hereditary information.

If, as a result of a gene mutation, a new characteristic appears in an organism (for example, polydactyly), then they are called neomorphic.

if, as a result of a gene mutation, the body loses a trait (for example, in PKU an enzyme disappears), then they are called amorphous.

- seimsense mutations - replacement of a nucleotide in a triplet leads to the appearance of a synonymous triplet that encodes the same protein. This is due to the degeneracy of the genetic code. For example: CTT – glutamine CTT – glutamine.

Mechanisms of occurrence of gene mutations (replacement, insertion, loss).

DNA consists of 2 polynucleotide chains. First, a change occurs in the 1st strand of DNA - this is a semi-mutational state or “primary DNA damage.” Every second, 1 primary DNA damage occurs in a cell.

When the damage moves to the second strand of DNA, they say that a mutation has been fixed, that is, a “complete mutation” has occurred.

Primary DNA damage occurs when the mechanisms of replication, transcription, and crossing over are disrupted

7. Frequency of gene mutations. Mutations are direct and reverse, dominant and recessive.

In humans, the frequency of mutations = 1x10 –4 – 1x10 –7, that is, on average, 20–30% of human gametes in each generation are mutant.

In Drosophila, the mutation frequency = 1x10 –5, that is, 1 gamete out of 100 thousand carries a gene mutation.

A. Direct mutation (recessive) is a mutation of a gene from a dominant state to a recessive state: A → a.

b. A reverse mutation (dominant) is a mutation of a gene from a recessive state to a dominant state: a → A.

Gene mutations occur in all organisms; genes mutate in different directions and at different frequencies. Genes that rarely mutate are called stable, and genes that often mutate are called mutable.

8. The law of homological series in hereditary variability N.I. Vavilov.

Mutation occurs in a variety of directions, i.e. accidentally. However, these accidents are subject to a pattern discovered in 1920. Vavilov. He formulated the law of homologous series in hereditary variability.

“Species and genera that are genetically close are characterized by similar series of hereditary variability with such regularity that, knowing the series of forms within one species, one can foresee the existence of parallel forms in other species and genera.”

This law allows us to predict the presence of a certain trait in individuals of different genera of the same family. Thus, the presence of alkaloid-free lupine in nature was predicted, because in the legume family there are genera of beans, peas, and beans that do not contain alkaloids.

In medicine, Vavilov's law allows the use of animals genetically close to humans as genetic models. They are used for experiments to study genetic diseases. For example, cataracts are being studied in mice and dogs; hemophilia - in dogs, congenital deafness - in mice, guinea pigs, dogs.

Vavilov’s law allows us to predict the appearance of induced mutations unknown to science, which can be used in breeding to create plant forms valuable to humans.

9. Antimutation barriers of the body.

- Accuracy of DNA replication. Sometimes errors occur during replication, then self-correction mechanisms are activated that are aimed at eliminating the incorrect nucleotide. The enzyme DNA polymerase plays an important role, and the error rate is reduced by 10 times (from 10 –5 to 10 –6).

- Degeneracy of the genetic code. Several triplets can encode 1 amino acid, so replacing 1 nucleotide in a triplet in some cases does not distort hereditary information. For example, CTT and CTC are glutamic acid.

- Extracting some genes responsible for important macromolecules: rRNA, tRNA, histone proteins, i.e. many copies of these genes are produced. These genes are part of moderately repetitive sequences.

- DNA redundancy– 99% is redundant and the mutagenic factor more often falls into these 99% of meaningless sequences.

- Chromosome pairing in the diploid set. In the heterozygous state, many harmful mutations do not appear.

- Culling mutant germ cells.

- DNA repair.

10. Reparation of genetic material. .

DNA repair is the removal of primary damage from DNA and its replacement with normal structures.

There are two forms of reparation: light and dark

A. Light reparation (or enzymatic photoreactivation). Repair enzymes are active only in the presence of light. This form of repair is aimed at removing primary DNA damage caused by UV rays.

Under the influence of UV rays, pyrimidine nitrogenous bases in DNA are activated, which leads to the formation of bonds between pyrimidine nitrogenous bases that are located nearby in the same DNA chain, that is, pyrimidine dimers are formed. Most often, connections arise: T=T; T=C; C=C.

Normally there are no pyrimidine dimers in DNA. Their formation leads to distortion of hereditary information and disruption of the normal course of replication and transcription, which subsequently leads to gene mutations.

The essence of photoreactivation: in the nucleus there is a special (photoreactivating) enzyme that is active only in the presence of light; this enzyme destroys pyrimidine dimers, that is, it breaks the bonds that have arisen between pyrimidine nitrogenous bases under the influence of UV rays.

Dark repair occurs in the dark and in light, that is, the activity of enzymes does not depend on the presence of light. It is divided into pre-replicative repair and post-replicative repair.

Pre-replicative repair occurs before DNA replication, and many enzymes are involved in this process:

o Endonuclease

o Exonuclease

o DNA polymerase

o DNA ligase

Stage 1. The enzyme endonuclease finds the damaged area and cuts it.

Stage 2. The enzyme exonuclease removes the damaged area from the DNA (excision), resulting in a gap.

Stage 3. The enzyme DNA polymerase synthesizes the missing section. Synthesis occurs according to the principle of complementarity.

Stage 4. Ligase enzymes connect or stitch the newly synthesized region to the DNA strand. In this way, the original DNA damage is repaired.

Post-replicative repair.

Let's say there is primary damage in the DNA.

Stage 1. The process of DNA replication begins. The enzyme DNA polymerase synthesizes a new strand that is completely complementary to the old intact strand.

Stage 2. The enzyme DNA polymerase synthesizes another new strand, but it bypasses the area where the damage is located. As a result, a gap was formed in the second new DNA strand.

Stage 3. At the end of replication, the DNA polymerase enzyme synthesizes the missing section complementary to the new DNA strand.

Stage 4. The ligase enzyme then connects the newly synthesized section to the DNA strand where there was a gap. Thus, the primary DNA damage did not transfer to another new strand, that is, the mutation was not fixed.

Subsequently, primary DNA damage can be eliminated during pre-replicative repair.

11. Mutations associated with impaired DNA repair and their role in pathology.

The ability to repair in organisms has been developed and consolidated during evolution. The higher the activity of repair enzymes, the more stable the hereditary material. The corresponding genes are responsible for repair enzymes, so if a mutation occurs in these genes, the activity of repair enzymes decreases. In this case, a person develops severe hereditary diseases that are associated with a decrease in the activity of repair enzymes.

