Features of mutational variability. Types of mutations

How do harmful genes arise?

Although the main property of genes is to copy themselves exactly, due to which there is a hereditary transmission of many traits from parents to children, this property is not absolute. The nature of the genetic material is dual. Genes also have the ability to change, acquire new properties. Such changes in genes are called mutations. And it is gene mutations that create the variability necessary for the evolution of living matter, the diversity of life forms. Mutations occur in any cells of the body, but only the genes of germ cells can be transmitted to offspring.

The reasons for mutations are that many environmental factors with which every organism interacts throughout life can disrupt the strict orderliness of the process of self-reproduction of genes, chromosomes as a whole, and lead to errors in inheritance. In experiments, the following factors causing mutations were established: ionizing radiation, chemicals and heat. It is obvious that all these factors are also present in the natural environment of a person (for example, the natural background of radiation, cosmic radiation). Mutations have always existed as quite a common natural phenomenon.

Being inherently errors in the transfer of genetic material, mutations are random and undirected, that is, they can be both beneficial and harmful and relatively neutral for the organism.

Beneficial mutations are fixed in the course of evolution and form the basis for the progressive development of life on Earth, while harmful mutations that reduce viability are, as it were, the reverse side of the coin. They underlie hereditary diseases in all their diversity.

Mutations are of two types:

• genetic (at the molecular level)
• and chromosomal (changing the number or structure of chromosomes to cellular level)

Both those and others can be caused by the same factors.

How often do mutations occur?
Is the appearance of a sick child often associated with a new mutation?

If mutations arose too often, then variability in living nature would prevail over heredity, and no stable forms of life would exist. Clearly, logic dictates that mutations are rare events, at least much rarer than the possibility of maintaining the properties of genes when passed from parents to children.

The actual mutation rate for individual human genes is on average from 1:105 to 1:108. This means that approximately one in a million germ cells in each generation carries a new mutation. Or, in other words, although this is a simplification, we can say that for every million cases of normal gene transfer, there is one case of mutation. It is important that, once having arisen, one or another new mutation can then be transmitted to subsequent generations, that is, fixed by the inheritance mechanism, since back mutations that return the gene to its original state are just as rare.

In populations, the ratio in the number of mutants and those who inherited a harmful gene from parents (segregants) among all patients depends both on the type of inheritance and on their ability to leave offspring. In classical recessive diseases, a deleterious mutation can pass unnoticed through many generations of healthy carriers until two carriers of the same deleterious gene marry, in which case almost every such birth of a sick child is due to inheritance rather than a new mutation. .

In dominant diseases, the proportion of mutants is in inverse relationship from the childbearing ability of patients. Obviously, when the disease leads to early death or the inability of patients to have children, then the inheritance of the disease from the parents is impossible. If the disease does not affect life expectancy or the ability to have children, then, on the contrary, inherited cases will predominate, and new mutations will be rare in comparison with them.

For example, with one of the forms of dwarfism (dominant achondroplasia), according to social and biological reasons dwarf reproduction is well below average, with about 5 times fewer children in this population compared to others. If we take the average multiplication factor in the norm as 1, then for dwarfs it will be equal to 0.2. This means that 80% of patients in each generation are the result of a new mutation, and only 20% of patients inherit dwarfism from their parents.

In hereditary diseases genetically linked to sex, the proportion of mutants among sick boys and men also depends on the relative fecundity of the patients, but cases of inheritance from mothers will always prevail here, even in those diseases when patients do not leave offspring at all. The maximum proportion of new mutations in such lethal diseases does not exceed 1/3 of the cases, since men account for exactly one third of the X chromosomes of the entire population, and two thirds of them fall on women, who, as a rule, are healthy.

Can I have a child with a mutation if I got overdose exposure?

The negative consequences of environmental pollution, both chemical and radioactive, are the problem of the century. Geneticists encounter it not as rarely as we would like in a wide range of issues: from occupational hazards to environmental degradation as a result of accidents at nuclear power plants. And the concern is understandable, for example, of people who survived the Chernobyl tragedy.

The genetic consequences of environmental pollution are indeed associated with an increase in the frequency of mutations, including harmful ones, leading to hereditary diseases. However, these consequences, fortunately, are not so catastrophic as to speak of the danger of the genetic degeneration of mankind, at least at the present stage. In addition, if we consider the problem with respect to specific individuals and families, then we can say with confidence that the risk of having a sick child due to exposure or other harmful effects as a result of a mutation is never high.

Although the frequency of mutations increases, but not so much as to exceed a tenth, or even a hundredth of a percent. In any case, for any person, even those exposed to obvious mutagenic factors, the risk negative consequences for offspring is much less than the genetic risk inherent in all people associated with the carriage of pathological genes inherited from ancestors.

In addition, not all mutations lead to an immediate manifestation in the form of a disease. In many cases, even if a child receives a new mutation from one of the parents, he will be born completely healthy. After all, a significant part of the mutations are recessive, that is, they do not show their harmful effects in carriers. And there are practically no cases where, with initially normal genes of both parents, a child receives the same new mutation simultaneously from the father and mother. The probability of such a case is so negligibly small that the entire population of the Earth is not enough to realize it.

It also follows from this that re-occurrence mutations in the same family is almost impossible. Therefore, if healthy parents have a sick child with a dominant mutation, then their other children, that is, brothers and sisters of the patient, must be healthy. However, for the offspring of a sick child, the risk of inheriting the disease will be 50% in accordance with the classical rules.

Are there deviations from the usual rules of inheritance and what are they associated with?

