Types of gene mutations. Types of mutations, causes, examples. Causes of gene mutations

Mutation means change in the amount and structure of DNA in a cell or organism. In other words, mutation is a change in genotype. A feature of a change in genotype is that this change as a result of mitosis or meiosis can be transmitted to subsequent generations of cells.

Most often, mutations mean a small change in the sequence of DNA nucleotides (changes in one gene). These are the so-called. However, in addition to them, there are also when changes affect large sections of DNA, or the number of chromosomes changes.

As a result of mutation, the body may suddenly develop a new trait.

The idea that mutation is the cause of the appearance of new traits transmitted through generations was first expressed by Hugo de Vries in 1901. Later, mutations in Drosophila were studied by T. Morgan and his school.

Mutation - harm or benefit?

Mutations that occur in “insignificant” (“silent”) sections of DNA do not change the characteristics of the organism and can be easily passed on from generation to generation (natural selection will not act on them). Such mutations can be considered neutral. Mutations are also neutral when a section of a gene is replaced by a synonymous one. In this case, although the sequence of nucleotides in a certain region will be different, the same protein (with the same amino acid sequence) will be synthesized.

However, a mutation can affect a significant gene, change the amino acid sequence of the synthesized protein, and, consequently, cause a change in the characteristics of the organism. Subsequently, if the concentration of mutation in a population reaches a certain level, this will lead to a change in the characteristic feature of the entire population.

In living nature, mutations arise as errors in DNA, so they are all a priori harmful. Most mutations reduce the viability of the organism and cause various diseases. Mutations that occur in somatic cells are not transmitted to the next generation, but as a result of mitosis, daughter cells are formed that make up a particular tissue. Often somatic mutations lead to the formation of various tumors and other diseases.

Mutations that occur in germ cells can be passed on to the next generation. Under stable environmental conditions, almost all changes in the genotype are harmful. But if environmental conditions change, it may turn out that a previously harmful mutation will become beneficial.

For example, a mutation that causes short wings in an insect is likely to be harmful in a population living in areas where there is no strong wind. This mutation will be akin to a deformity or a disease. Insects possessing it will have difficulty finding mating partners. But if stronger winds begin to blow in the area (for example, a forest area was destroyed as a result of a fire), then insects with long wings will be blown away by the wind and it will be more difficult for them to move. In such conditions, short-winged individuals may gain an advantage. They will find partners and food more often than longwings. After some time, there will be more short-winged mutants in the population. Thus, the mutation will take hold and become normal.

Mutations are the basis of natural selection and this is their main benefit. For the body, the overwhelming number of mutations is harmful.

Why do mutations occur?

In nature, mutations occur randomly and spontaneously. That is, any gene can mutate at any time. However, the frequency of mutations varies among different organisms and cells. For example, it is related to the duration life cycle: the shorter it is, the more often mutations occur. Thus, mutations occur much more often in bacteria than in eukaryotic organisms.

Except spontaneous mutations(occurring in natural conditions) there are induced(by a person in laboratory conditions or unfavorable environmental conditions) mutations.

Basically, mutations arise as a result of errors during replication (doubling), DNA repair (restoration), unequal crossing over, incorrect divergence of chromosomes in meiosis, etc.

This is how damaged DNA sections are constantly restored (repaired) in cells. However, if, for various reasons, the repair mechanisms are disrupted, then errors in the DNA will remain and accumulate.

The result of a replication error is the replacement of one nucleotide in a DNA chain with another.

What causes mutations?

Increased level causes mutations x-ray radiation, ultraviolet and gamma rays. Mutagens also include α- and β-particles, neutrons, cosmic radiation (all these are high-energy particles).

Mutagen- this is something that can cause mutation.

In addition to various radiations, many chemicals have a mutagenic effect: formaldehyde, colchicine, tobacco components, pesticides, preservatives, some medications, etc.

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Subtitles

Nick Vujicic was born with a rare hereditary disease called Tetra-Amelia syndrome. The boy was missing full arms and legs, but had one partial foot with two fused toes; this allowed the boy, after surgical separation of his fingers, to learn to walk, swim, skateboard, work on a computer and write. After experiencing disability as a child, he learned to live with his disability, sharing his experiences with others and becoming a world-renowned motivational speaker. In 2012, Nick Vujicic got married. And subsequently the couple had 2 absolutely healthy sons. In 2015, a baby was born in Egypt with one eye in the middle of his forehead. Doctors said the newborn boy suffered from cyclopia, an unusual condition whose name comes from the one-eyed giants of Greek mythology. The disease was a consequence of radiation exposure in the womb. Cyclopia is one of the rarest forms of birth defects. Babies born with this condition often die soon after birth because they often have other serious defects, including damage to the heart and other organs. In the USA, in the state of Iowa, Isaac Brown lives, who has been diagnosed with a very unusual disease. The essence of this disease is that the child does not feel pain. Because of this, Isaac's parents are forced to constantly monitor their son to prevent serious injury to the child. The boy's ability not to feel pain is the result of a rare genetic disease. Of course, when a boy is injured, he experiences pain, only these sensations are several times weaker than in other people. After breaking his leg, Isaac realized that there was simply something wrong with his leg, since he could not walk as usual, but there was no pain. In addition to the fact that the baby does not feel pain, during the examination he was found to have anhidrosis, that is, there is no ability to regulate his own body temperature. Experts are currently studying samples of the boy's DNA in the hope of finding a defect in the genes and developing methods for treating such a disease. A little American girl named Gabby Williams has a rare condition. She will remain forever young. Now she is 11 years old and weighs 5 kilograms. At the same time, she has the face and body of a child. Her strange deviation was dubbed real story Benjamin Button, because the girl ages a year in four years. And this is an amazing phenomenon, over which dozens of specialists are racking their brains. When she was born, she was purple and blind. Tests showed she had a brain abnormality and her optic nerve was damaged. She has two heart defects, a cleft palate, and an abnormal swallowing reflex, so she can only eat through a tube in her nose. The girl is also completely mute. The baby can only cry or sometimes smile. There are no deviations in DNA, but Gabby hardly ages in comparison with other people, and no one knows what the reason is. Javier Botet suffers from a rare genetic disorder known as Marfan Syndrome. People with this disease are tall, thin, and have elongated limbs and fingers. Their bones are not only elongated, but also have amazing flexibility. It is worth noting that without treatment and care, those suffering from Marfan Syndrome rarely live beyond the age of forty. Javier Botet is 2 meters tall and weighs only 45 kg. These specific external data, features of the physical structure and genetic system helped Botet become “one of the people” in horror films. He played the terrifyingly thin zombie in the Report trilogy, as well as creepy ghosts in Mom, Crimson Peak and The Conjuring 2.

