Mutations according to the nature of gene action. Types of mutations

Subsequence nuclear DNA for any two people it is almost 99.9% identical. Only a very small fraction of the DNA sequence differs between different people, providing genetic variability. Some differences in DNA sequence have no effect on phenotype, while others are direct causes of disease. Between the two extremes are changes responsible for genetically determined phenotypic variability in anatomy and physiology, food tolerance, responses to treatment or medication side effects, susceptibility to infections, tumor susceptibility, and perhaps even variability in various personality traits, athletic abilities, and artistic performance. talent.

One of the important concepts of human genetics and medical genetics - that genetic diseases are only the most obvious and often extreme manifestation of genetic differences, one end of a continuum of variations from rare variants, causing disease, through more frequent variations that increase susceptibility to disease, to the most common variations that are not clearly related to the disease.

Types of mutations in humans

Any change in the nucleotide sequence or arrangement of DNA. Mutations can be classified into three categories: those that affect the number of chromosomes in a cell (genomic mutations), those that change the structure of individual chromosomes (chromosomal mutations), and those that change individual genes (gene mutations). Genomic mutations are changes in the number of intact chromosomes (aneuploidy) resulting from errors in chromosome segregation in meiosis or mitosis.

Chromosomal mutations- changes affecting only part of the chromosome, such as partial duplications, deletions, inversions and translocations, which can occur spontaneously or arise due to abnormal segregation of translocated chromosomes during meiosis. Gene mutations are changes in the DNA sequence of the nuclear or mitochondrial genome, ranging from mutations in a single nucleotide to changes spanning many millions of base pairs. Many types of mutations are represented by a variety of alleles at individual loci in more than a thousand different genetic diseases, as well as among the millions of DNA variants found throughout the genome in the normal population.

Description of different mutations not only increases awareness of human genetic diversity and the fragility of the human genetic heritage, but also promotes the information needed to detect and screen for genetic diseases in specific families at risk and also, for some diseases, in the population as a whole.

Genomic mutation, resulting in the loss or duplication of an entire chromosome, changes the dosage and thus the expression level of hundreds or thousands of genes. Likewise, a chromosomal mutation that affects most of one or more chromosomes can also affect the expression of hundreds of genes. Even a small gene mutation can have large consequences, depending on which gene is affected and what the change in expression of that gene causes. A gene mutation in the form of a change in a single nucleotide in the coding sequence can lead to a complete loss of gene expression or the formation of a protein with altered properties.

Some DNA changes, however, do not have phenotypic effects. A chromosomal translocation or inversion may not affect a critical part of the genome and may have absolutely no phenotypic effects. A mutation within a gene may have no effect because it either does not change the amino acid sequence of the polypeptide or, even if it does, the change in the encoded amino acid sequence does not change the functional properties of the protein. Therefore, not all mutations have clinical consequences.

All three types of mutations occur with significant frequency in many different cells. If a mutation occurs in the DNA of germ cells, it can be passed on to subsequent generations. In contrast, somatic mutations occur randomly in only a subset of cells in certain tissues, leading to somatic mosaicism, as seen, for example, in many tumors. Somatic mutations cannot be passed on to subsequent generations.

With the development of oncology, scientists have learned to find weak points in tumors - mutations in the genome of tumor cells.

A gene is a piece of DNA that has been inherited from parents. A child receives half of its genetic information from its mother and half from its father. There are more than 20,000 genes in the human body, each of which plays a specific and important role. Changes in genes dramatically disrupt the course of important processes inside the cell, the functioning of receptors, the production of necessary proteins. These changes are called mutations.

What does gene mutation mean in cancer? These are changes in the genome or in tumor cell receptors. These mutations help the tumor cell survive in difficult conditions, multiply faster and avoid death. But there are mechanisms by which mutations can be disrupted or blocked, thereby causing the death of the cancer cell. In order to target a specific mutation, scientists have created a new type of anticancer therapy called Targeted Therapy.