There are more than 100 such diseases in humans. Some of them:

Fanconi anemia– decrease in the number of red blood cells, hearing loss, disorders in the cardiovascular system, deformation of the fingers, microcephaly.

Bloom's syndrome - low birth weight of the newborn, slowed growth, increased susceptibility to viral infection, increased risk of cancer. A characteristic sign: with a short stay in sunlight, butterfly-shaped pigmentation appears on the skin of the face (dilation of blood capillaries).

Xeroderma pigmentosum– burns appear on the skin from light, which soon degenerate into skin cancer (in such patients, cancer occurs 20,000 times more often). Patients are forced to live under artificial lighting.

The incidence of the disease is 1: 250,000 (Europe, USA), and 1: 40,000 (Japan)

Two types of progeria– premature aging of the body.

12. Gene diseases, mechanisms of their development, inheritance, frequency of occurrence.

Gene diseases (or molecular diseases) are quite widely represented in humans, there are more than 1000 of them.

A special group among them are congenital metabolic defects. These diseases were first described by A. Garod in 1902. The symptoms of these diseases are different, but there is always a violation of the transformation of substances in the body. In this case, some substances will be in excess, others in deficiency. For example, a substance (A) enters the body and is further converted under the action of enzymes into a substance (B). Next, substance (B) should turn into substance (C), but this is prevented by a mutation block

(), as a result, substance (C) will be in short supply, and substance (B) will be in excess.

Examples of some diseases caused by congenital metabolic defects.

PKU(phenylketonuria, congenital dementia). Genetic disease, inherited in an autosomal recessive manner, occurs with a frequency of 1:10,000. Phenylalanine is an essential amino acid for the construction of protein molecules and, in addition, serves as a precursor for thyroid hormones (thyroxine), adrenaline and melanin. The amino acid phenylalanine in liver cells must be converted by an enzyme (phenylalanine-4-hydroxylase) into tyrosine. If the enzyme responsible for this transformation is absent or its activity is reduced, the content of phenylalanine in the blood will be sharply increased, and the content of tyrosine will be decreased. An excess of phenylalanine in the blood leads to the appearance of its derivatives (phenylacetic, phenyllactic, phenylpyruvic and other ketonic acids), which are excreted in the urine and also have a toxic effect on the cells of the central nervous system, which leads to dementia.

With a timely diagnosis and transfer of the infant to a diet devoid of phenylalanine, the development of the disease can be prevented.

Albinism is common. Genetic disease is inherited in an autosomal recessive manner. Normally, the amino acid tyrosine is involved in the synthesis of tissue pigments. If a mutation block occurs, the enzyme is absent or its activity is reduced, then tissue pigments are not synthesized. In these cases, the skin has a milky white color, the hair is very light, due to the lack of pigment in the retina, blood vessels are visible, the eyes have a reddish-pink color, and increased sensitivity to light.

Alcapnonuria. Genetic disease, inherited in an autosomal recessive manner, occurs with a frequency of 3-5:1,000,000. The disease is associated with a violation of the conversion of homogentisic acid, as a result of which this acid accumulates in the body. Excreted in the urine, this acid leads to the development of kidney diseases; in addition, alkalized urine with this anomaly quickly darkens. The disease also manifests itself as staining of cartilage tissue, and arthritis develops in old age. Thus, the disease is accompanied by damage to the kidneys and joints.

Gene diseases associated with carbohydrate metabolism disorders.

Galactosemia. Genetic disease, inherited in an autosomal recessive manner, occurs with a frequency of 1:35,000-40,000 children.

The blood of a newborn contains the monosaccharide galactose, which is formed during the breakdown of milk disaccharide. lactose for glucose and galactose. Galactose is not directly absorbed by the body; it must be converted by a special enzyme into an digestible form - glucose-1-phosphate.

The hereditary disease galactosemia is caused by a dysfunction of the gene that controls the synthesis of the enzyme protein that converts galactose into an digestible form. In the blood of sick children there will be very little of this enzyme and a lot of galactose, which is determined by biochemical analysis.

If the diagnosis is made in the first days after the birth of the child, then he is fed formulas that do not contain milk sugar, and the child develops normally. Otherwise, the child grows up weak-minded.

Cystic fibrosis. Genetic disease, inherited in an autosomal recessive manner, occurs with a frequency of 1:2,000-2,500. The disease is associated with a mutation in the gene that is responsible for the carrier protein embedded in the plasma membrane of cells. This protein regulates the permeability of the membrane to Na and Ca ions. If the permeability of these ions in the cells of the exocrine glands is impaired, the glands begin to produce a thick, viscous secretion that closes the ducts of the exocrine glands.

There are pulmonary and intestinal forms of cystic fibrosis.

Marfan syndrome. Genetic disease is inherited in an autosomal dominant manner. Associated with a disorder in the metabolism of fibrillin protein in connective tissue, which is manifested by a complex of symptoms: “spider” fingers (arachnodactyly), high stature, subluxation of the lens, heart and vascular defects, increased release of adrenaline into the blood, stoop, sunken chest, high arch of the foot, weakness ligaments and tendons, etc. It was first described in 1896 by the French pediatrician Antonio Marfan.

LECTURE 10 Structural mutations of chromosomes.

1. Structural mutations of chromosomes (chromosomal aberrations).

The following types of chromosomal aberrations are distinguished.

– deletions

– duplications

– inversions

– ring chromosomes

– translocations

– transpositions

With these mutations, the structure of chromosomes changes, the order of genes in the chromosomes changes, and the dosage of genes in the genotype changes. These mutations occur in all organisms, they are:

Spontaneous (caused by a factor of unknown nature) and induced (the nature of the factor that caused the mutation is known)

Somatic (affecting the hereditary material of somatic cells) and generative (changes in the hereditary material of gametes)

Useful and harmful (the latter is much more common)

Balanced (the genotype system does not change, which means the phenotype does not change) and unbalanced (the genotype system changes, which means the phenotype also changes

If a mutation affects two chromosomes, they speak of interchromosomal rearrangements.

If the mutation affects chromosome 1, we speak of intrachromosomal rearrangements.

2. Mechanisms of occurrence of structural mutations of chromosomes.

The “disconnection-connection” hypothesis. It is believed that breaks occur in one or more chromosomes. Chromosome sections are formed, which are then connected, but in a different sequence. If the break occurs before DNA replication, then 2 chromatids are involved in this process - these are isochromatid gap If a break occurs after DNA replication, then 1 chromatid is involved in the process - this chromatid gap

The second hypothesis: a process similar to crossing over occurs between non-homologous chromosomes, i.e. non-homologous chromosomes exchange sections.