Causes of mutations

Mutations are divided into spontaneous And induced. Spontaneous mutations occur spontaneously throughout the life of an organism under normal conditions. environment with a frequency of about 10 − 9 (\displaystyle 10^(-9)) - 10 − 12 (\displaystyle 10^(-12)) per nucleotide for the cellular generation of an organism.

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, transcription and genetic recombination.

Relationship between mutations and DNA replication

Many spontaneous chemical changes in nucleotides result in mutations that occur during replication. For example, due to the deamination of cytosine opposite guanine, 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, forming couple U-A, and during the next replication it is replaced by couple T-A, 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

Tautomeric model of mutagenesis

It is assumed that one of the reasons for the formation of base substitution mutations is deamination of 5-methylcytosine, which can cause transitions from cytosine to thymine. Due to the deamination of the 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).

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(altered alleles act in the same direction as wild-type alleles; only less protein product is synthesized), amorphous(a mutation looks like a complete loss of gene function, e.g. white in Drosophila), antimorphic(the mutant trait changes, for example, the color of the corn grain changes from purple to brown) and neomorphic.

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

genomic;
chromosomal;
genetic.

A point mutation, or single base substitution, is a type of mutation in DNA or RNA that is characterized by the replacement of one nitrogenous base with another. The term also applies to pairwise nucleotide substitutions. The term point mutation also includes insertions and deletions of one or more nucleotides. There are several types of point mutations.

Complex mutations also occur. These are changes in DNA when one section of it is replaced by a section of a different length and a different nucleotide composition.

Point mutations can appear opposite damage to the DNA molecule that can stop DNA synthesis. For example, opposite cyclobutane pyrimidine dimers. Such mutations are called target mutations (from the word “target”). Cyclobutane pyrimidine dimers cause both targeted base substitution mutations and targeted frameshift mutations.

Sometimes point mutations occur in so-called undamaged regions of DNA, often in a small vicinity of photodimers. Such mutations are called untargeted base substitution mutations or untargeted frameshift mutations.

Point mutations do not always form immediately after exposure to a mutagen. Sometimes they appear after dozens of replication cycles. This phenomenon is called delayed mutations. With genomic instability, the main cause of the formation of malignant tumors, the number of untargeted and delayed mutations increases sharply.

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).

By influence on gene expression mutations are divided into two categories: mutations such as base pair substitutions And reading frame shift 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.

The primary mutation is sometimes called direct mutation, and a mutation that restores the original structure of the gene is 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.

Kidney mutations(sports) - persistent somatic mutations occurring in the cells of plant growth points. Lead to clonal variability. They are preserved during vegetative propagation. Many varieties of cultivated plants are bud mutations.

Consequences of mutations for cells and organisms

Mutations that impair cell activity in multicellular organism, often lead to cell destruction (in particular, to programmed cell death - apoptosis). If intra- and extracellular protective mechanisms do not recognize the mutation and the cell undergoes division, then the mutant gene will be passed on to all descendants of the cell and, most often, leads to the fact that all these cells begin to function differently.

In addition, the frequency of mutations of different genes and different regions within one gene naturally varies. It is also known that higher organisms use “targeted” (that is, occurring in certain sections of DNA) mutations in their mechanisms

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. The other (most) part of gene mutations leads to the synthesis of a defective protein that is unable to perform its inherent function. It is gene mutations that determine the development of most hereditary forms of pathology. The most common monogenic diseases are: cystic fibrosis, hemochromatosis, adrenogenital syndrome, phenylketonuria, neurofibromatosis, Duchenne-Becker myopathies and a number of other diseases. Clinically, they manifest themselves as signs of metabolic disorders (metabolism) in the body. The mutation may be:

1) in the replacement of a base in a codon, this is a so-called missense mutation - a replacement of a nucleotide in the coding part of a gene, leading to a replacement of an amino acid in a polypeptide;
2) in such a change in codons, which will lead to a stop in reading information, this is a so-called nonsense mutation - a replacement of a nucleotide in the coding part of a gene, leads to the formation of a terminator codon (stop codon) and the cessation of translation;
3) disruption of information reading, a shift in the reading frame, called frameshift, when molecular changes in DNA lead to changes in triplets during translation of the polypeptide chain.

Other types of gene mutations are also known. Based on the type of molecular changes, they are distinguished: deletions (from the Latin deletio - destruction), when a DNA segment ranging in size from one nucleotide to a gene is lost; duplication (from Latin duplicatio - doubling), i.e. duplication or reduplication of a DNA segment from one nucleotide to entire genes; inversions (from Latin inversio - inversion), i.e. a 180° rotation of a DNA segment ranging in size from two nucleotides to a fragment including several genes; insertions (from Latin insertio - attachment), i.e. insertion of DNA fragments ranging in size from one nucleotide to an entire gene.

Molecular changes affecting one to several nucleotides are considered a point mutation. The fundamental and distinctive feature of a gene mutation is that it 1) leads to a change in genetic information, 2) can be transmitted from generation to generation. A certain part of gene mutations can be classified as neutral mutations, since they do not lead to any changes in the phenotype. For example, due to the degeneracy of the genetic code, the same amino acid can be encoded by two triplets that differ in only one base. On the other hand, the same gene can change (mutate) into several different states. For example, the gene that controls the AB0 blood group has three alleles: 0, A and B, the combinations of which determine 4 blood groups. The ABO blood group is a classic example of genetic variation in normal human characteristics. It is gene mutations that determine the development of most hereditary forms of pathology. Diseases caused by such mutations are called genetic, or monogenic, diseases, that is, diseases whose development is determined by a mutation of one gene.

