Mutations in the genes
If it became clear from the foregoing what the genes are doing, it should also be clear that a change in the structure of the gene, the sequence of nucleotides, can lead to changes in the protein encoded by this gene. Changes in the structure of the gene are called mutations. These changes in the structure of the gene can occur for various reasons, ranging from random errors in doubling DNA to the effect on the gene of ionizing radiation or special chemicals called mutagens. The first type of change leads to so-called spontaneous mutations, and the second - to induced mutations. Mutations in genes can occur in the sex cells, and then they will be transmitted 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 particular cell clone that originated from the mutant cell. It is known that mutations of gene of somatic cells in some cases can 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 effect on the structure of the polypeptide chain encoded by the gene, due to the degeneracy of the genetic code. The replacement of the third nitrogenous base in the triplet will almost never have any consequences. Such mutations are called silent substitutions. At the same time, single-nucleotide substitutions can cause a substitution of one amino acid for another due to a change in the genetic code of the mutated triplet.
Single nucleotide substitution of the base 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 turns out to be shortened compared to the normal chain. The mutations that cause the formation of the stop codon are called nonsense mutations.
As a result of the nonsense mutation at which the A-T is replaced by G-C in the DNA molecule, the synthesis stops in the polypeptide chain on the stop codon.
Single nucleotide replacement in a normally located stop codon, on the contrary, can make it meaningful, and then the mutant mRNA, and then the mutant polypeptide, are longer than normal.
The next class of molecular mutations are deletions( insertions) or insertions( insertions) of nucleotides. When a triple of nucleotides is deleted or inserted, then if the triplet is encoding, a certain amino acid either disappears in the polypeptide or a new amino acid appears. However, if, as a result of the deletion or insertion, the number of nucleotides inserted or removed is not a multiple of three, then the meaning for all others following the insertion or deletion of the codons of the mRNA molecule is changed or lost. Such mutations are called shift mutations of the reading frame. Often they lead to the formation of a stop codon following the insertion or deletion of the nucleotide sequence of mRNA.
Gene conversion is the direct transfer of a fragment of one allele into another allele or fragment of a pseudogen into a gene. Since there are many mutations in the pseudogen, this transfer disrupts the structure of the normal gene and can be considered as a mutation. To carry out the gene conversion between the pseudogen and the gene, their pairing and subsequent atypical crossing-over are necessary, at which breaks in the strands of DNA occur.
A new and completely unexpected type of mutation has recently been 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 or even 12 nucleotides located in both gene exons and introns or even untranslated regionsgenes. These mutations are called dynamic or unstable. Most diseases caused by mutations associated with the expansion of the repetition zone are hereditary neurological diseases. This is Huntington's chorea, spinal and bulbar muscular atrophy, spinocerebellar ataxia, myotonic dystrophy, Friedreich's ataxia.
The mechanism for expanding the repetition zone is not fully understood. In a population in healthy individuals, there is usually a certain variability in the number of nucleotide repeats found in different genes. The number of nucleotide repeats is inherited both in generations and during the division of somatic cells. However, after the number of repetitions different for different genes exceeds a certain critical threshold, which is also different for different genes, they usually become unstable and can increase in size either during meiosis or in the first division of the fragmentation of a fertilized egg.
The effects of mutations in
genes The phenotypic effect of mutations can be expressed either in the loss of a function or in the acquisition of a new function.
Most autosomal recessive diseases result from the loss of function of the corresponding mutant gene. This is manifested by a sharp decrease in the activity of enzymes( 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 mutation of the gene with this effect is called the null allele. The same mutation in different individuals can manifest themselves differently, regardless of the level at which its effects are evaluated: molecular, biochemical or phenotypic. The reasons for these differences can consist both in the influence on the manifestation of the mutation of other genes, and of external causes, if they are understood quite widely.
Among the mutations with loss of function, it is customary to single out dominantly 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. The most common manifestations of dominant negative mutations are found in proteins consisting of two or more polypeptide chains, such as, for example, collagens.
It was natural to expect that when replicating the DNA that occurs during each cell division, there should be quite a lot of molecular mutations. However, this actually is not present, since in the cells there is a repair of DNA damage. Several dozens of enzymes involved in this process are known. They recognize the altered base, remove it, cut the DNA strand, and replace it with the correct base, using a complementary undamaged DNA strand for this.
The enzyme recognition of the repair of the altered base in the DNA chain is due to the fact that the correct pairing of the altered nucleotide with the complementary base of the second DNA strand is disrupted. There are also mechanisms of repair and other types of DNA damage. It is believed that more than 99% of all newly emerging molecular mutations are repaired in the norm. If, however, mutations occur in genes that control the synthesis of repair enzymes, the frequency of spontaneous and induced mutations increases dramatically, and this increases the risk of developing various cancers.
A change in the structure of a gene, a sequence of nucleotides, can lead to changes in the protein encoded by this gene. Changes in the structure of the gene are called mutations. Mutations can occur for various reasons, ranging from random errors in DNA doubling and ending with the effect on the gene of ionizing radiation or special chemicals called mutagens.
Mutations can be classified according to the nature of the change in the sequence of nucleotides: deletion, insertion, substitution, etc., or from the nature of the changes in protein biosynthesis: missense, nonsense mutation of the reading frame shift, etc.
There are also mutations stable and dynamic.
The phenotypic effect of mutations can be expressed either in the loss of a function or in the acquisition of a new function.
Most of the newly emerging 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 organism level, mutant genes alter the phenotype of the individual.
The phenotype is the sum of all the external characteristics of a person, and when we talk about external characteristics, we mean not only really external signs, such as height or color of the eyes, but also different physiological and biochemical characteristics that can change as a resultaction of genes.
The phenotypic signs that medical genetics deals with are hereditary diseases and the symptoms of hereditary diseases. It is quite obvious that the distance between the symptoms of a hereditary disease, such as, for example, absence of an auricle, convulsions, mental retardation, cysts in the kidneys, and the change in one protein as a result of a mutation in a particular gene is enormous.
A mutant protein that is a 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 some normal or pathological symptom. In addition, the products of genes involved in the formation of any phenotypic trait can interact with environmental factors and be modified under their influence. The phenotype, in contrast to the genotype, can change throughout life, the genotype remains constant. The most striking evidence of this is our own ontogeny. During life, outwardly we change, getting old, and the genotype is not. Different genotypes may be behind the same phenotype, and, on the contrary, phenotypes can be different for the same genotype. The latter statement is supported by the results of the study of monozygotic twins. Their genotypes are identical, and phenotypically they can differ in body weight, height, behavior and other characteristics. However, when we are dealing with monogenic hereditary diseases, we see that usually the action of a mutant gene is not hidden by the numerous interactions of its pathological product with the products of other genes or with environmental factors.