3. Deletions, their essence, forms, phenotypic effect. Pseudo-dominance..

Deletion (deficiency) is the loss of a section of a chromosome.

1 break may occur in the chromosome, and it will lose the terminal region, which will be destroyed by enzymes (deficiency)

there may be two breaks in the chromosome with the loss of the central region, which will also be destroyed by enzymes (interstitial deletion).

In the homozygous state, deletions are always lethal; in the heterozygous state, they manifest themselves as multiple developmental defects.

Deletion detection:

Differential staining of chromosomes

According to the shape of the loop, which is formed during the conjugation of homologous chromosomes in prophase of meiosis 1. The loop occurs on a normal chromosome.

The deletion was first studied in the Drosophila fly, resulting in the loss of a section of the X chromosome. In the homozygous state, this mutation is lethal, and in the heterozygous state, it manifests itself phenotypically as a notch on the wing (Notch mutation). When analyzing this mutation, a special phenomenon was identified, which was called pseudo-dominance. In this case, the recessive allele is phenotypically manifested, since the region of the chromosome with the dominant allele is lost due to deletion.

In humans, deletions most often occur in chromosomes 1 to 18. For example, a deletion of the short arm of the fifth chromosome in a heterozygous state manifests itself phenotypically as “cry the cat” syndrome. A child is born with a large number of pathologies, lives from 5 days to a month (very rarely up to 10 years), his crying resembles the sharp meow of a cat.

An interstitial deletion can occur on chromosome 21 or 22 of hematopoietic stem cells. In the heterozygous state, it manifests itself phenotypically as pernicious anemia.

4. Duplications, inversions, ring chromes. Mechanism of occurrence. Phenotypic manifestation.

Duplication– doubling of a section of a chromosome (this section can be repeated many times). Duplications can be direct or reverse.

With these mutations, the dose of genes in the genotype increases, and in the homozygous state these mutations are lethal. In the heterozygous state, they are manifested by multiple developmental defects. However, these mutations may have played a role during evolution. The hemoglobin gene families may have arisen in this way.

Perhaps repeatedly repeated sequences of DNA nucleotides appeared as a result of duplications.

Detection of duplications:

Figure of a loop in prophase of meiosis 1. The loop arises on a mutated chromosome.

Inversion – tearing off a section of a chromosome, rotating it 180° and attaching it to the old place. During inversions, the dose of genes does not change, but the order of genes in the chromosome changes, i.e. the clutch group changes. There are no end inversions.

In the homozygous state, inversions are lethal; in the heterozygous state, they manifest themselves as multiple developmental defects.

Detecting inversions:

Differential staining.

Figure in the form of two oppositely located loops in prophase of meiosis 1.

There are 2 types of inversions:

paracentric inversion, which does not affect the centromere, because breaks occur within one chromosome arm

pericentric inversion, which affects the centromere, because breaks occur on both sides of the centromere.

With pericentric inversion, the configuration of the chromosome may change (if the ends of the rotated sections are not symmetrical). And this makes subsequent conjugation impossible.

The phenotypic manifestation of inversions is the mildest compared to other chromosomal aberrations. If recessive homozygotes die, then heterozygotes most often experience infertility.

Ring chromosomes. Normally, there are no ring chromosomes in the human karyotype. They can appear when the body is exposed to mutagenic factors, especially radioactive radiation.

In this case, 2 breaks occur in the chromosome, and the resulting section closes into a ring. If a ring chromosome contains a centromere, then a centric ring is formed. If there is no centromere, then an acentric ring is formed; it is destroyed by enzymes and is not inherited.

Ring chromosomes are detected by karyotyping.

In the homozygous state, these mutations are lethal, and in the heterozygous state, they appear phenotypically as deletions.

Ring chromosomes are markers of radiation exposure. The higher the radiation dose, the more ring chromosomes there are, and the worse the prognosis.

5. Translocations, their essence. Reciprocal translocations, their characteristics and medical significance. Robertsonian translocations and their role in hereditary pathology.

Translocation is the movement of a section of a chromosome. There are mutual (reciprocal) and non-reciprocal (transposition) translocations.

Reciprocal translocations occur when two non-homologous chromosomes exchange their sections.

A special group of translocations are Robertsonian translocations (centric fusions). Acrocentric chromosomes are affected - they lose their short arms, and their long arms are connected.

The reason for 4-5% of cases of the birth of a downborn child is Robertsonian translocations. In this case, the long arm of chromosome 21 moves to one of the chromosomes of group D (13, 14, 15, chromosome 14 is often involved).

Types of eggs sperm zygote Consequences

14 + 14, 21 14,14,21 monosomy 21 (lethal)

14/21,21 + 14, 21 14/21,21,14,21 trisomy 21 (down)

21 + 14, 21 21,14,21, monosomy 14 (lethal)

14,14/21 + 14, 21 14,14/21,14,21 trisomy 14 (lethal)

14/21 + 14, 21 14/21,14,21 phenotypically healthy

As we can see, a woman with a Robertsonian translocation can give birth to a healthy child.

The loss of short arms does not affect anything, since the nucleolus-forming zones are located there, and they are also in other chromosomes.

A patient with a translocation form of Down syndrome has 46 chromosomes in his cells. The ovary after the translocation will have 45 chromosomes. However, with a balanced mutation, the woman will have 45 chromosomes.

Detection of translocations:

Differential staining.

Figure of a cross in prophase of meiosis 1.

6. Transpositions. Mobile genetic elements. Mechanisms of movement through the genome and significance.

If translocations are not reciprocal, then they speak of transposition.

A special group of transposons are Mobile Genetic Elements (MGEs), or jumping genes, which are found in all organisms. In the Drosophila fly they make up 5% of the genome. In humans, MGEs are grouped into the ALU family.

MGEs consist of 300-400 nucleotides, repeated 300 thousand times in the human genome.

At the MGE ends there are nucleotide repeats consisting of 50-100 nucleotides. Repetitions can be forward or reverse. Nucleotide repeats appear to influence MGE movement.

There are two options for MGE movement throughout the genome.

1. using the process of reverse transcription. This requires the enzyme reverse transcriptase (revertase). This option occurs in several stages:

on DNA, the enzyme RNA polymerase (another name is transcriptase) synthesizes mRNA,

On mRNA, the enzyme reverse transcriptase synthesizes one strand of DNA,

DNA polymerase enzyme ensures the synthesis of the second strand of DNA,

the synthesized fragment closes into a ring,

the DNA ring is inserted into another chromosome or into another location on the same chromosome.