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MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS

EDUCATIONAL INSTITUTION "GRODNO STATE MEDICAL UNIVERSITY"

Department Medical biology and general genetics

ABSTRACT

at the rate "Medical biology and general genetics" on the topic of:

« Gene mutations as a cause of hereditary human diseases »

Completed by a 1st year student

Faculty of Pediatrics,

Savko Anton Iosifovich

Teacher: Ambrushkevich

Yuri Georgievich

Grodno State Medical University 2016

Introduction

Heredity has always been one of the most difficult to explain phenomena in human history. Many scientists have put forward their hypotheses about the occurrence of hereditary pathology. However, their assumptions were not based on rigorous scientific observations. In the 20th century, with the development of genetics, it was found out and scientifically confirmed that such pathologies are of a hereditary nature. Previously, such diseases were considered diseases of unknown etiology. Medical genetics is the study of hereditary diseases.

Recent years have been characterized by rapid development of the general and medical genetics.

The introduction into clinical practice of biochemical and cytogenetic research methods at the tissue, molecular and submolecular levels has contributed to the deciphering of many forms of diseases that were previously considered nosological forms with an unclear etiology. An increase in the level of diagnostics has led to the identification of many diseases that until recently were classified as clinical rarities - rare and rare forms of pathology.

Currently, about 2000 hereditary diseases and genetically determined syndromes are known. Their number is constantly growing, and dozens of new forms of hereditary pathology are described every year. On modern stage In the development of medicine, the recognition of various hereditary diseases and genetically determined syndromes is of exceptional importance.

Mutations and their classification

Mutamtion- persistent (that is, one that can be inherited by the descendants of a given cell or organism) transformation of the genotype, occurring under the influence of the external or internal environment.

The term “mutation” was introduced by Hugo de Vries (1901), a Dutch botanist and geneticist, to characterize random genetic changes. There are spontaneous and induced mutation processes.

Spontaneous mutations occur in any population without any visible external influence. The frequency of spontaneous mutations is low: 10-5 - 10-8 per gene/generation.

Induced mutations arise as a result of artificial mutagenesis, i.e. due to the action of mutagenic factors such as temperature, exposure to x-rays, chemical substances and biochemical factors.

Properties of mutations:

mutations occur suddenly, spasmodically;

mutations are inherited, i.e. passed on from generation to generation;

mutations are not directed - any locus can undergo mutations, causing changes in both minor and vital signs;

the same mutations can occur repeatedly;

According to their manifestation, mutations can be beneficial and harmful, dominant and recessive.

Mutations can be classified in the following order.

Based on the location of the mutation and the nature of inheritance, they are distinguished:

Generative mutations occur in the cells of the reproductive primordium, germ cells and are inherited.

Somatic mutations that occur in the cells of the body and are not inherited.

Depending on the effect on the vitality and fertility of the organism, mutations can be divided into:

Lethal - the embryo dies in the early stages of development

Semi-lethal - lead to a decrease in the viability of an individual that does not survive to the reproductive period

Conditionally lethal - capable of not manifesting itself in some conditions and leading to the death of the organism in other conditions

Sterile - affect fertility, even infertility

Neutral - the most common

Based on the location of the altered genetic material, mutations are:

1. Nuclear (chromosomal)

2. Cytoplasmic (mitochondrial, plastid).

Based on the nature of changes in the level of organization of genetic material, they are distinguished:

Gene, or point, mutations, as a result of which the structure of a specific gene changes

Chromosomal mutations, or chromosomal aberrations, lead to disruption existing groups linkage of genes on one chromosome or another

Genomic mutations leading to the addition or loss of one or more chromosomes or the complete haploid set of chromosomes.

Gene mutations

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

Overall frequency of gene diseases in human populations - 2-4%.

Gene mutations in humans are the causes of many forms of hereditary pathology. Currently, more than 3 thousand such hereditary diseases have been described. Enzymopathy is the most common manifestation of gene diseases. Also, mutations that cause hereditary diseases can affect structural, transport and embryonic proteins. Pathological mutations can occur during different periods of ontogenesis. Most of them manifest themselves in utero (up to 25% of all hereditary pathology) and in prepubertal age (45%). About 25% of pathological mutations appear during puberty and adolescence, and only 10% of monogenic diseases develop after the age of 20 years.

Sickle cell anemia

This autosomal recessive disease begins to manifest itself only a few months after birth, since the fetal hemoglobin present in the baby's blood in the first few months after birth does not contain the abnormal chain. Besides, high level fetal hemoglobin in young children after the appearance of the abnormal chain reduces the sickling of red blood cells due to increased affinity for oxygen. In carriers, symptoms of the disease appear only when the level of oxygen in the air is very low (for example, at high altitude) or during severe dehydration. Typically, these crises occur approximately 0.8 times per year per patient. Sickle cell anemia occurs when glutamic acid is replaced by valine, which causes a change in its structure and functions.

Most characteristic manifestation Sickle cell anemia in young children is a lesion of the osteoarticular system: severe pain in the joints. mutation gene disease genomic therapy

Cystic fibrosis

Cystic fibrosis, or cystic fibrosis of the pancreas, is a systemic hereditary disease caused by a mutation in the cystic fibrosis transmembrane regulator gene and characterized by damage to the exocrine glands, severe dysfunction of the respiratory system and gastrointestinal tract.

The disease is based on a gene mutation. The pathological gene is localized in the middle of the long arm of chromosome 7. Cystic fibrosis is inherited in an autosomal recessive manner and is registered in most European countries with a frequency of 1: 2000 newborns. If both parents are heterozygous, then the risk of having a child with cystic fibrosis is 25%. According to research, the frequency of heterozygous carriage of the pathological gene is 2-5%.