The drugs used in this treatment are called targeted drugs. target - target. They block gene mutations in cancer, thereby starting the process of destroying the cancer cell. Each cancer location is characterized by its own mutations, and for each type of mutation only a specific targeted drug is suitable.

That is why modern cancer treatment is based on the principle of deep tumor typing. This means that before starting treatment, molecular genetic research tumor tissue, allowing you to determine the presence of mutations and select individual therapy that will give the maximum antitumor effect.

In this section we will tell you what there are gene mutations in cancer, why it is necessary to do a molecular genetic study, and what drugs affect certain gene mutations in cancer.

First of all, mutations are divided into natural And artificial. Natural mutations occur involuntarily, while artificial ones occur when the body is exposed to various mutagenic risk factors.

There is also classification of mutations based on the presence of changes in genes, chromosomes or the entire genome. Accordingly, mutations are divided into:

1. Genomic mutations- These are cell mutations, as a result of which the number of chromosomes changes, which leads to changes in the cell’s genome.

2. Chromosomal mutations- These are mutations in which the structure of individual chromosomes is rearranged, resulting in the loss or doubling of part of the genetic material of the chromosome in the cell.

3. Gene mutations- These are mutations in which there is a change in one or more different parts of a gene in a cell.

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

Types of gene mutations

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

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

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

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

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

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

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

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

Effects of gene mutation

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

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

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

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

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

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

There are also stable and dynamic mutations.

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

Most newly occurring mutations are corrected by DNA repair enzymes.

Monogenic diseases

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

Phenotype

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

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

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

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

Within the framework of the formal classification, there are:

Genomic mutations – changes in the number of chromosomes;
chromosomal mutations – rearrangement of the structure of individual chromosomes;
gene mutations – and/or sequences components genes (nucleotides) in the DNA structure, the consequence of which is a change in the quantity and quality of the corresponding protein products.

Gene mutations occur by substitution, deletion (loss), translocation (movement), duplication (doubling), inversion (change) of nucleotides within individual genes. In the case when we are talking about transformations within one nucleotide, the term used is point mutation.

Such transformations of nucleotides cause the appearance of three mutant codes:

With a changed meaning (missense mutation), when in the polypeptide encoded by this gene, one amino acid is replaced by another;
with unchanged meaning (neutral mutations) - replacement of nucleotides is not accompanied by replacement of amino acids and does not have a noticeable effect on the structure or function of the corresponding protein;
meaningless (nonsense mutations), which can cause the termination of the polypeptide chain and have the greatest damaging effect.

Mutations in different parts of the gene

If we consider a gene from the position of structural and functional organization, then the deletions, insertions, substitutions and movements of nucleotides that occur in it can be divided into two groups:

1. mutations in the regulatory regions of the gene (in the promoter part and in the polyadenylation site), which cause quantitative changes in the corresponding products and manifest themselves clinically depending on the maximum level of proteins, but their function is still preserved;

2. mutations in the coding regions of the gene:
in exons – cause premature termination protein synthesis;
in introns – they can generate new splicing sites, which ultimately replace the original (normal) ones;
at splicing sites (at the junction of exons and introns) - lead to the translation of nonsense proteins.

To eliminate the consequences of this type of damage, there are special repair mechanisms. The essence of which is to remove the erroneous section of DNA, and then the original one is restored at this place. Only if the repair mechanism does not work or cannot cope with the damage does a mutation occur.

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

■ mutations occur suddenly;

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

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

■ the same mutations can occur repeatedly;

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

Mutations by cell type in which changes occur:

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

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

Mutations by impact on life activity:

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

sublethal - reduce the viability of individuals;

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

Mutations behind changes in the hereditary apparatus

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

Variety of gene mutations:

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

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

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

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

Variety of chromosomal mutations:

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

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

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

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

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

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

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

2) reduction in the number of chromosome sets;

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

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

monosomy - reduction in the number of chromosomes by one;

nullisomia - complete absence of one pair of chromosomes.

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