2. using the transposase enzyme, which cuts out the MGE and transfers it to another chromosome or to another place on the same chromosome

During evolution, MGE played a positive role, because they carried out the transfer of genetic information from one species of organisms to others. An important role in this was played by retroviruses, which contain RNA as hereditary material and also contain reverse transcriptase.

MGEs move throughout the genome very rarely, one movement per hundreds of thousands of events in the cell (movement frequency 1 x 10–5).

In each specific organism, MGEs do not play a positive role, because moving through the genome, they change the functioning of genes and cause gene and chromosomal mutations.

7. Induced mutagenesis. Physical, chemical and biological mutagenic factors.

Induced mutations occur when mutagenic factors act on the body, which are divided into 3 groups:

Physical (UVL, X-ray and radiation radiation, electromagnetic fields, high temperatures).

Thus, ionizing radiation can act directly on DNA and RNA molecules, causing damage (gene mutations) in them. The indirect impact of this

mutagen on the hereditary apparatus of cells consists in the formation of genotoxic substances (H 2 O 2, OH -, O 2 -,).

Chemical mutagenic factors. There are over 2 million chemicals that can cause mutations. These are salts of heavy metals, chemical analogues of nitrogenous bases (5-bromouracil), alkylating compounds (CH 3, C 2 H 5).

8. Radiation mutations. Genetic danger of environmental pollution.

Radiation mutations are mutations caused by radiation. In 1927, the American geneticist Heinrich Mehler first showed that irradiation with X-rays 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 (quanta, electrons, protons and neutrons) enter the nucleus, water molecules are ionized with the formation of free radicals (OH -, O 2 -). Possessing great chemical activity, they cause DNA breaks, damage to nucleotides or their destruction; all this leads to the occurrence of mutations.

Since man is an open system, various environmental pollution factors can enter the human body. Many of these factors can change or damage the hereditary material of living cells. The consequences of these factors are so serious that humanity cannot ignore environmental pollution.

9. Mutagenesis and carcinogenesis.

The mutation theory of cancer was first proposed by Hugo De Vries in 1901. Nowadays, there are many theories of carcinogenesis.

One of them is the gene theory of carcinogenesis. It is known that the human genome contains more than 60 oncogenes that can regulate cell division. They are in an inactive state in the form of proto-oncogenes. Under the influence of various mutagenic factors, proto-oncogenes are activated and become oncogenes, which cause intense cell proliferation and tumor development.

LECTURE 11 Chromosome number mutations. Haploidy, polyploidy,

Aneuploidy.

1. The essence of chromosome number mutations, causes and mechanisms of occurrence.

Each type of organism is characterized by its own karyotype. The constancy of the karyotype over a number of generations is maintained through the processes of mitosis and meiosis. Sometimes during mitosis or meiosis the segregation of chromosomes is disrupted, resulting in cells with an altered number of chromosomes. In cells, the number of entire haploid sets of chromosomes can change, in which case mutations such as:

Haploidy – single set of chromosomes (n)

Polyploidy – an increase in the number of chromosomes that is a multiple of the haploid set (3n, 4n, etc.)

Aneuploidy is a change in the number of individual chromosomes (46 +1).

The set of chromosomes can change both in somatic cells and in germ cells.

Causes of chromosome divergence disorders:

increased cytoplasmic viscosity

change in cell polarity

dysfunction of the spindle.

All these reasons lead to the so-called “anaphase lag” phenomenon.

This means that during anaphase of mitosis or meiosis, chromosomes are distributed unevenly, i.e. some chromosome or group of chromosomes does not keep up with the rest of the chromosomes and is lost to one of the daughter cells.

2. Haploidy, nature of karyotype changes, prevalence, phenotypic manifestation.

Haploidy is a reduction in the number of chromosomes in the cells of an organism to haploid. In cells, the number of chromosomes and the dose of genes sharply decreases, that is, the genotype system changes, which means the phenotype also changes.

If from the above it has become clear what genes do, then it should also be clear that changes in the structure of a gene, the sequence of nucleotides, can lead to changes in the protein encoded by this gene. Changes in the structure of a gene are called mutations. These changes in the structure of the gene can occur for a variety of reasons, ranging from random errors during DNA duplication to the effect of ionizing radiation or special chemicals called mutagens on the gene. The first type of changes leads to so-called spontaneous mutations, and the second - to induced mutations. Mutations in genes can occur in germ cells, and then they will be passed on to the next generation and some of them will lead to the development of a hereditary disease. Mutations in genes also occur in somatic cells. In this case, they will be inherited only in a specific clone of cells that originated from the mutant cell. It is known that mutations in somatic cell genes can in some cases cause cancer.

Types of gene mutations

One of the most common types of mutations is the substitution of one pair of nitrogenous bases. Such a substitution may have no consequences for the structure of the polypeptide chain encoded by the gene due to the degeneracy of the genetic code. Substitution of the third nitrogenous base in a triplet will almost never have any consequences. Such mutations are called silent substitutions. At the same time, single-nucleotide substitutions can cause the replacement of one amino acid with another due to a change in the genetic code of the mutated triplet.

A single nucleotide base change in a triplet can turn it into a stop codon. Since these mRNA codons stop the translation of the polypeptide chain, the synthesized polypeptide chain is shortened compared to the normal chain. Mutations that cause the formation of a stop codon are called nonsense mutations.

As a result of a nonsense mutation, in which A-T is replaced by G-C in a DNA molecule, synthesis in the polypeptide chain stops at the stop codon.

A single-nucleotide substitution in a normally located stop codon, on the contrary, can make it meaningful, and then the mutant mRNA, and then the mutant polypeptide, turn out to be longer than normal ones.

The next class of molecular mutations are deletions (losses) or insertions (insertions) of nucleotides. When a triplet of nucleotides is deleted or inserted, then if this triplet is coding, either a certain amino acid disappears in the polypeptide or a new amino acid appears. However, if, as a result of a deletion or insertion, a number of nucleotides that is not a multiple of three is inserted or deleted, then the meaning for all the others following the insertion or deletion of the codons of the mRNA molecule changes or is lost. Such mutations are called frameshift mutations. They often lead to the formation of a stop codon in the mRNA nucleotide sequence following the insertion or deletion.