Currently, about 1000 mutations of the cystic fibrosis gene have been identified. The consequence of a gene mutation is a disruption of the structure and function of the protein, which leads to thickening of the secretions of the exocrine glands, difficulty in evacuation of the secretion and a change in its physicochemical properties, which, in turn, determines the clinical picture of the disease. Changes in the pancreas, respiratory organs, and gastrointestinal tract are recorded already in the prenatal period.

The first symptoms of the disease appear in most cases during the first year of life. In 30-40% of patients, cystic fibrosis is diagnosed in the first days of life in the form of intestinal obstruction. Often, on the 3-4th day of life, pneumonia occurs, which becomes protracted. Intestinal obstruction can develop at a later age of the patient.

The prognosis for cystic fibrosis remains serious to this day. The mortality rate is 50-60%, and among young children it is higher. Late diagnosis of the disease and inadequate therapy significantly worsen the prognosis. Currently, it is possible to diagnose this disease in the early stages of pregnancy, therefore great importance acquires medical and genetic counseling for families with cystic fibrosis patients.

Marfan syndrome

This is a hereditary disease characterized by systemic damage connective tissue, manifested by “pathological changes in the musculoskeletal system, eyes and cardiovascular system.

It has been established that in Marfan syndrome the main defect is associated with collagen disorders, although the possibility of damage to the elastic fibers of the connective tissue cannot be excluded. Both sexes are affected equally often.

Some clinical signs of the syndrome can be observed already at birth, for example, arachnodactyly - elongation of the fingers and toes, but the symptom complex manifests itself most clearly in school children. Patients have a pronounced asthenic type of build (tall growth, thinning of the subcutaneous tissue, muscle weakness). Characteristic signs of the disease are dolichocephaly - a change in the shape of the head, when the longitudinal size significantly exceeds the transverse, the so-called bird's face - narrow, with closely spaced eyes, a thin nose and a protruding upper jaw (prognathia); deformation of the ears, high palate. Sometimes there is a splitting of the hard palate (cleft palate). Limbs, fingers and toes are elongated, rib cage funnel-shaped or keel-shaped, the ribs are thin and long, the intercostal spaces are wide, the spine is curved , Looseness of the joints, sometimes with hyperextension in the knee joints, and flat feet are noted. X-ray examination of the bones reveals thinning of the cortex and bone trabeculae.

Intelligence in patients with Marfan syndrome is usually preserved.

Chromosomal mutations

Chromosomes are carriers of genetic information at a more complex - cellular level of organization. Hereditary diseases can also be caused by chromosomal defects that arise during the formation of germ cells.

Each chromosome contains its own set of genes, located in a strict linear sequence, that is, certain genes are located not only in the same chromosomes in all people, but also in the same sections of these chromosomes.

Normal cells of the body contain a strictly defined number of paired chromosomes (hence the pairing of the genes they contain). In humans, in each cell, except the sex cells, there are 23 pairs (46) of chromosomes. Sex cells (eggs and sperm) contain 23 unpaired chromosomes - a single set of chromosomes and genes, since paired chromosomes separate during cell division. During fertilization, when the sperm and egg merge, a fetus - an embryo - develops from one cell (now with a complete double set of chromosomes and genes).

But the formation of germ cells sometimes occurs with chromosomal “errors”. These are mutations that lead to changes in the number or structure of chromosomes in a cell. This is why a fertilized egg may contain an excess or deficiency of chromosomal material compared to the norm. Obviously, such a chromosomal imbalance leads to gross disturbances in fetal development. This manifests itself in the form of spontaneous miscarriages and stillbirths, hereditary diseases, and syndromes called chromosomal. The most famous among chromosomal diseases are: Shereshevsky-Turner syndrome, Klinefelter syndrome, “cry of the cat” syndrome, childhood progeria.

Shereshevsky-Turner syndrome

X chromosome monosomy is the only known sex chromosome monosomy in humans. This anomaly is observed in phenotypically female individuals with delayed growth and sexual development with underdeveloped internal genital organs. Most characteristic feature is the absence of gonads, due to poor development or absence of secondary sexual characteristics during puberty.

In a child with this disease, cords of connective tissue are formed instead of the ovaries, and the uterus is underdeveloped. Very often the syndrome is combined with underdevelopment of other organs. Already at birth, the girl is found to have thickening of the skin folds on the back of her head and typical swelling of her hands and feet. Often the child is born small, with low body weight.

A child has a typical appearance at an early age:

Proportionally low stature (the final height of patients does not exceed 150 cm);

Shortening of the lower jaw;

Protruding, low-set ears;

A short neck with wing-like folds running from the head to the shoulders (sphinx neck), on which a low hair growth line is noted;

Wide chest with widely spaced, inverted nipples;

Curvature of the arms in the area of the elbow joints is often observed;

Shortened 4th and 5th metacarpal bones, which makes the fingers short;

Convex nails;

Possible malformations of other organs and systems:

Cardiovascular system - heart defects;

Urinary tract - underdevelopment of the kidneys, duplication of the ureters, duplication and horseshoe kidney;

Organs of vision - ptosis (drooping of the eyelid), strabismus, formation of the “third eyelid”.

Secondary sexual characteristics are weakly expressed (sometimes completely absent) and are manifested in the following:

Underdevelopment of the mammary glands;

Abnormal development of the labia majora and minora, uterus, vagina;

The ovaries are not identified;

Amenorrhea (lack of menstruation);

Pubic and armpit hair is not noticeable.

With early detection and timely treatment, increased height can be achieved. The prognosis of the disease regarding complete recovery is unfavorable. Patients remain infertile.

With this disease, lethal outcome (death) is possible, which is primarily due to congenital defects of vital organs. There is no significant mental retardation in patients; they can successfully study and perform any work that is not related to physical and significant neuropsychic stress. The frequency of occurrence of the syndrome is one in three thousand girls born.