Yes, there are. As an exception - sometimes only because of its rarity, such as the appearance of women with hemophilia. They occur more often, but in any case, deviations are due to the complex and numerous relationships of genes in the body and their interaction with the environment. In fact, exceptions reflect all the same fundamental laws of genetics, but at a more complex level.

For example, many dominantly inherited diseases are characterized by a strong variability in their severity, to the point that sometimes the symptoms of the disease in the carrier of the pathological gene may be completely absent. This phenomenon is called incomplete penetrance of the gene. Therefore, in the pedigrees of families with dominant diseases, the so-called slip generations are sometimes found, when the known carriers of the gene, having both diseased ancestors and diseased descendants, are practically healthy.

In some cases, a more thorough examination of such carriers reveals, although minimal, erased, but quite definite manifestations. But it also happens that with the methods at our disposal it is not possible to detect any manifestations of a pathological gene, despite clear genetic evidence that a particular person has it.

The reasons for this phenomenon are not yet well understood. It is believed that the harmful effect of a mutant gene can be modified and compensated by other genes or environmental factors, but the specific mechanisms of such modification and compensation in certain diseases are unclear.

It also happens that in some families, recessive diseases are transmitted in several generations in a row so that they can be confused with dominant ones. If patients marry carriers of the gene for the same disease, then half of their children also inherit a "double dose" of the gene - a condition necessary for the manifestation of the disease. The same thing can happen in the next generations, although such "casuistry" occurs only in multiple consanguineous marriages.

Finally, the division of signs into dominant and recessive is not absolute either. Sometimes this division is simply conditional. The same gene can be considered dominant in some cases, and recessive in others.

By applying subtle methods of research, it is often possible to recognize the action recessive gene in a heterozygous state, even in perfectly healthy carriers. For example, the gene for sickle cell hemoglobin in the heterozygous state causes the sickle shape of red blood cells, which does not affect human health, and in the homozygous state it leads to a serious illness - sickle cell anemia.

What is the difference between gene and chromosomal mutations.
What are chromosomal diseases?

Chromosomes are carriers of genetic information at a more complex - cellular level of organization. hereditary diseases can also be caused by chromosomal defects that arose 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 for all people, but also in the same parts of these chromosomes.

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

But the formation of germ cells sometimes occurs with chromosomal "errors". These are mutations that lead to a change in the number or structure of chromosomes in a cell. That is why a fertilized egg may contain an excess or deficiency of chromosomal material compared to the norm. It is obvious that such a chromosomal imbalance leads to gross violations of the development of the fetus. This manifests itself in the form of spontaneous miscarriages and stillbirths, hereditary diseases, syndromes, called chromosomal.

The most famous example of a chromosomal disease is Down's disease (trisomy - the appearance of an extra 21st chromosome). Symptoms of this disease are easily detected by the appearance of the child. This is a skin fold in the inner corners of the eyes, which gives the face a Mongoloid look, and a large tongue, short and thick fingers, upon careful examination, such children also reveal heart defects, vision and hearing, and mental retardation.

Fortunately, the likelihood of recurrence in the family of this disease and many others chromosomal abnormalities small: in the vast majority of cases, they are due to random mutations. In addition, it is known that random chromosomal mutations occur more often at the end of the childbearing period.

Thus, with the increase in the age of mothers, the probability of a chromosomal error during the maturation of the egg also increases, and therefore, such women have increased risk the birth of a child with chromosomal disorders. If the overall incidence of Down syndrome among all newborns is approximately 1:650, then for the offspring of young mothers (25 years and younger) it is significantly lower (less than 1:1000). The individual risk reaches an average level by the age of 30, it is higher by the age of 38 - 0.5% (1:200), and by the age of 39 - 1% (1:100), at the age of over 40 it increases to 2- 3%.

Can people with chromosomal abnormalities be healthy?

Yes, they can with some types of chromosomal mutations, when not the number, but the structure of chromosomes changes. The fact is that structural rearrangements at the initial moment of their appearance may turn out to be balanced - not accompanied by an excess or deficiency of chromosomal material.

For example, two unpaired chromosomes can exchange their sections carrying different genes if, during chromosome breaks, sometimes observed in the process of cell division, their ends become as if sticky and stick together with free fragments of other chromosomes. As a result of such exchanges (translocations), the number of chromosomes in the cell is preserved, but in this way new chromosomes arise in which the principle of strict pairing of genes is violated.

Another type of translocation is the gluing of two almost whole chromosomes with their "sticky" ends, as a result of which total number chromosomes is reduced by one, although the loss of chromosomal material does not occur. A person - the carrier of such a translocation, is completely healthy, however, the balanced structural rearrangements that he has are no longer accidental, but quite naturally lead to chromosomal imbalance in his offspring, since essential part germ cells of carriers of such translocations have extra or, conversely, insufficient chromosomal material.

Sometimes such carriers cannot have healthy children at all (although such situations are extremely rare). For example, in carriers of a similar chromosomal anomaly - a translocation between two identical chromosomes (say, the fusion of the ends of the same 21st pair), 50% of the eggs or spermatozoa (depending on the sex of the carrier) contain 23 chromosomes, including a double one, and the remaining 50% contain one chromosome less than expected. When fertilized, cells with a double chromosome will receive another, 21st chromosome, and as a result, children with Down's disease will be born. Cells with the missing chromosome 21 during fertilization give a non-viable fetus, which is spontaneously aborted in the first half of pregnancy.