Gene conversion is the direct transfer of a fragment of one allele to another allele or a fragment of a pseudogene to a gene. Since there are many mutations in a pseudogene, such a transfer disrupts the structure of a normal gene and can be considered a mutation. To carry out gene conversion between a pseudogene and a gene, their pairing and subsequent atypical crossing over, in which breaks occur in the DNA strands, are necessary.

Recently, a new and completely unexpected type of mutation was discovered, which is manifested by an increase in the number of repeats (most often trinucleotide), but cases of an increase in the number of repeats consisting of 5 and even 12 nucleotides, located both in exons of genes and introns or even untranslated regions of genes, have also been described . These mutations are called dynamic or unstable. Most diseases caused by mutations associated with expansion of the repeat zone are hereditary neurological diseases. These are Huntington's chorea, spinal and bulbar muscular atrophy, spinocerebellar ataxia, myotonic dystrophy, Friedreich's ataxia.

The mechanism for expanding the repeat zone is not fully understood. In a population, healthy individuals typically exhibit some variation in the number of nucleotide repeats found in different genes. The number of nucleotide repeats is inherited both across generations and during somatic cell division. However, after the number of repeats, which varies for different genes, exceeds a certain critical threshold, which also varies for different genes, they usually become unstable and can increase in size either during meiosis or in the first divisions of the fertilized egg.

Effects of gene mutation

Most autosomal recessive diseases result from loss of function of the corresponding mutant gene. This is manifested by a sharp decrease in enzyme activity (most often), which may be due to a decrease in either their synthesis or their stability. In the case where the function of the corresponding protein is completely absent, the gene mutation with this effect is called a null allele. The same mutation can manifest itself differently in different individuals, regardless of the level at which its effects are assessed: molecular, biochemical or phenotypic. The reasons for these differences may lie in the influence of mutations of other genes on the manifestation, as well as external environmental reasons, if they are understood broadly enough.

Among loss-of-function mutations, it is customary to distinguish dominant negative mutations. These include mutations that not only lead to a decrease or loss of the function of their own product, but also disrupt the function of the corresponding normal allele. Most often, manifestations of dominant negative mutations are found in proteins consisting of two or more polypeptide chains, such as collagens.

It was natural to expect that with the DNA replication that occurs during each cell division, quite a lot of molecular mutations should occur. However, this is not actually the case, since DNA damage repair occurs in cells. Several dozen enzymes are known to be involved in this process. They recognize the changed base, remove it by cutting the DNA strand, and replace it with the correct base using the complementary, intact DNA strand.

Recognition of the changed base in the DNA chain by repair enzymes occurs due to the fact that the correct pairing of the changed nucleotide with the complementary base of the second DNA strand is disrupted. There are also mechanisms for repairing other types of DNA damage. It is believed that more than 99% of all newly occurring molecular mutations are normally repaired. If, however, mutations occur in the genes that control the synthesis of repair enzymes, then the frequency of spontaneous and induced mutations increases sharply, and this increases the risk of developing various cancers.

Changes in the structure of a gene or nucleotide sequence can lead to changes in the protein encoded by this gene. Changes in the structure of a gene are called mutations. Mutations can occur for a variety of reasons, ranging from random errors during DNA duplication to the effect of ionizing radiation or special chemicals called mutagens on a gene.

Mutations can be classified depending on the nature of the change in the nucleotide sequence: deletions, insertions, substitutions, etc., or on the nature of the changes during protein biosynthesis: missense, nonsense frameshift mutations, etc.

There are also stable and dynamic mutations.

The phenotypic effect of mutations can be either loss of function or gain of new function.

Most newly occurring mutations are corrected by DNA repair enzymes.

Monogenic diseases

In somatic cells of human organs and tissues, each gene is represented by two copies (each copy is called an allele). The total number of genes is approximately 30,000 (the exact number of genes in the human genome is still unknown).

Phenotype

At the organismal level, mutant genes change the phenotype of an individual.

Phenotype is understood as the sum of all external characteristics of a person, and when we talk about external characteristics, we mean not only actual external characteristics, such as height or eye color, but also various physiological and biochemical characteristics that can change as a result of action genes.

The phenotypic traits that medical genetics deals with are hereditary diseases and symptoms of hereditary diseases. It is quite obvious that there is a huge distance between the symptoms of a hereditary disease, such as, say, absence of an ear, seizures, mental retardation, kidney cysts, and a change in one protein as a result of a mutation in a particular gene.

A mutant protein, the product of a mutant gene, must somehow interact with hundreds or even thousands of other proteins encoded by other genes in order to eventually change a normal or pathological trait. In addition, the products of genes involved in the formation of any phenotypic trait can interact with environmental factors and be modified under their influence. The phenotype, unlike the genotype, can change throughout life, while the genotype remains constant. The most striking evidence of this is our own ontogenesis. During our lives, we change externally as we age, but our genotype does not. Behind the same phenotype there can be different genotypes, and, on the contrary, with the same genotype the phenotypes can differ. The latter statement is supported by the results of studies of monozygotic twins. Their genotypes are identical, but phenotypically they can differ in body weight, height, behavior and other characteristics. At the same time, when we are dealing with monogenic hereditary diseases, we see that usually the action of a mutant gene is not hidden by numerous interactions of its pathological product with the products of other genes or with environmental factors.

Almost any change in the structure or number of chromosomes, in which the cell retains the ability to reproduce itself, causes a hereditary change in the characteristics of the organism. According to the nature of the genome change, i.e. sets of genes contained in a haploid set of chromosomes, gene, chromosomal and genomic mutations are distinguished. hereditary mutant chromosomal genetic

Gene mutations are molecular changes in the structure of DNA that are not visible in a light microscope. Gene mutations include any changes in the molecular structure of DNA, regardless of their location and effect on viability. Some mutations have no effect on the structure or function of the corresponding protein. Another (large) part of gene mutations leads to the synthesis of a defective protein that is unable to perform its inherent function.

Based on the type of molecular changes, there are:

Deletions (from the Latin deletio - destruction), i.e. loss of a DNA segment from one nucleotide to a gene;

Duplications (from the Latin duplicatio doubling), i.e. duplication or reduplication of a DNA segment from one nucleotide to entire genes;

Inversions (from the Latin inversio - inversion), i.e. a 180-degree rotation of a DNA segment ranging in size from two nucleotides to a fragment including several genes;

Insertions (from the Latin insertio - attachment), i.e. insertion of DNA fragments ranging in size from one nucleotide to an entire gene.