Klinefelter syndrome

The origin of the additional X chromosome in the karyotype of a patient with the classic variant of Klinefelter syndrome is due to the nondisjunction of sex chromosomes during meiosis in the parents. Violation of the correct distribution of sex chromosomes during the process of meiosis leads to the formation of gametes with an abnormal set of sex chromosomes. Their participation in fertilization leads to the appearance of a zygote with a disorder in the sex chromosome system - aneuploidy.

When the sex chromosomes do not diverge in meiosis of both parents and subsequent fertilization of such gametes, more complex chromosome complexes are formed (ХХХУ; ХХУУ; ХХХХУ; ХХХУУ, etc.). Nondisjunction or lagging of the sex chromosome during mitotic division can lead to the appearance of different cell clones.

The extra X chromosome is inherited from the mother in 60% of cases, especially during late pregnancy. The risk of inheriting the paternal X chromosome does not depend on the father's age.

It manifests itself for the first time as a delay in puberty, some physique features appear (disproportionately long limbs, girlish sophistication). Some mental retardation is noted in only 25% of cases. In other patients, against the background of normal mental development, hypoemotionality, submissiveness and other behavioral characteristics may be observed. Sexual desire and potency are usually reduced. Although the external genitalia are most often correctly formed, secondary sexual characteristics are poorly developed. Some adult men have no facial hair at all. Most patients have female-type pubic hair. Hair growth on the trunk is usually absent. Up to 70% of cases in patients with Klinefelter syndrome develop bilateral, painless gynecomastia. If gynecomastia has already developed, then, as a rule, it is irreversible and, unlike puberty or age-related gynecomastia, cannot be treated with medication. The testicles are reduced in size, softer, or, conversely, more dense.

The life expectancy of patients with Klinefelter syndrome does not differ from the average. The clinical picture of Klinefelter syndrome in old and senile age is complicated by a number of diseases. Some of these diseases are more common in women: cholelithiasis, obesity, varicose veins.

Klinefelter syndrome is very common. For every 500 newborn boys, there is 1 child with this pathology.

Childhood progeria

Progeria, or Hutchinson-Gilford syndrome, manifests itself from birth or at an early age with growth retardation and an even more pronounced lag in weight (usually not exceeding 15-20 kg), as well as skin changes. The skin is thinned, shiny, dry (due to decreased sweating), and tightly stretched. Loose and wrinkled on fingers and toes. In the lower abdomen and upper thighs, the skin is thickened, rough, and its condition resembles scleroderma. Superficial veins are distinguished due to the almost complete absence of the subcutaneous fat layer. There may be pigmented brown spots on areas of the body free from clothing. Characterized by total alopecia, including eyebrows and eyelashes, only vellus hair is preserved. Thinning, brittle or completely absent nails. Growth retardation is most pronounced in the first year of life and during puberty. The body proportions are normal; the head is relatively large with somewhat prominent frontal tubercles and a reduced size of the facial skull, which causes a characteristic face with exophthalmos, micrognathia, a small thin beak-shaped nose, and overlapping teeth. The ears are protruding, teeth erupt with a long delay, and sometimes are completely absent. Ophthalmologically, clouding of the lens is detected. The chest is narrow, pear-shaped. The limbs are thin, with prominent joints and short distal phalanges of the fingers. Patients are delayed in sexual development and are infertile. Sometimes there are neurological disorders in the form of asymmetrical cranial innervation. Intelligence decreases at a later stage of the disease due to progressive atherosclerosis. The life expectancy of such patients is from 7 to 27 years. Death most often occurs from myocardial infarction or status epilepticus, the nature of which remains unclear.

This disease is extremely rare, so all its victims are currently known to medicine. Supposedly there are about a hundred of them around the world. The etiology and pathogenesis of this disease are unknown. In most cases, it occurs sporadically, in several families it is registered in siblings, incl. from consanguineous marriages, which indicates the possibility of an autosomal recessive type of inheritance.

Genomic mutations

The evolutionary balance in the doses of individual genes in a given species and the distribution of these genes among linkage groups remain a stable characteristic of the genome of each species. However, both at the gene and chromosomal levels of organization hereditary material, and at the genomic level it is capable of acquiring mutational changes. These changes can be used as evolutionary material. At the same time, the accelerated pace of the evolutionary process observed at individual stages historical development, as a rule, are caused not so much by the accumulation of gene mutations, but by significant changes in the structure of the entire genome. The latter include changes in the dosage ratio of various genes and changes in the composition of linkage groups within the genome.

The cause of structural changes in the genome may be a disruption of those processes that normally ensure its stability, primarily the processes occurring in meiosis.

Structural changes in the genome can be expressed in a different distribution of genes among linkage groups. When individual chromosomes are connected in the same way that two independent ones are formed from one chromosome, this leads to a change in the number of linkage groups in the genome. When the location of individual genes changes, which often affects the nature of their functioning (position effect).

Any mutational changes in the hereditary material of gametes - generative mutations - become the property of the next generation if such gametes are involved in fertilization. Therefore, deviations during mitosis or meiosis in gamete precursor cells are of great evolutionary significance. If mutations of any rank (gene, chromosomal or genomic) occur in somatic cells - somatic mutations - they are transmitted only to the descendants of these cells, i.e. do not go beyond the boundaries of the given organism. The exception is somatic mutations that arise in the cells of the organs of vegetative reproduction, from which they are transmitted to a new generation of organisms. One of the causes of somatic mutations is pathological mitoses. If the normal course of mitosis is disrupted (non-disjunction of chromatids of individual chromosomes, multipolar mitoses, etc.), daughter cells receive an abnormal hereditary program and their further development deviates from the norm. Pathological mitoses are often observed in malignant tumor cells.

Thus, despite the existence of mechanisms that ensure the stability of the genome structure, evolutionarily significant changes can appear at this level of organization of the hereditary material. They are capable of providing a fairly sharp leap in the historical development of living nature.

