MEDICAL BIOLOGY, ANATOMY, HUMAN PHYSIOLOGY AND PATHOLOGY - Ya.I.Fedoniuk 2010

BIOLOGY

CHAPTER 1. BIOLOGICAL BASES OF HUMAN VITAL ACTIVITY

1.4. ONTOGENETIC LEVEL OF LIFE ORGANIZATION

1.4.2. Basics of human genetics

Spontaneous and Induced Mutations

Spontaneous (natural) mutations occur haphazardly under natural conditions. Among spontaneous mutations, Gene Mutations hold the greatest evolutionary significance. They increase the number of alleles at a specific locus and, consequently, the gene pool of the population, its heterozygosity, and intrapopulation Variability. The capacity to mutate (mutability) is a characteristic feature of a gene. Any gene can mutate at any time, in various directions, and for undetermined reasons. In this regard, spontaneous mutations are referred to as random. The average frequency of spontaneous mutations is low—10^-4-10^-6 per locus per generation in higher organisms. However, since The Genome contains numerous genes, the total number of mutations is substantial. Assuming the average mutation rate in humans is 10^-5, every individual carries between 1 and 10 mutations absent in either parent. Different genes within the same Organism mutate at varying frequencies, but for a given gene, the average mutation rate remains relatively constant. A mutation in humans leading to dwarfism occurs in 5-13 Gametes per million, muscular dystrophy in 8-11, and microcephaly in 27. The smallest segment of a gene capable of mutating is called a muton, which may be equivalent to a single nucleotide pair. Given the Abundance of NUCLEOTIDES within a single gene, the theoretical number of mutations for that gene can be significant. According to the international Phenylalanine Hydroxylase Mutation Consortium, by 2000, over 400 mutations of the phenylalanine hydroxylase gene had been identified, including 255 missense mutations, 22 nonsense mutations, and 47 splice-site mutations, among others.

Spontaneous mutations arise independently of their adaptive value and can be beneficial, harmful, or neutral. The majority of mutations are deleterious. This is because mutations occur within an integrated and coadapted genetic system, where each gene influences the entire system, and the system, in turn, affects each gene. This genetic system has evolved under the control of natural Selection to ensure the optimal adaptation of the population to its environment. Therefore, any alteration in the genetic system is more likely to be detrimental than beneficial. When harmful mutations manifest phenotypically, they fall under the scrutiny of natural selection and are eliminated through the death or reduced fecundity of their carriers. The eliminating action of natural selection in humans is especially pronounced during early embryonic development. While 41.5% of all pregnancies are terminated by spontaneous abortions, chromosomal abnormalities account for 5-6% of these—which is 10 times greater than the proportion of live-born children presenting with chromosomal syndromes (0.5-0.6% among live births). The spontaneous mutation rate depends on the age of the parents, particularly the fathers. In women over 35, the probability of giving birth to a child with Down syndrome increases sharply (p. 71).

Mutations are classified as dominant or recessive. Under conditions of complete dominance and full penetrance, dominant mutations manifest as early as the first generation, immediately subjecting them to positive or negative selection. The majority of mutations are recessive, persist in populations in a heterozygous state, remain phenotypically unexpressed, and are shielded from natural selection until they transition into the homozygous state (aa). In the heterozygous state, recessive mutations constitute a reservoir of hereditary variability that is utilized in each generation during sexual reproduction to generate novel gene combinations (new genotypes). METABOLISM/2.html">THE CONCEPT OF mutation "harmfulness" is relative to a degree. A recessive allele may be lethal in the homozygous state while promoting organismal survival in the heterozygous state.

Endogenous factors of spontaneous mutagenesis include: 1) DNA Replication errors; 2) DNA Repair errors; 3) DNA recombination errors; 4) the action of mutator and antimutator genes; 5) the transposition of Mobile Genetic Elements (MGEs).

Induced (artificial) mutations are caused experimentally by human intervention using mutagens at doses that intentionally exceed permissible levels. The frequency of induced mutations is several orders of magnitude higher than that of spontaneous mutations. Artificial mutagenesis serves as a vital source of starting material in plant and microorganism breeding.