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

The effects of gene mutations are extremely varied. Most of them do not appear phenotypically because they are recessive. This is very important for the existence of the species, since most newly occurring mutations are harmful. However, their recessive nature allows them to persist for a long time in individuals of the species in a heterozygous state without harm to the body and manifest themselves in the future upon transition to a homozygous state.

Currently, there are more than 4,500 monogenic diseases. The most common of them are: cystic fibrosis, phenylketonuria, Duchenne-Becker myopathies and a number of other diseases. Clinically, they manifest themselves as signs of metabolic disorders (metabolism) in the body.

At the same time, there are a number of cases where a change in only one base in a certain gene has a noticeable effect on the phenotype. One example is the genetic abnormality of sickle cell anemia. The recessive allele, which causes this hereditary disease in the homozygous state, is expressed in the replacement of just one amino acid residue in the B-chain of the hemoglobin molecule (glutamic acid? ?> valine). This leads to the fact that in the blood red blood cells with such hemoglobin are deformed (from rounded ones become sickle-shaped) and quickly collapse. At the same time, acute anemia develops and a decrease in the amount of oxygen carried by the blood is observed. Anemia causes physical weakness, disturbances in the functioning of the heart and kidneys, and can lead to early death in people homozygous for the mutant allele.

Chromosomal mutations are the causes of chromosomal diseases.

Chromosomal mutations are structural changes to individual chromosomes, usually visible under a light microscope. A chromosomal mutation involves a large number (from tens to several hundreds) of genes, which leads to a change in the normal diploid set. Although chromosomal aberrations generally do not change the DNA sequence of specific genes, changes in the copy number of genes in the genome lead to genetic imbalance due to a lack or excess of genetic material. There are two large groups of chromosomal mutations: intrachromosomal and interchromosomal (see Fig. 2).

Intrachromosomal mutations are aberrations within one chromosome (see Fig. 3). These include:

Deletions are the loss of one of the chromosome sections, internal or terminal. This can cause a disruption of embryogenesis and the formation of multiple developmental anomalies (for example, a deletion in the region of the short arm of the 5th chromosome, designated 5p-, leads to underdevelopment of the larynx, heart defects, mental retardation. This symptom complex is known as the “cry of the cat” syndrome, because in sick children, due to an anomaly of the larynx, crying resembles a cat’s meow);

Inversions. As a result of two points of chromosome breaks, the resulting fragment is inserted into its original place after a rotation of 180 degrees. As a result, only the order of the genes is disrupted;

Duplications are the doubling (or multiplication) of any part of a chromosome (for example, trisomy on the short arm of chromosome 9 causes multiple defects, including microcephaly, delayed physical, mental and intellectual development).

Rice. 2.

Interchromosomal mutations, or rearrangement mutations, are the exchange of fragments between non-homologous chromosomes. Such mutations are called translocations (from the Latin trans - for, through and locus - place). This:

Reciprocal translocation - two chromosomes exchange their fragments;

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

? “centric” fusion (Robertsonian translocation) is the joining of two acrocentric chromosomes in the region of their centromeres with the loss of short arms.

When chromatids are transversely broken through centromeres, “sister” chromatids become “mirror” arms of two different chromosomes containing the same sets of genes. Such chromosomes are called isochromosomes.

Rice. 3.

Translocations and inversions, which are balanced chromosomal rearrangements, do not have phenotypic manifestations, but as a result of segregation of rearranged chromosomes in meiosis, they can form unbalanced gametes, which will lead to the emergence of offspring with chromosomal abnormalities.

Genomic mutations, like chromosomal ones, are the causes of chromosomal diseases.

Genomic mutations include aneuploidies and changes in the ploidy of structurally unchanged chromosomes. Genomic mutations are detected by cytogenetic methods.

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

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

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

The most common genomic mutations include:

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

Monosomy is the presence of only one of two homologous chromosomes. With monosomy for any of the autosomes, normal development of the embryo is not possible. The only monosomy in humans that is compatible with life - monosomy on the X chromosome - leads to Shereshevsky-Turner syndrome (45,X).

The reason leading to aneuploidy is the non-disjunction of chromosomes during cell division during the formation of germ cells or the loss of chromosomes as a result of anaphase lag, when during movement to the pole one of the homologous chromosomes may lag behind other non-homologous chromosomes. The term nondisjunction means the absence of separation of chromosomes or chromatids in meiosis or mitosis.

Chromosome nondisjunction most often occurs during meiosis. The chromosomes, which normally should divide during meiosis, remain joined together and move to one pole of the cell in anaphase, thus producing two gametes, one of which has an extra chromosome, and the other does not have this chromosome. When a gamete with a normal set of chromosomes is fertilized by a gamete with an extra chromosome, trisomy occurs (i.e., there are three homologous chromosomes in the cell); when a gamete without one chromosome is fertilized, a zygote with monosomy occurs. If a monosomic zygote is formed on any autosomal chromosome, then the development of the organism stops at the earliest stages of development.

According to the type of inheritance they distinguish dominant And recessive mutations. Some researchers identify semi-dominant and codominant mutations. Dominant mutations are characterized by a direct effect on the body, semi-dominant mutations mean that the heterozygous form is intermediate in phenotype between the AA and aa forms, and codominant mutations are characterized by the fact that heterozygotes A 1 A 2 show signs of both alleles. Recessive mutations do not appear in heterozygotes.

If a dominant mutation occurs in gametes, its effects are expressed directly in the offspring. Many mutations in humans are dominant. They are common in animals and plants. For example, a generative dominant mutation gave rise to the Ancona breed of short-legged sheep.

An example of a semi-dominant mutation is the mutational formation of the heterozygous form Aa, intermediate in phenotype between the organisms AA and aa. This occurs in the case of biochemical traits when the contribution of both alleles to the trait is the same.

An example of a codominant mutation is the alleles I A and I B, which determine blood group IV.

In the case of recessive mutations, their effects are hidden in diploids. They appear only in the homozygous state. An example is recessive mutations that determine human gene diseases.

Thus, the main factors in determining the probability of manifestation of a mutant allele in an organism and population are not only the stage of the reproductive cycle, but also the dominance of the mutant allele.

Direct mutations? These are mutations that inactivate wild-type genes, i.e. mutations that change the information encoded in DNA in a direct way, resulting in a change from the original (wild) type organism to a mutant type organism.