Down syndrome

According to recent decades, this pathology occurs in every 700 babies born. Statistics from the last few years show a different figure - 1 child born with a pathology per 1,100 newborns, which became possible thanks to highly accurate prenatal diagnosis and early termination of such pregnancies. About 80% of children with this pathology are born to women under 35 years of age - despite the relatively low risk of the fetus developing this chromosomal pathology, a peak birth rate is observed in this age group. Every year, about 5,000 newborn babies with Down syndrome are added worldwide.

The causes of Down syndrome lie in the intrauterine formation of a chromosomal pathology of the fetus, characterized by the formation of additional copies of the genetically embedded material of the 21st chromosome, either the entire chromosome (trisomy), or sections of the chromosome (for example, due to translocation). Normal karyotype healthy person consists of 46 chromosomes, and in Down syndrome the karyotype is formed by 47 chromosomes. The causes of Down syndrome are in no way related to environmental conditions, parental behavior, taking any medications or other negative phenomena. These are random chromosomal events that, unfortunately, cannot be prevented or changed in the future.

Trisomy on chromosome 21 (which is approximately 90% of cases of the disease) is not inherited and is not transmitted hereditarily; the same applies to the mosaic form of pathology. The translocation form of the disease can be hereditary if one of the parents had a balanced chromosomal rearrangement (this means that part of a chromosome changes places with part of some other chromosome, without leading to pathological processes). When such a chromosome is passed on to the next generation, an excess of genes on chromosome 21 occurs, leading to the disease.

Signs of Down syndrome in newborns are determined immediately after birth: shortened skull; small size heads; irregular ear shape; flattened facial skull; saddle nose; flat bridge of the nose; small mouth; small chin; thick, grooved tongue; oblique eye shape; open mouth; skin folds located on the inner corners of the eyes; short neck; fold of skin on the neck; short upper and lower limbs; short fingers; flattened, wide palms; horizontal fold on the palms; concave shape of the little fingers; visible distance between the first and second toes; weak muscle tone. When children with Down syndrome are born, almost all of the external signs listed above will be detected. The diagnosis is confirmed after a genetic karyotype test.

Edwards syndrome

Edwards syndrome, or trisomy 18 syndrome, is the second most common genomic disease after Down's disease, which is characterized by a complex of multiple developmental defects.

The average age of the mother is 32.5 years, the father - 35 years. The duration of pregnancy exceeds normal (on average 42 weeks), weak fetal activity, polyhydramnios, a small placenta are diagnosed, often there is only one umbilical artery; Some children are born in a state of asphyxia, with very low body weight and severe malnutrition.

The phenotypic manifestations of Edwards syndrome are quite characteristic. The skull is dolichocephalic, compressed from the sides, with a low forehead and a wide protruding occiput; sometimes microcephaly or hydrocephalus occurs. The palpebral fissures are narrow, epicanthus, ptosis (prolapse of the organ) are observed, intramural pathology, microphthalmia, coloboma, and cataracts are also observed. The bridge of the nose is depressed, but the bridge of the nose is thin (protrudes), the ears are located very low, and the lobe and tragus are often absent. Underdevelopment of the helix and antihelix.

Characteristic microretrognathia (small and posteriorly displaced jaw). The mouth is small, triangular in shape with a short upper lip, the palate is high, sometimes with a slit, the neck is short, often with a pterygoid fold.

Various anomalies of the musculoskeletal system are noted: the chest is expanded, the sternum is shortened, the pelvis is narrow, the limbs are deformed, limited mobility in the hip joints, and descriptions of hip dislocations are found. The hands and fingers are short, 1 finger of the hand is located distally and hypoplastic. The fingers are clenched into a fist according to the “flexor anomaly” type: fingers II and V are pressed to the palm, the first toe is short and wide, syndactyly of fingers II and III. The “swing” shape of the foot is typical for trisomy 18.

Characteristic general muscle hypotonia. Boys often have cryptorchidism (undescended testicles into the scrotum), hypospadias (anomaly anatomical structure penis), clitoral hypertrophy in girls.

An intellectual defect corresponds to oligophrenia in the stage of idiocy or deep imbecility. Often such patients develop convulsive syndrome.

At autopsy, Edwards syndrome is found a large number of malformations of almost all organs and systems. WITH different frequencies There are anomalies of the central nervous system: underdevelopment of the corpus callosum, cerebellum, atrophy of the cerebral convolutions.

Almost 95% of patients with Edwards syndrome have defects of the heart and large vessels, the most common ventricular septal defect and patent ductus arteriosus. About half of all cases of trisomy 18 are accompanied by congenital anomalies of the digestive organs: disturbances in the placement of the intestines (Meckel's diverticulum), a sharp narrowing of the esophagus or anus. With the same frequency, malformations of the genitourinary system occur - a segmented or horseshoe-shaped kidney, duplication of the ureters, underdevelopment of the ovaries.

The prognosis for life is unfavorable, the average life expectancy for boys is 2-3 months, for girls - 10 months. 30% of patients die during the first month of life, only 10% of patients survive to a year. With mosaic variants, the prognosis for life is slightly better.

Alzheimer's disease

Alzheimer's disease, or progressive senile dementia, is a hereditary disease. Begins on average at 55 years of age. Two described possible options course of the disease. In the first, classic, dementia develops relatively quickly, focal symptoms appear later. In the second, there is a slow course with gradually increasing dementia, mnestic disorders and focal symptoms.

Memory impairment plays a central role in the clinical picture of Alzheimer's disease: progressive decline in memory, fixation amnesia, amnestic disorientation, and reproductive disorders. Disorders of attention, perception, and numerous false recognitions are increasing. In addition to agraphia and alexia, acalculia also occurs. There is an increasing loss of skills, disinhibition of drives, and patients are aimlessly fussy. Subsequently, movements are automated. There are speech disorders: sensory aphasia, amnestic aphasia, the transition of speech spontaneity to speech excitation, and sometimes logoclonia.