Carriers of other types of translocations can also have healthy offspring. However, there is a risk of a chromosomal imbalance leading to a gross developmental pathology in the offspring. This risk for the offspring of carriers of structural rearrangements is significantly higher than the risk of chromosomal abnormalities as a result of random new mutations.

In addition to translocations, there are other types of structural rearrangements of chromosomes that lead to similar negative consequences. Fortunately, the inheritance of chromosomal abnormalities with a high risk of pathology is much less common in life than random chromosomal mutations. The ratio of cases of chromosomal diseases among their mutant and hereditary forms, approximately 95% and 5%, respectively.

How many hereditary diseases are already known?
Is their number increasing or decreasing in the history of mankind?

Based on general biological concepts, one would expect an approximate correspondence between the number of chromosomes in the body and the number of chromosomal diseases (and in the same way between the number of genes and gene diseases). Indeed, several dozen chromosomal anomalies with specific clinical symptoms are currently known (which actually exceeds the number of chromosomes, because different quantitative and structural changes of the same chromosome cause different diseases).

The number of known diseases caused by mutations of single genes (at the molecular level) is much larger and exceeds 2000. It is estimated that the number of genes in all human chromosomes is much greater. Many of them are not unique, as they are presented in the form of multiply repeated copies in different chromosomes. In addition, many mutations can manifest themselves not as diseases, but lead to embryonic death of the fetus. So the number of gene diseases roughly corresponds to the genetic structure of the organism.

With the development of medical genetic research throughout the world, the number of known hereditary diseases is gradually increasing, and many of them, which have become classics, have been known to people for a very long time. Now in the genetic literature there is a kind of boom in publications about supposedly new cases and forms of hereditary diseases and syndromes, many of which are usually called by the names of the discoverers.

Every few years, the famous American geneticist Victor McKusick publishes catalogs of human hereditary traits and diseases, compiled on the basis of computer analysis of world literature data. And every time each subsequent edition differs from the previous one by an increasing number of such diseases. Obviously, this trend will continue, but rather it reflects the improvement in the recognition of hereditary diseases and more attention to them than real increase their numbers in the process of evolution.

Gene mutations are molecular changes in the structure of DNA that are not visible under a light microscope. Gene mutations include any changes in the molecular structure of DNA, regardless of their location and impact on viability. Some mutations have no effect on the structure and function of the corresponding protein. Another (most) part of gene mutations leads to the synthesis of a defective protein that is unable to perform its proper function. It is gene mutations that determine the development of most hereditary forms of pathology.

The most common monogenic diseases in humans are: cystic fibrosis, hemochromatosis, adrenogenital syndrome, phenylketonuria, neurofibromatosis, Duchenne-Becker myopathies and a number of other diseases. Clinically, they are manifested by signs of metabolic disorders (metabolism) in the body. The mutation may be:

1) in a base substitution in a codon, this is the so-called missense mutation(from English, mis - false, incorrect + lat. sensus - meaning) - a nucleotide substitution in the coding part of the gene, leading to an amino acid substitution in the polypeptide;

2) in such a change in codons, which will lead to a stop in reading information, this is the so-called nonsense mutation(from Latin non - no + sensus - meaning) - replacement of a nucleotide in the coding part of the gene leads to the formation of a terminator codon (stop codon) and the termination of translation;

3) a violation of reading information, a shift in the reading frame, called frameshift(from the English frame - frame + shift: - shift, movement), when molecular changes in DNA lead to a change in triplets during the translation of the polypeptide chain.

Other types of gene mutations are also known. According to the type of molecular changes, there are:

division(from lat. deletio - destruction), when there is a loss of a DNA segment ranging in size from one nucleotide to a gene;

duplications(from lat. duplicatio - doubling), i.e. duplication or re-duplication of a DNA segment from one nucleotide to entire genes;

inversions(from lat. inversio - turning over), i.e. a 180° turn of a DNA segment ranging in size from two nucpeotides to a fragment that includes several genes;

insertions(from lat. insertio - attachment), i.e. insertion of DNA fragments ranging in size from one nucleotide to the whole gene.

Molecular changes affecting one to several nucleotides are considered as point mutations.

Fundamental and distinctive for 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 only in one base. On the other hand, the same gene can change (mutate) into several different states.

For example, the gene that controls the blood group of the AB0 system. has three alleles: 0, A and B, combinations of which determine 4 blood groups. The AB0 blood group is a classic example of the genetic variability of normal human traits.

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

Genomic and chromosomal mutations

Genomic and chromosomal mutations are the causes of chromosomal diseases. Genomic mutations include aneuploidy and changes in the ploidy of structurally unchanged chromosomes. Detected by cytogenetic methods.

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

Polyploidy- 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, for the 21st pair, with Down syndrome, for the 18th pair for Edwards syndrome, for the 13th pair for Patau syndrome; for sex chromosomes: XXX, XXY, XYY);

monosomy- the presence of only one of the two homologous chromosomes. With monosomy for any of the autosomes normal development 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, X0).

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 lagging, when one of the homologous chromosomes can lag behind all other non-homologous chromosomes during the movement to the pole. The term "nondisjunction" means the absence of separation of chromosomes or chromatids in meiosis or mitosis. The loss of chromosomes can lead to mosaicism, in which there is one e uploid(normal) cell line, and the other monosomic.

Chromosome nondisjunction is most commonly observed during meiosis. Chromosomes, which normally divide during meiosis, remain attached together and move to one pole of the cell in anaphase. Thus, two gametes arise, 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 monosomal zygote is formed on any autosomal (non-sex) chromosome, then the development of the organism stops at the earliest stages of development.