Back mutations represent reversions to the original (wild) types from mutants. These reversions are of two types. Some of the reversions are caused by repeated mutations of a similar site or locus with restoration of the original phenotype and are called true reverse mutations. Other reversions are mutations in some other gene that change the expression of the mutant gene towards the original type, i.e. the damage in the mutant gene remains, but it seems to restore its function, resulting in the restoration of the phenotype. Such restoration (full or partial) of the phenotype despite the preservation of the original genetic damage (mutation) is called suppression, and such reverse mutations are called suppressor (extragenic). As a rule, suppression occurs as a result of mutations in genes encoding the synthesis of tRNA and ribosomes.

In general, suppression can be:

? intragenic? when a second mutation in an already affected gene changes a codon defective as a result of a direct mutation in such a way that an amino acid is inserted into the polypeptide that can restore the functional activity of this protein. Moreover, this amino acid does not correspond to the original one (before the first mutation occurred), i.e. no true reversibility observed;

? introduced? when the structure of tRNA changes, as a result of which the mutant tRNA includes in the synthesized polypeptide another amino acid instead of that encoded by a defective triplet (resulting from a direct mutation).

Compensation for the effect of mutagens due to phenotypic suppression is not excluded. It can be expected when the cell is exposed to a factor that increases the likelihood of errors in reading mRNA during translation (for example, some antibiotics). Such errors can lead to the substitution of the wrong amino acid, which, however, restores the protein function impaired as a result of direct mutation.

Mutations, in addition to their qualitative properties, are also characterized by the method of their occurrence. Spontaneous(random) - mutations that occur under normal living conditions. They are the result of natural processes occurring in cells, arising in the natural radioactive background of the Earth in the form of cosmic radiation, radioactive elements on the surface of the Earth, radionuclides incorporated into the cells of organisms that cause these mutations or as a result of DNA replication errors. Spontaneous mutations occur in humans in somatic and generative tissues. The method for determining spontaneous mutations is based on the fact that children develop a dominant trait, although their parents do not have it. A Danish study showed that approximately one in 24,000 gametes carries a dominant mutation. The frequency of spontaneous mutation in each species is genetically determined and maintained at a certain level.

Induced mutagenesis is the artificial production of mutations using mutagens of various natures. There are physical, chemical and biological mutagenic factors. Most of these factors either directly react with nitrogenous bases in DNA molecules or are included in nucleotide sequences. The frequency of induced mutations is determined by comparing cells or populations of organisms treated and untreated with the mutagen. If the frequency of a mutation in a population increases 100 times as a result of treatment with a mutagen, then it is believed that only one mutant in the population will be spontaneous, the rest will be induced. Research on the creation of methods for the targeted effect of various mutagens on specific genes is of practical importance for the selection of plants, animals and microorganisms.

Based on the type of cells in which mutations occur, generative and somatic mutations are distinguished (see Fig. 4).

Generative mutations occur in the cells of the reproductive primordium and in the germ cells. If a mutation (generative) occurs in genital cells, then several gametes can receive the mutant gene at once, which will increase the potential ability of several individuals (individuals) to inherit this mutation in the offspring. If a mutation occurs in a gamete, then probably only one individual (individual) in the offspring will receive this gene. The frequency of mutations in germ cells is influenced by the age of the organism.

Rice. 4.

Somatic mutations occur in the somatic cells of organisms. In animals and humans, mutational changes will persist only in these cells. But in plants, due to their ability to reproduce vegetatively, the mutation can spread beyond the somatic tissues. For example, the famous winter apple variety “Delicious” originates from a mutation in a somatic cell, which, as a result of division, led to the formation of a branch that had the characteristics of a mutant type. This was followed by vegetative propagation, which made it possible to obtain plants with the properties of this variety.

The classification of mutations depending on their phenotypic effect was first proposed in 1932 by G. Möller. According to the classification, the following were identified:

Amorphous mutations. This is a condition in which the trait controlled by the pathological allele is not expressed because the pathological allele is inactive compared to the normal allele. Such mutations include the albinism gene and about 3,000 autosomal recessive diseases;

Antimorphic mutations. In this case, the value of the trait controlled by the pathological allele is opposite to the value of the trait controlled by the normal allele. Such mutations include genes of about 5-6 thousand autosomal dominant diseases;

Hypermorphic mutations. In the case of such a mutation, the trait controlled by the pathological allele is more pronounced than the trait controlled by the normal allele. Example? heterozygous carriers of genes for diseases of genome instability. Their number is about 3% of the world's population, and the number of diseases themselves reaches 100 nosologies. Among these diseases: Fanconi anemia, ataxia telangiectasia, xeroderma pigmentosum, Bloom's syndrome, progeroid syndromes, many forms of cancer, etc. Moreover, the frequency of cancer in heterozygous carriers of the genes for these diseases is 3-5 times higher than normal, and in patients themselves ( homozygotes for these genes), the incidence of cancer is tens of times higher than normal.

Hypomorphic mutations. This is a condition in which the expression of a trait controlled by a pathological allele is weakened compared to the trait controlled by a normal allele. Such mutations include mutations in pigment synthesis genes (1q31; 6p21.2; 7p15-q13; 8q12.1; 17p13.3; 17q25; 19q13; Xp21.2; Xp21.3; Xp22), as well as more than 3000 forms of autosomal recessive diseases.

Neomorphic mutations. Such a mutation is said to occur when the trait controlled by the pathological allele is of a different (new) quality compared to the trait controlled by the normal allele. Example: synthesis of new immunoglobulins in response to the penetration of foreign antigens into the body.

Speaking about the enduring significance of G. Möller’s classification, it should be noted that 60 years after its publication, the phenotypic effects of point mutations were divided into different classes depending on the effect they had on the structure of the protein product of the gene and/or its level of expression.

MAIN CAUSES OF GENE MUTATIONS AT THE PRESENT STAGE

Pylaikina Vladlena Vladislavovna

Nikonova Anna Valerievna

1st year students, Department of Dentistry, PSU, Russian Federation, Penza

Saldaev Damir Abesovich

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

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

Major discoveries of modern genetics are due to the ability of genes to undergo restructuring, or in other words, organisms are able to mutate.

Gene mutations are violations of the nucleotide sequence.

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

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

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

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

There are also spontaneous and induced mutations. Spontaneous mutations appear randomly throughout the life of an organism under normal environmental conditions.

Induced mutations are heritable changes in the genome that arise as a result of various mutations under artificial conditions or under adverse environmental influences.

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

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

Relationship between mutations and DNA recombination. Unequal crossing over often leads to mutations. It usually occurs when there are several duplicated copies of the original gene on a 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 also very common. 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 when the repair mechanism for some reason does not work or cannot cope with the elimination of damage. The consequence of DNA repair disorders is a severe hereditary disease - progeria.