At the end of the disease, dementia is profound total character. In half of the cases, states of hallucinatory confusion, fragmentary delusional ideas, and short-term attacks of psychomotor agitation are noted. A third of patients have seizures. In cases of familial forms, convulsive seizures are combined with the early stage of the disease (at 30-35 years). Extrapyramidal disorders (usually Parkinson-like syndrome) occur in a number of patients, more often at the end of the disease. In the final stage of the disease, decerebrate rigidity, cachexia, bulimia, oral automatism syndromes, and endocrine disorders are detected.

The genetic cause of Alzheimer's disease is a defect in various parts of chromosome 21; genes in these regions control the growth of local groups of neurons.

The defect leads to the formation of beta-amyloid accumulations (amyloid bodies, Glenner bodies) in the posterior frontal parts of the dominant hemisphere, which disrupt microcirculation.

In the pathogenesis, deficiency of acetylcholine transferase, decreased acetylcholine synthesis and slower neuronal conduction are important. The morphology of dementia of the Alzheimer's type (Alzheimer's disease) has now been studied in detail and is characterized by a number of typical signs: atrophy of the brain substance, loss of neurons and synapses, granulovacuolar degeneration, gliosis, senile plaques and neurofibrillary tangles, as well as amyloid angiopathy. However, only two of them - senile plaques and neurofibrillary tangles - are considered as key neuromorphological phenomena of the disease and have diagnostic significance.

Cortical atrophy leads to compensatory hydrocephalus and dilation of the lateral ventricles. With an increase in cerebrospinal fluid production, the severity of dementia increases. An autoimmune factor plays a role in the etiology and pathogenesis of the disease. Since amyloid can accumulate around blood vessels, vascular factors are also involved in the pathogenesis. The disease should be differentiated from Pick's disease, brain tumors, and cardiovascular diseases.

A dominant type of inheritance is assumed; polygenic inheritance is also possible with different thresholds of manifestation in different families. Among women, the disease occurs 3-4 times more often than among men.

Treatment of hereditary diseases

Treatment of hereditary diseases is very difficult, lengthy and often ineffective. There are three main directions of therapy: a direct attempt to “correct” the altered gene, an impact on the basic mechanisms of disease development, and, finally, treatment of individual symptoms that the patient has.

“Correction” of gene defects is possible only with the help of genetic engineering methods, which is understood as the integration into the genome of a cell of normal, non-defective genes that perform the same function. Initially, gene therapy was developed for the treatment and prevention of monogenic hereditary diseases. However, for last years the emphasis has shifted towards more common diseases - cancer, cardiovascular pathology, AIDS, etc.

Gene therapy is based on replacing defective genes with normal ones. The question of the possibility of treating hereditary diseases arose as soon as scientists developed ways to transfer genes into certain cells, where they are transcribed and translated. The question also arose: which patients should be treated first - those who are more numerous or whose diseases are more studied? The majority was inclined to believe that gene therapy should be created for those diseases about which more is known: the known affected gene, protein, tissue of their localization.

Currently, much attention is being paid to research on gene therapy for diseases that affect many people: hypertension, high cholesterol, diabetes, some forms of cancer, etc.

Considering that gene therapy is associated with changes in the hereditary apparatus, special requirements for clinical research:

clear knowledge of the gene defect and how the symptoms of the disease are formed;

reproduction of a genetic model in animals;

lack of alternative therapy, or existing therapy is impossible or ineffective;

safety for the patient.

Hereditary gene therapy is transgenic and changes all cells in the body. It is not used in humans.

With such treatment, it is possible to isolate cells from the patient's body to introduce the necessary gene into them, after which they are returned to the patient's body. Retroviruses containing genetic information in the form of RNA are used as vectors. The retrovirus is provided by recombinant RNA (viral RNA + RNA copy of the human gene).

Another approach to gene therapy involves the use of viruses, laboratory-grown cells, and even artificial carriers to introduce genes directly into the patient's body. For example, an adenovirus devoid of pathogenic properties is contained in an aerosol bottle. When a patient inhales an aerosol suspension, the virus penetrates the cells of the lungs and brings them the functional gene for cystic fibrosis. If cells are resistant to genetic manipulation, scientists influence nearby cells. The latter have an effect on cells defective in a certain genome. Thus, gene therapy is being tested in mice that have damage to the same area of the brain as in patients with Alzheimer's disease. The nerve growth factor gene penetrates into fibroblasts. These cells are implanted into a cut in the brain and secrete a growth factor that is needed by neurons. Neurons begin to grow and produce the appropriate neurotransmitters.

Some success has been achieved in the use of gene therapy in the treatment of malignant neoplasms. A tumor cell is isolated into which genes encoding anti-cancer substances of the immune system such as interferons and interleukins are introduced. Once reintroduced into the tumor, the cells begin to produce these substances, thereby killing themselves and the surrounding malignant cells.

For a number of hereditary diseases, various therapeutic diets have been developed that, by eliminating or limiting certain substances in the diet, achieve normal mental and physical development of children and prevent the progression of metabolic disorders. Thus, special diet therapy has been developed for phenylketonuria and other hereditary diseases of amino acid metabolism, galactosemia, fructosemia. Considering that the action of pathological genes is constant, treatment of such patients should be long-term, sometimes throughout life. Such treatment requires constant biochemical monitoring and medical supervision.

In some cases, hormone replacement therapy is used, for example, insulin for diabetes.

For some hereditary diseases, the body is “cleansed” by prescribing special drugs that remove harmful metabolic products, as well as purifying the blood (hemosorption), plasma (plasmophoresis), lymph (lymphosorption), etc.

Sometimes surgical treatment is used.

Unfortunately, little is known about most hereditary diseases. In cases where it is known which tissues are affected, introducing a normal gene into them is difficult. Despite this, medical genetics has made significant progress in the treatment of certain diseases.

Conclusion

On this basis, we can conclude that mutations most often manifest themselves in the form of diseases. And it is of paramount importance to prevent the emergence and development hereditary disease has the prevention of the disease or its timely detection. IN this issue Consultation with a geneticist should play an important role.