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

Intrachromosomal mutations are aberrations within one chromosome. These include:

—deletions(from lat. deletio - destruction) - the loss of one of the sections of the chromosome, internal or terminal. This can cause a violation of embryogenesis and the formation of multiple developmental anomalies (for example, division in the region of the short arm of the 5th chromosome, denoted as 5p-, leads to underdevelopment of the larynx, heart defects, lagging mental development). This symptom complex is known as the "cat's cry" syndrome, since in sick children, due to an anomaly of the larynx, crying resembles a cat's meow;

—inversions(from lat. inversio - turning over). As a result of two points of breaks in the chromosome, the resulting fragment is inserted into its original place after turning by 180°. As a result, only the order of the genes is violated;

— duplications(from Lat duplicatio - doubling) - doubling (or multiplication) of any part of the chromosome (for example, trisomy along one of the short arms of the 9th chromosome causes multiple defects, including microcephaly, delayed physical, mental and intellectual development).

Schemes of the most frequent chromosomal aberrations:
Division: 1 - terminal; 2 - interstitial. Inversions: 1 - pericentric (with capture of the centromere); 2 - paracentric (within one chromosome arm)

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

Reciprocal translocation, when two chromosomes exchange their fragments;

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

- "centric" fusion (Robertsonian translocation) - the connection of two acrocentric chromosomes in the region of their centromeres with the loss of short arms.

With a transverse rupture of chromatids through the centromeres, "sister" chromatids become "mirror" arms of two different chromosomes containing the same sets of genes. Such chromosomes are called isochromosomes. Both intrachromosomal (deletions, inversions and duplications) and interchromosomal (translocations) aberrations and isochromosomes are associated with physical changes in the structure of chromosomes, including mechanical breaks.

Hereditary pathology as a result of hereditary variability

The presence of common species features allows you to combine all people on earth into a single species. Homo sapiens. Nevertheless, we can easily, with one glance, single out the face of a person we know in the crowd. strangers. The extraordinary diversity of people, both within a group (for example, diversity within an ethnic group) and between groups, is due to their genetic difference. Currently, it is believed that all intraspecific variability is due to different genotypes that arise and are maintained by natural selection.

It is known that the human haploid genome contains 3.3x10 9 pairs of nucleotide residues, which theoretically allows to have up to 6-10 million genes. However, the data contemporary research indicate that the human genome contains approximately 30-40 thousand genes. About a third of all genes have more than one allele, that is, they are polymorphic.

The concept of hereditary polymorphism was formulated by E. Ford in 1940 to explain the existence of two or more distinct forms in a population, when the frequency of the rarest of them cannot be explained only by mutational events. Since gene mutation is a rare event (1x10 6 ), the frequency of the mutant allele, which is more than 1%, can only be explained by its gradual accumulation in the population due to the selective advantages of the carriers of this mutation.

The multiplicity of splitting loci, the multiplicity of alleles in each of them, along with the phenomenon of recombination, creates an inexhaustible genetic diversity of man. Calculations show that in the entire history of mankind there has not been, is not and in the foreseeable future there will not be a genetic repetition on the globe, i.e. each person born is a unique phenomenon in the universe. The uniqueness of the genetic constitution largely determines the characteristics of the development of the disease in each individual person.

Humanity has evolved as groups of isolated populations, long time living in the same environmental conditions, including climatic and geographical characteristics, diet, pathogens, cultural traditions, etc. This led to the fixation in the population of combinations of normal alleles specific for each of them, the most adequate environmental conditions. In connection with the gradual expansion of the habitat, intensive migrations, resettlement of peoples, situations arise when combinations of specific normal genes that are useful under certain conditions in other conditions do not ensure the optimal functioning of some body systems. This leads to the fact that part of the hereditary variability, due to an unfavorable combination of non-pathological human genes, becomes the basis for the development of so-called diseases with a hereditary predisposition.

In addition, in a person as a social being, natural selection proceeded more and more over time. specific forms, which also expanded hereditary diversity. What could be swept aside in animals was preserved, or, conversely, what animals saved was lost. Thus, the full satisfaction of the needs for vitamin C led in the process of evolution to the loss of the L-gulonodactone oxidase gene, which catalyzes the synthesis ascorbic acid. In the process of evolution, humanity also acquired undesirable signs that are directly related to pathology. For example, in humans, in the process of evolution, genes have appeared that determine sensitivity to diphtheria toxin or to the polio virus.

Thus, in humans, as in any other biological species, there is no sharp line between hereditary variability, leading to normal variations in traits, and hereditary variability, which causes the occurrence of hereditary diseases. Man, having become a biological species of Homo sapiens, as if paid for the "reasonableness" of his species by the accumulation of pathological mutations. This position underlies one of the main concepts of medical genetics about the evolutionary accumulation of pathological mutations in human populations.

The hereditary variability of human populations, both maintained and reduced by natural selection, forms the so-called genetic load.

Some pathological mutations can persist and spread in populations for a historically long time, causing the so-called segregation genetic load; other pathological mutations arise in each generation as a result of new changes in the hereditary structure, creating a mutation load.

The negative effect of the genetic load is manifested by increased mortality (death of gametes, zygotes, embryos and children), reduced fertility (reduced reproduction of offspring), reduced life expectancy, social disadaptation and disability, and also causes an increased need for medical care.