Repair gene mutations lead to multiple changes in the frequency of mutations of other genes. In 1964, F. Hanawalt and D. Petitjohn proved that 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 leads to the development of xeroderma pigmentosum and malignant tumors of the integument.

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

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

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

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

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

Point mutations can occur as a result of spontaneous mutations that occur during DNA replication. They can also appear as a result of external factors (exposure to ultraviolet or x-ray radiation, high temperature or chemicals) and during the synthesis of a DNA molecule that has damage.

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

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

Bibliography:

1. Ayala F., Kaiger J. Modern genetics 3 volumes. M., “Mir”, 1988
2. Gvozdev V.A. Mobile DNA of eukaryotes. Part 2. Role in the regulation of gene activity and genome evolution // Soros. education magazine. - 1998. - No. 8. - P. 15-21.
3. Golovachev G.D. Human heredity., T., “Science”, 1983.
4. Golubeva A.A. Rare genetic diseases in children // Bulletin of medical Internet conferences. - 2013. - T. 3. - No. 2. - P. 446.
5. Green N., Stout W., Taylor D., Biology 3 volumes, M, “World”, 1990
6. Jonczyk P., Fijalkowska I., Kiezla Z. Overproduction of DNA polymerase subunit. Counteracting SOS mutagens // Scientific Academy. USA - 1988. - 85. - pp. 2124-2127.
7. Dubinin N.P. New in modern genetics M, “Science”, 1989
8. Cannistraro V.D., Taylor D.S. 5-methylcytosine deamination in cyclobutane dimers //Molecular Biology. - 2009. - 392. - P. 1145-1157.
9. Rovenskikh D.N., Maksimov V.N., Tatarnikova N.P., Usov S.A., Voevoda M.I. The role of molecular genetic factors in the risk of developing acute deep vein thrombosis of the lower extremities // Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences. - 2012. - T. 32. - No. 4. - P. 90-94.
10. Spradling A.C., Stam D., Beaton A. Single insertion P-element mutations of 25% of vital Drosophila genes // Genetics. 1999. - pp. 135-177.
11. Chugunova O.L., Shumikhina M.V. Modern ideas about hereditary thrombophilia in children and its role in the development of kidney diseases // Questions of practical pediatrics. - 2011. - T. 6. - No. 5. - P. 40-48.
12. Yarygin V.N., Vasiliev V.I. “Biology” // Higher school. 2008. - P. 84.

Mutations- persistent changes in the genetic apparatus that occur suddenly and lead to changes in certain hereditary characteristics of the body. The foundations of the doctrine of mutation were laid by the Dutch botanist and geneticist De Vries (1848-1935), who proposed this term. The main provisions of mutation theory are:

■ mutations occur suddenly;

■ changes caused by mutations are stable and can be inherited;

■ mutations are not directed, that is, they can be beneficial, harmful or neutral for organisms;

■ the same mutations can occur repeatedly;

■ the ability to form mutations is a universal property of all living organisms.

Mutations by cell type in which changes occur:

generative - arise in germ cells and are inherited during sexual reproduction;

somatic - arise in non-reproductive cells and are inherited during vegetative or asexual reproduction.

Mutations by impact on life activity:

lethal - cause the death of organisms even before birth or before the onset of the ability to reproduce;

sublethal - reduce the viability of individuals;

neutral - under normal conditions do not affect the viability of organisms.

Mutations behind changes in the hereditary apparatus

Gene mutations - persistent changes in individual genes caused by a violation of the nucleotide sequence in nucleic acid molecules. These mutations arise due to the loss of certain nucleotides, the appearance of extra ones, and a change in the order of their arrangement. Disturbances in the DNA structure lead to mutations only when repair does not occur.

Variety of gene mutations:

1 ) dominant, subdominant /(appear partially) and recessive,

2 ) loss of nucleotide(deletion), nucleotide duplication(duplications), change in the order of nucleotides(inversion), nucleotide pair change(transitions and transversions).

The significance of gene mutations lies in the fact that they make up the majority of mutations with which the evolution of the organic world and selection are associated. Also, gene mutations are the cause of such a group of hereditary diseases as genetic diseases. Gene diseases are caused by the action of a mutant gene, and their pathogenesis is associated with the products of one gene (lack of protein, enzyme or structural disorder). An example of gene diseases is hemophilia, color blindness, albinism, phenylketonuria, galactosemia, sickle cell anemia, etc.

Chromosomal mutations (aberrations) - These are mutations that occur as a result of chromosome rearrangements. They are a consequence of the breakage of chromosomes with the formation of fragments, which are then combined. They can occur both within the same chromosome and between homologous and non-homologous chromosomes.

Variety of chromosomal mutations:

■ flaw (deletion) arises due to the loss of a chromosome of one or another section;

■ doubling (duplication) is associated with the inclusion of an extra duplicate segment of the chromosome;

■ reversal (inversion) is observed when chromosomes break and the section rotates 180°;

■ transfer (translocation) - a section of the chromosome of one pair is attached to a non-homologous chromosome.

Chromosomal mutations mainly cause severe abnormalities incompatible with life (deficiencies and reversals), are the main source of gene increase (doubling) and increase the variability of organisms due to gene recombination (transfer).

Genomic mutations- These are mutations associated with changes in the number of sets of chromosomes. The main types of genomic mutations are:

1) polyploidy - increase in the number of chromosome sets;

2) reduction in the number of chromosome sets;

3) aneuploidy (or heteroploidy) - a change in the number of chromosomes of individual pairs

polysemy - an increase in the number of chromosomes by one - trisomy, by two (tetrasomy) or more chromosomes;

monosomy - reduction in the number of chromosomes by one;

nullisomia - complete absence of one pair of chromosomes.

Genomic mutations are one of the mechanisms of speciation (polyploidy). they are used to create polyploid varieties that are characterized by higher yields, to obtain forms that are homozygous for all genes (reducing the number of sets of chromosomes). Genomic mutations reduce the viability of organisms and cause a group of hereditary diseases such as chromosomal. Chromosomal diseases - these are hereditary diseases caused by quantitative (polyploidy, aneuploidy) or structural (deletions, inversions, etc.) chromosome rearrangements (for example, “cry of the cat” syndrome (46, 5), Down syndrome (47, 21+), Edwards syndrome (47 ,18+), Turner syndrome (45, XO), Patau syndrome (47,13+), Klinefelter syndrome (47, XXY), etc.).