Bibliography

1 - L.O. Badalyan / Hereditary diseases / L.O. Badalyan, Yu.E. Veltishchev Publisher: Medicine, 1980, 415 pp.;

2- E.K. Ginter / Medical genetics / Textbook for medical students. universities / Publisher: Medicine, 2003, 446 pp.;

3- E.V. Andryushchenko [et al.] / Children's diseases / Handbook / Ed. House: "Russian doctor", 1997, 191 pp.;

4- E.K. Ginter, E.V. Balanovskaya, Bukina A.M. [and others] / Hereditary diseases in human populations / Publisher: Medicine, 2002, 936 pp.;

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Characteristics of transformations

The most common pathologies that provoke human gene mutations are neurofibromatosis, adrenogenital syndrome, cystic fibrosis, and phenylketonuria. This list can also include hemochromatosis, Duchenne-Becker myopathies and others. These are not all examples of gene mutations. Their clinical signs are usually metabolic disorders (metabolic process). Gene mutations may include:

Substitution in a base codon. This phenomenon is called a missense mutation. In this case, a nucleotide is replaced in the coding part, which, in turn, leads to a change in amino acid in the protein.
Changing a codon in such a way that the reading of information is suspended. This process is called nonsense mutation. When a nucleotide is replaced in this case, a stop codon is formed and translation is terminated.
Reading impairment, frame shift. This process is called "frameshifting". When DNA undergoes a molecular change, triplets are transformed during translation of the polypeptide chain.

Classification

According to the type of molecular transformation, the following gene mutations exist:

Duplication. In this case, a repeated duplication or doubling of a DNA fragment occurs from 1 nucleotide to genes.
Deletion. In this case, there is a loss of a DNA fragment from the nucleotide to the gene.
Inversion. In this case, a rotation of 180 degrees is noted. section of DNA. Its size can be either two nucleotides or an entire fragment consisting of several genes.
Insertion. In this case, DNA sections are inserted from the nucleotide to the gene.

Molecular transformations involving from 1 to several units are considered as point changes.

Distinctive features

Gene mutations have a number of features. First of all, it should be noted their ability to be inherited. In addition, mutations can provoke a transformation of genetic information. Some of the changes can be classified as so-called neutral. Such gene mutations do not provoke any disturbances in the phenotype. Thus, due to the innateness of the code, the same amino acid can be encoded by two triplets that differ only in 1 base. At the same time, a certain gene can mutate (transform) into several different states. It is these kinds of changes that provoke most hereditary pathologies. If we give examples of gene mutations, we can turn to blood groups. Thus, the element that controls their AB0 systems has three alleles: B, A and 0. Their combination determines blood groups. Belonging to the AB0 system, it is considered a classic manifestation of the transformation of normal characteristics in humans.

Genomic transformations

These transformations have their own classification. The category of genomic mutations includes changes in the ploidy of structurally unchanged chromosomes and aneuploidy. Such transformations are determined by special methods. Aneuploidy is a change (increase - trisomy, decrease - monosomy) in the number of chromosomes of the diploid set, which is not a multiple of the haploid one. When the number increases by a multiple, we speak of polyploidy. These and most aneuploidies in humans are considered lethal changes. Among the most common genomic mutations are:

Monosomy. In this case, only one of the 2 homologous chromosomes is present. Against the background of such a transformation, healthy embryonic development is impossible for any of the autosomes. The only thing compatible with life is monosomy on the X chromosome. It provokes Shereshevsky-Turner syndrome.
Trisomy. In this case, three homologous elements are detected in the karyotype. Examples of such gene mutations: Down syndrome, Edwards syndrome, Patau syndrome.

Provoking factor

The reason why aneuploidy develops is considered to be non-disjunction of chromosomes during the process of cell division against the background of the formation of germ cells or the loss of elements due to anaphase lag, while when moving towards the pole, a homologous link may lag behind a non-homologous one. The concept of "nondisjunction" indicates the absence of separation of chromatids or chromosomes in mitosis or meiosis. This disorder can lead to mosaicism. In this case, one cell line will be normal and the other will be monosomic.

Nondisjunction in meiosis

This phenomenon is considered the most common. Those chromosomes that should normally divide during meiosis remain connected. In anaphase they move to one cell pole. As a result, 2 gametes are formed. One of them has an extra chromosome, and the other is missing an element. In the process of fertilization of a normal cell with an extra link, trisomy develops; gametes with a missing component develop monosomy. When a monosomic zygote is formed for some autosomal element, development stops at the initial stages.

Chromosomal mutations

These transformations represent structural changes of elements. Typically, they are visualized using a light microscope. Chromosome mutations typically involve tens to hundreds of genes. This provokes changes in the normal diploid set. Typically, such aberrations do not cause sequence transformation in DNA. However, when the number of gene copies changes, a genetic imbalance develops due to a lack or excess of material. There are two broad categories of these transformations. In particular, intra- and interchromosomal mutations are distinguished.

Environmental influence

Humans evolved as groups of isolated populations. They lived for quite a long time in the same environmental conditions. We are talking, in particular, about the nature of nutrition, climatic and geographical characteristics, cultural traditions, pathogens, etc. All this led to the consolidation of combinations of alleles specific to each population, which were most appropriate for living conditions. However, due to the intensive expansion of the area, migrations, and resettlement, situations began to arise when useful combinations of certain genes that were in one environment in another ceased to ensure the normal functioning of a number of body systems. In this regard, part of the hereditary variability is caused by an unfavorable complex of non-pathological elements. Thus, the cause of gene mutations in this case is changes in the external environment and living conditions. This, in turn, became the basis for the development of a number of hereditary diseases.

Natural selection

Over time, evolution took place in more specific species. This also contributed to the expansion of ancestral diversity. Thus, those signs that could disappear in animals were preserved, and, conversely, what remained in animals was swept aside. In the course of natural selection, people also acquired undesirable traits that were directly related to diseases. For example, during human development, genes appeared that can determine sensitivity to polio or diphtheria toxin. Having become Homo sapiens, the human species in some way “paid for its intelligence” with the accumulation of pathological transformations. This provision is considered the basis of one of the basic concepts of the doctrine of gene mutations.