The English geneticist J. Hodden was the first to draw the attention of researchers to the existence of a genetic load, although the term itself was proposed by G. Meller back in the late 40s. The meaning of the concept of "genetic cargo" is associated with a high degree the genetic variability necessary for a biological species to be able to adapt to changing environmental conditions.

With spontaneously occurring changes in DNA that cause various pathologies of development and growth in living organisms, they speak of mutations. To understand their essence, it is necessary to learn more about the causes leading to them.

Geneticists argue that mutations are characteristic of all organisms on the planet without exception (living ones) and that they have existed forever, and one organism can have several hundred of them. However, they differ in the degree of severity and the nature of the manifestation, which determine the factors provoking them, as well as the affected gene chain.

They are natural and artificial, i.e. induced in the laboratory.

Most common factors, leading to such changes from the point of view of genetics, are the following:

ionizing radiation and X-rays. Influencing the body radiation accompanied by a change in the charge of electrons in atoms. This causes a failure in the normal course of physical-chemical and chemical-biological processes;

very high temperature often causes changes when the sensitivity threshold of a particular individual is exceeded;

when cells divide, delays may occur, as well as their too rapid growth, which also becomes an impetus for negative changes;

"defects" that occur in DNA, in which it is not possible to return the atom to its original state even after restoration.

Varieties

On the this moment more than thirty types of deviations in the gene pool of a living organism and genotype are known that cause mutations. Some are quite safe and do not appear outwardly in any way, i.e. do not lead to internal and external deformities, so the living organism does not feel discomfort. Others, on the contrary, are accompanied by severe discomfort.

To understand what mutations are, you should familiarize yourself with the mutagenic classification, grouped according to the reasons that cause defects:

genetic and somatic, differing in the typology of cells that have undergone changes. Somatic is characteristic of mammalian cells. They can be transmitted exclusively by inheritance (for example, a different eye color). Its formation takes place in the mother's womb. genetic mutation characteristic of plants and invertebrates. It is caused by negative environmental factors. An example of a manifestation is mushrooms appearing on trees, etc.;

nuclear refers to mutations in the location of the cells that have undergone changes. Such variants are not amenable to treatment, since the DNA itself is directly affected. The second type of mutation is cytoplasmic (or atavism). It affects any fluids that interact with the cell nucleus and the cells themselves. Such mutations are curable;

explicit (natural) and induced (artificial). The appearance of the first suddenly and without visible reasons. The latter are associated with the failure of physical or chemical processes;

genetic and genomic that differ in their expression. In the first variant, the changes relate to disorders that change the sequence of nucleotide construction in newly formed DNA strands (phenylketonuria can be considered as an example).

In the second case, there is a change in the quantitative chromosome set, and Down's disease, Konovalov-Wilson's disease, etc.

Meaning

The harm of mutations for the body is undeniable, since this not only affects its normal development, but often leads to death. Mutations cannot be beneficial. This also applies to cases of the appearance of superpowers. They are always preconditions for natural selection, lead to the emergence of new types of organisms (living) or to complete extinction.

Now it is clear that the processes that affect the structure of DNA, leading to minor or deadly violations, affect the normal development and vital activity of the organism.

Waiting for the birth of a child is the most wonderful time for parents, but also the most terrifying. Many are worried that the baby may be born with some kind of handicap, physical or mental disabilities.

Science does not stand still, it is possible to check the baby for developmental abnormalities at a short time in pregnancy. Almost all of these tests can show whether everything is fine with the child.

Why does it happen that completely different children can be born to the same parents - healthy child and a child with disabilities? It is determined by genes. In the birth of an underdeveloped baby or a child with physical disabilities, gene mutations associated with a change in the DNA structure affect. Let's talk about this in more detail. Consider how this happens, what gene mutations are, and their causes.

What are mutations?

Mutations are physiological and biological changes in cells in the structure of DNA. The reason may be radiation (during pregnancy, you can not take x-rays, for the presence of injuries and fractures), ultra-violet rays(long exposure to the sun during pregnancy or being in a room with UV lamps on). Also, such mutations can be inherited from ancestors. All of them are divided into types.

Gene mutations with a change in the structure of chromosomes or their number

These are mutations in which the structure and number of chromosomes are changed. Chromosomal regions can fall out or double, move to a non-homologous zone, turn one hundred and eighty degrees from the norm.

The reasons for the appearance of such a mutation is a violation in crossover.

Gene mutations are associated with a change in the structure of chromosomes or their number, are the cause serious disorders and illness in the child. Such diseases are incurable.

Types of chromosomal mutations

In total, two types of basic chromosomal mutations are distinguished: numerical and structural. Aneuploidies are types according to the number of chromosomes, that is, when gene mutations are associated with a change in the number of chromosomes. This is the emergence of an additional or several of the latter, the loss of any of them.

Gene mutations are associated with a change in structure when chromosomes break and then reunite, disrupting the normal configuration.

Types of numerical chromosomes

According to the number of chromosomes, mutations are divided into aneuploidy, that is, species. Consider the main ones, find out the difference.

• trisomy

Trisomy is the occurrence of an extra chromosome in the karyotype. The most common occurrence is the appearance of the twenty-first chromosome. It becomes the cause of Down syndrome, or, as this disease is also called, trisomy of the twenty-first chromosome.

Patau's syndrome is detected on the thirteenth, and on the eighteenth chromosome they are diagnosed. These are all autosomal trisomies. Other trisomies are not viable, they die in the womb and are lost in spontaneous abortions. Those individuals who have additional sex chromosomes (X, Y) are viable. Clinical manifestation these mutations are very few.

