Mutational variability in humans

  - classification of mutations

  - Spontaneous and induced mutations

    The term "mutation" was introduced by Gustav de Vries (1901) to characterize random genetic changes. There are spontaneous and induced mutation processes.

An induced mutation process is the occurrence of hereditary changes under the influence of the directed action of external and internal environmental factors. The occurrence of mutations without established causes is called a spontaneous mutational process.

Mutational variability is caused by both the impact of environmental factors on the body and its physiological state.

 The frequency of mutations depends on:

- the genotype of the organism;

- phase of ontogenesis;

- sex of ontogenesis; and

- stage of gametogenesis;

- mitotic and meiotic cycles of chromosomes;

- chemical structure of individual chromosomes, etc.

  Properties of mutations:

- Mutations occur suddenly, in a jump-like manner;

- Mutations are inherited, i.e. passed from generation to generation;

- mutations are not directed - any locus (part of the chromosome) can undergo mutation, causing changes in both minor and vital traits;

- the same mutations can occur repeatedly;

- Mutations can be beneficial and harmful, dominant and recessive.

  Classification of mutations:

    Mutations can be grouped - classified by the nature of the manifestation, by the place or level of their occurrence.

    Mutations can be dominant and recessive according to the nature of their manifestation. Most of them are recessive and do not appear in heterozygotes. As a rule, mutations are harmful because they disrupt a well-balanced system of biochemical transformations. Dominant mutations are manifested immediately in homo- and heterozygous organisms, and in most cases such individuals are unviable and die at early stages of ontogenesis. Mutations that drastically affect viability, partially or completely stop development, are called semi-lethal, and incompatible with life - lethal. In humans, such mutations include the recessive hemophilia gene.

    Mutations by place of origin. Mutations that occur in somatic tissues are called somatic mutations. Somatic cells make up the population formed during asexual reproduction (cell division). Somatic mutations determine the genotypic diversity of tissues, are often not inherited and are limited to the individual in whom they occurred. Somatic mutations occur in diploid cells, so they are manifested only in dominant genes or in recessive genes, but in the homozygous state. The earlier a mutation occurs in human embryogenesis, the larger the area of somatic cells that deviates from the norm. Conversely, the later in the developmental process an organism is exposed to a mutational effect, the smaller the tissue area that is formed from the mutated cell. For example, the color of the iris - white or brown segments on a blue iris - is caused by a somatic mutation. It is believed that the consequence of somatic mutations is cancerous degeneration. Malignant growth is caused by carcinogens, among which the most negative are penetrating radiation and active chemical compounds (substances).Although somatic mutations are not inherited, they reduce the reproductive capacity of the organism in which they occurred.

    The earlier a mutation occurs in germ cells, the greater the proportion of germ cells that will carry the new mutation. The upper limit of the proportion of cells that will contain an induced or spontaneous mutation is 50 percent. It is believed that the largest number of mutations in germ cells occurs in the ovocytes. Since spermatogonia undergo constant division, selection against mutations that cause harmful effects can occur among them, and the frequency of mutations decreases by the time of puberty. A woman, on the other hand, is born with almost all mutant changes; there is no parallel mitotic selection in the germ cell line. Not only do ovocytes not undergo mitosis, they remain inactive for decades until they become eggs. During this period, the ovocytes age and become disproportionately susceptible to spontaneous mutation.The germ cells are most affected by cesium-137, strontium-90, and carbon-14.Generative mutations during sexual reproduction are passed on to subsequent generations. Dominant mutations appear already in the first generation, and recessive mutations - only in the second and subsequent generations, with the transition to the homozygous state.

    Mutations by the nature of the change in the hereditary material:

  1. Changes caused by the replacement of one or more nucleotides within a single gene are called gene or point mutations. They cause changes in both the structure of proteins and the functional activity of a protein molecule. 

  2. Changes in the structure of chromosomes are called chromosomal mutations or aberrations. Such mutations can occur as a result of the loss of a part of a chromosome (deletion), doubling of a part of a chromosome (duplication), detachment and rotation of a part of a chromosome by 180° (inversion). If the change affects vital parts of the gene, such a mutation will lead to death. For example, the loss of a small portion of the 21st chromosome in humans causes a serious blood disease, acute leukemia. In some cases, the severed part of the chromosome can join a non-homologous chromosome (translocation), which will lead to a new combination of genes and changes in their interaction.

  3. Changes in the karyotype that are multiple or non-multiple of the haploid number of chromosomes are called genomic mutations. As a result of a mismatch of a pair of homologous chromosomes during meiosis, one of the resulting gametes contains one chromosome less and the other one more than the normal haploid set. The fusion of such an abnormal gamete with a normal haploid gamete during fertilization results in the formation of a zygote with fewer or more chromosomes than the diploid set characteristic of this species.

    Somatic mutations

- gene

- genomic

- chromosomal aberrations 

    Somatic mutations are changes of a hereditary nature in somatic cells that occur at different stages of an individual's development. They are often not transmitted by heredity but remain as long as the organism affected by the mutation lives.

    Genomic, chromosomal, and gene aberrations in somatic cells are the result of mutagenic factors. In humans, these are the etiological factors of hereditary diseases. Diseases caused by genomic (changes in the number of chromosomes) and chromosomal (changes in the structure of chromosomes) mutations are called chromosomal diseases. A change in the number of chromosomes is determined by doubling or reducing the entire set of chromosomes. This leads to polyploidy or haploidy (respectively). Extra or deletion of one or more chromosomes leads to heteroploidy or aneuploidy. Changes in chromosome structure are rearrangements or aberrations. This disrupts the balance of the set of genes and the normal development of the organism. As a consequence of chromosomal imbalance, the embryo or fetus dies in utero, and congenital malformations occur. The greater the amount of chromosomal material affected by the mutational effect, the earlier the disease will appear in ontogeny and the more severe the disorders of physical and mental development of the individual. A characteristic feature of chromosomal imbalance is the multiplicity of malformations of various organs and systems.

   Chromosomal diseases account for about 0.5-1% of all hereditary diseases in humans.

   Gene or point mutations are the result of molecular changes at the DNA level. In humans, they cause genetic diseases. In humans, the following types of gene mutations have been described that lead to the development of hereditary diseases: nonsense, nonsense, frameshift, deletions, insertions, splicing disorders, and an increase in the number (expansion) of trinucleotide repeats. Mutations of transcribed regions (which determine the amino acid sequence in the protein molecule to be synthesized) lead to the synthesis of an abnormal product. Mutations of transcribed regions can lead to a decrease in the rate of protein synthesis.

    Phenotypically, gene mutations are manifested at the molecular, cellular, tissue and organ levels. The number of genetic diseases is about 3500-4500. Gene mutations are divided into single-site and multisite. Single-site mutations are those that affect changes in a single site (region), while multisite mutations affect several sites of a gene locus.   There are direct and reversible gene mutations. Direct mutations are mutations that inactivate wild-type genes and cause the appearance of a mutant type. Reverse mutations are changes to the upstream form from the mutant form.

Most genes are resistant to mutations, but some genes are subject to mutations quite often.

    Somatic mutations cause genotypic diversity in the tissues of one individual and are mostly not inherited during sexual reproduction. In asexual reproduction, if an organism develops from a single cell or group of cells in which a mutation has occurred, such changes can be transmitted to the offspring. Somatic mutations are used in organisms that reproduce vegetatively. Somatic mutations form the basis for the selection of cultivated plants, in particular citrus.