Gene mutations associated with a change in number occur according to certain reasons. Trisomy most often occurs during divergence in anaphase (meiosis 1). The result of this discrepancy is that both chromosomes fall into only one of the two daughter cells, the second remains empty.

Less commonly, nondisjunction of chromosomes may occur. This phenomenon is called a violation in the divergence of sister chromatids. Occurs in meiosis 2. This is exactly the case when two completely identical chromosomes lodge in one gamete, causing a trisomic zygote. Nondisjunction occurs in early stages the process of crushing an egg that has been fertilized. Thus, a clone of mutant cells arises, which can cover a larger or smaller part of the tissues. Sometimes it manifests itself clinically.

Many associate the twenty-first chromosome with the age of a pregnant woman, but this factor is up to today does not have unequivocal confirmation. The reasons why chromosomes do not separate remain unknown.

• monosomy

Monosomy is the absence of any of the autosomes. If this happens, then in most cases the fetus cannot be carried, premature birth occurs in the early stages. The exception is monosomy due to the twenty-first chromosome. The reason why monosomy occurs can be both the nondisjunction of chromosomes and the loss of a chromosome during its journey in anaphase to the cell.

For sex chromosomes, monosomy leads to the formation of a fetus with an XO karyotype. The clinical manifestation of such a karyotype is Turner's syndrome. In eighty percent of cases out of a hundred, the appearance of monosomy on the X chromosome is due to a violation of meiosis of the father of the child. This is due to the nondisjunction of the X and Y chromosomes. Basically, a fetus with an XO karyotype dies in the womb.

According to the sex chromosomes, trisomy is divided into three types: 47 XXY, 47 XXX, 47 XYY. is trisomy 47XXY. With such a karyotype, the chances of carrying a child are divided fifty to fifty. The cause of this syndrome may be the nondisjunction of the X chromosomes or the nondisjunction of X and Y of spermatogenesis. The second and third karyotypes can occur in only one out of a thousand pregnant women, they practically do not manifest themselves and in most cases are discovered by specialists quite by accident.

• polyploidy

These are gene mutations associated with a change in the haploid set of chromosomes. These sets can be tripled or quadrupled. Triploidy is most often diagnosed only when a spontaneous abortion has occurred. There were several cases when the mother managed to bear such a baby, but they all died before reaching and one month old. The mechanisms of gene mutations in the case of triplodia are determined by the complete divergence and non-divergence of all chromosome sets of either female or male germ cells. Also, a double fertilization of one egg can serve as a mechanism. In this case, the placenta degenerates. Such a rebirth is called a cystic skid. As a rule, such changes lead to the development of mental and physiological disorders in the baby, termination of pregnancy.

What gene mutations are associated with a change in the structure of chromosomes

Structural changes in chromosomes are the result of rupture (destruction) of the chromosome. As a result, these chromosomes are connected, violating their former appearance. These modifications can be unbalanced and balanced. Balanced have no excess or lack of material, so they do not appear. They can appear only if there was a gene that is functionally important at the site of the destruction of the chromosome. A balanced set may have unbalanced gametes. As a result, the fertilization of the egg with such a gamete can cause the appearance of a fetus with an unbalanced chromosome set. With such a set, the fetus develops a number of malformations, severe types of pathology appear.

Types of structural modifications

Gene mutations occur at the level of gamete formation. It is impossible to prevent this process, just as it is impossible to know for sure that it can happen. There are several types of structural modifications.

• deletions

This change is associated with the loss of part of the chromosome. After such a break, the chromosome becomes shorter, and its torn off part is lost during further cell division. Interstitial deletions are the case when one chromosome breaks in several places at once. Such chromosomes usually create a non-viable fetus. But there are also cases when babies survived, but because of such a set of chromosomes, they had Wolf-Hirshhorn syndrome, “cat's cry”.

• duplications

These gene mutations occur at the level of organization of doubled DNA sections. Basically, duplication cannot cause such pathologies that cause deletions.

• translocations

Translocation occurs due to the transfer of genetic material from one chromosome to another. If a break occurs simultaneously in several chromosomes and they exchange segments, then this causes a reciprocal translocation. The karyotype of such a translocation has only forty-six chromosomes. The translocation itself is detected only with a detailed analysis and study of the chromosome.

Changing the nucleotide sequence

Gene mutations are associated with a change in the sequence of nucleotides, when they are expressed in a modification of the structures of certain sections of DNA. According to the consequences, such mutations are divided into two types - without a frameshift and with a shift. To know exactly the causes of changes in DNA sections, you need to consider each type separately.

Mutation without frameshift

These gene mutations are associated with the change and replacement of nucleotide pairs in the DNA structure. With such substitutions, DNA length is not lost, but amino acids can be lost and replaced. There is a possibility that the structure of the protein will be preserved, this will serve. Let us consider in detail both variants of development: with and without replacement of amino acids.

Amino acid substitution mutation

Changes in amino acid residues in polypeptides are called missense mutations. There are four chains in the human hemoglobin molecule - two "a" (it is located on the sixteenth chromosome) and two "b" (coding on the eleventh chromosome). If "b" - the chain is normal, and it contains one hundred and forty-six amino acid residues, and the sixth is glutamine, then hemoglobin will be normal. In this case, glutamic acid must be encoded by the GAA triplet. If, due to a mutation, GAA is replaced by GTA, then instead of glutamic acid, valine is formed in the hemoglobin molecule. Thus, instead of normal hemoglobin HbA will appear another hemoglobin HbS. Thus, the replacement of one amino acid and one nucleotide will cause a serious serious illness - sickle cell anemia.

This disease is manifested by the fact that red blood cells become shaped like a sickle. In this form, they are not able to deliver oxygen normally. If at the cellular level homozygotes have the HbS / HbS formula, then this leads to the death of the child in the very early childhood. If the formula is HbA / HbS, then the erythrocytes have a weak form of change. Such a slight change has a useful quality - the body's resistance to malaria. In those countries where there is a danger of contracting malaria the same as in Siberia with a cold, this change has a beneficial quality.

Mutation without amino acid substitution

Nucleotide substitutions without amino acid exchange are called Seimsense mutations. If GAA is replaced by GAG in the DNA region encoding the "b" chain, then due to the fact that it will be in excess, the replacement of glutamic acid cannot occur. The structure of the chain will not be changed, there will be no modifications in the erythrocytes.

Frameshift Mutations

Such gene mutations are associated with a change in the length of DNA. The length can become shorter or longer, depending on the loss or gain of nucleotide pairs. Thus, the entire structure of the protein will be completely changed.

Intragenous suppression may occur. This phenomenon occurs when there is room for two mutations to cancel each other out. This is the moment when a nucleotide pair is added after one has been lost, and vice versa.

Nonsense Mutations

This is special group mutations. It occurs rarely, in its case, the appearance of stop codons. This can happen both with the loss of nucleotide pairs and with their addition. When stop codons appear, polypeptide synthesis stops completely. This can create null alleles. None of the proteins will match this.

There is such a thing as intergenic suppression. This is such a phenomenon when the mutation of some genes suppresses mutations in others.

Are there any changes during pregnancy?

Gene mutations associated with a change in the number of chromosomes can in most cases be identified. To find out if the fetus has malformations and pathologies, screening is prescribed in the first weeks of pregnancy (from ten to thirteen weeks). This is a series of simple examinations: blood sampling from a finger and a vein, ultrasound. On ultrasound, the fetus is examined in accordance with the parameters of all limbs, nose and head. These parameters, with a strong non-compliance with the norms, indicate that the baby has developmental defects. This diagnosis is confirmed or refuted based on the results of a blood test.

Also under the close supervision of physicians are expectant mothers, whose babies may develop mutations at the gene level, which are inherited. That is, these are those women in whose relatives there were cases of the birth of a child with mental or physical disabilities identified Down syndrome, Patau and other genetic diseases.

Mutations arising under the influence of special influences - ionizing radiation, chemicals, temperature factors, etc. - are called induced, In turn, spontaneous mutations are called "arising without intentional exposure, under the influence of environmental factors or as a result of biochemical and physiological changes in the body .

The term “mutation” was introduced in 1901 by G. de Vries, who described spontaneous mutations in one of the plant species. Different genes in one species mutate at different frequencies, the frequency of mutation and similar genes in different genotypes is not the same. Sleep frequency. gene mutation is small and usually amounts to a few, less often tens and very rarely hundreds of cases per 1 million gametes (in corn, the frequency of spontaneous mutation of different genes ranges from 0 to 492 per 10 6 gametes).

Mutation classification. Depending on the nature of the changes that occur in the genetic apparatus of the organism, mutations are divided into gene (point), chromosomal and genomic.

Gene mutations. Gene mutations make up the most important and largest proportion of mutations. They represent permanent change individual genes and arise as a result of replacing one or more nitrogenous bases in the DNA structure with others, dropping out or adding new bases, which leads to a violation of the order of reading information. As a result, there is a change in protein synthesis, which in turn causes the appearance of new or altered features . Gene mutations cause a change in a trait in different directions, leading to strong or weak changes in morphological, biochemical, and physiological properties.

In bacteria, for example, gene mutations most often affect traits such as shape and shape. color of colonies, rate of their division, ability to ferment various sugars, resistance to antibiotics, sulfonamides and others medicines, reaction to temperature influences, susceptibility to infection by bacteriophages, a number of biochemical signs.

One type of gene mutation is multiple allelism, in which not two forms of one gene arise (dominant and recessive), but a whole series of mutations of this gene, causing various changes trait controlled by the gene. For example, in Drosophila, a series of 12 alleles is known that arises from mutations in the same gene that determines eye color. A series of multiple alleles are genes that determine coat color in rabbits, the difference in blood types at person and others.

Chromosomal mutations. Mutations of this type, also called chromosomal rearrangements, or aberrations, result from significant changes in the structure of chromosomes. The mechanism of occurrence of chromosomal rearrangements is the breaks of chromosomes formed during the mutagenic effect, the subsequent loss of some fragments and the reunification of the remaining parts of the chromosome in a different order compared to the normal chromosome. Chromosomal rearrangements can be detected using a light microscope. The main ones are: shortages, division, duplications, inversions, translocations and transpositions.

shortages called rearrangement of chromosomes due to the loss of the terminal fragment. In this case, the chromosome becomes shortened, loses part of the genes contained in the lost fragment. The lost part of the chromosome is removed from the nucleus during meiosis,

deletion - also the loss of a section of the chromosome, but not the end fragment, but its middle part. If the lost site is very small and does not carry genes that strongly affect the viability of the organism, the deletion will only cause a change in the phenotype, in some cases it can cause death or serious hereditary pathology. Deletions are easily detected by microscopic examination, since in meiosis, during conjugation, a section of a normal chromosome, devoid of a homologous site in a chromosome with a deletion, forms a characteristic loop (Fig. 89).

At duplications duplication of a part of the chromosome occurs. Denoting conditionally the sequence of any parts of the chromosome as ABC, with duplication, we can observe the following arrangement of these sections: AAVS, AVVS or ABCC. When duplicating the entire area we have selected, it will look like ABSABC, i.e., a whole block of genes is duplicated. It is possible to repeat the same section multiple times (ABBVS or ABSASABC), duplication not only in neighboring, but also in more distant parts of the same chromosome. In Drosophila, for example, an eight-fold repetition of one of the sections of the chromosomes is described. The addition of extra genes affects the body less than their loss, so duplications affect the phenotype to a lesser extent than shortages and deletions.

At inversions the order of the genes on the chromosome changes. Inversions occur as a result of two chromosome breaks, with the resulting

fragment, is built into its original place, having previously turned over 180 °. Schematically, the inversion can be represented as follows. in the region of the chromosome that carries the genome ABCDEFG, breaks occur between genes BUT and B, E and F; resulting fragment BCDE flips over and snaps back into place. As a result, the section under consideration will have the structure AEDCBFG. The number of genes does not change during inversions, so they have little effect on the phenotype of the organism. Cytologically, inversions are easily detected by their characteristic location in meiosis at the time of conjugation of homologous chromosomes.

Translocations associated with the exchange of sites between non-homologous chromosomes or the attachment of a site of one chromosome to the chromosome of a non-homologous pair. Translocations are identified by the genetic consequences they cause.

transposition called the recently discovered phenomenon of inserting a small fragment of a chromosome carrying several genes into some other part of the chromosome, i.e., transferring part of the genes to another place in the genome. The mechanism of transposition occurrence is still poorly understood, but there is evidence that it differs from the mechanism of other chromosomal rearrangements.

Genomic mutations. Polyploidy. Each of the existing species of living organisms has a characteristic set of chromosomes. It is constant in number, all chromosomes of the set are different and presented once. Such a main haploid set of chromosomes of an organism contained in its germ cells is denoted by the symbol X; somatic cells normally contain two haploid set (2x) and are diploid. If the chromosomes of a diploid organism, having doubled in number during mitosis, do not diverge into two daughter cells and remain in the same nucleus, a phenomenon of multiple increase in the number of chromosomes occurs, called polyploidy.

Autopolyploidy. Polyploid forms can have 3 main sets of chromosomes (triploid), 4 (tetraploid), 5 (pentaploid), 6 (hexaploid) or more chromosome sets. Polyploids with multiple repetitions of the same basic set of chromosomes are called autopolyploids. Arise autopolyploids either as a result of chromosome division without subsequent cell division, or by participating in the fertilization of germ cells with an unreduced number of chromosomes, or by fusion of somatic cells or their nuclei. In the experiment, the effect of polyploidization is achieved by the action of temperature shocks (high or low temperature) or exposure to a number of chemicals, among which the alkaloid colchicine, acenaphthene, and drugs are the most effective. In both cases, blockade of the mitotic spindle occurs and, as a result, the chromosomes doubled during mitosis do not separate into two new cells and unite them in one nucleus.

polyploid series. Basic number of chromosomes X at different kinds plants are different, but within the same genus, species often have a number of chromosomes that is a multiple of X, form the so-called polyploid series. In wheat, for example, where X= 7, species with 2x, 4x and 6x number of chromosomes are known. The rose, where the base number is also 7, has a polyploid series, different types which contain 2x, 3 x, 4 x, 5x, 6x, 8x. The polyploid series of potatoes is represented by species with 12, 24, 36, 48, 60, 72, 96, 108 and 144 chromosomes (x = 12).

Autopolyploidy is prevalent mainly in plants, because in animals it causes a disruption in the mechanism of chromosomal sex determination.

distribution in nature. Due to their inherent wider reaction rate, polyploid plants adapt more easily to adverse environmental conditions, tolerate temperature fluctuations and drought more easily, which gives advantages in settling high-mountainous and northern regions. So, in the northern latitudes they are up to 80 % of all types common there. The number of polyploid species changes sharply in the transition from the high-mountain regions of the Pamirs with its exceptionally severe climate to the more favorable conditions of Altai and the Alpine Meadows of the Caucasus. Among the studied cereals, the proportion of polyploid species in the Pamirs is 90%, in Altai - 72%, in the Caucasus - only 50%.

Features of biology and genetics. Polyploid plants are characterized by an increase in cell size, as a result of which all their organs - leaves, stems, flowers, fruits, root crops - are larger. Due to the specifics of the mechanism of chromosome segregation in polyploids during crossing, splitting by phenotype in F 2 is 35:1.

As a result of distant hybridization and subsequent doubling of the number of chromosomes, hybrids develop polyploid forms containing two or more repetitions of different sets of chromosomes and are called allopolyploids.

In some cases, polyploid plants have reduced fecundity, which is associated with their origin and the characteristics of meiosis. In polyploids with an even number of genomes, homologous chromosomes during meiosis are more often conjugated in pairs, or several pairs together, without disturbing the course of meiosis. If one or more chromosomes do not find a pair for themselves in meiosis and do not take part in conjugation, gametes with an unbalanced number of chromosomes are formed, which leads to their death and a sharp decrease in the fecundity of polyploids. Even greater disturbances occur in meiosis in polyploids with an odd number of sets. In allopolyploids that arose during the hybridization of two species and have two parental genomes, during conjugation, each chromosome finds a partner among the chromosomes of its species. Polyploidy plays an important role in plant evolution and is used in breeding practice.