Theoretical Basis of Mutagenesis

Summary

Mutations are changes in the hereditary material which are propagated throuah successive generations in cells and whole organisms. Mutations can occur spontaneously or under the influence of physical and chemical mutagenic agents. Depending on the type and size of the change in the genome we distinguish: point or gene mutations (base pair substitutions, frameshift mutations, small deletions), chromosome mutations or aberrations (e. g. , large deletions, translocations), aneuploidy (trisomy, monosomy, etc. ) and genome mutations (polyploidy). All these types of mutations are known to occur in man. Their phenotypic consequences can, even within one class of mutation, vary from lethality, malformations, and metabolic disorders to mild or even hardly detectable changes. Estimates suggest that a minimum of 10–11% of all live born will manifest at birth, or during development, or later in adulthood, a very wide range of serious genetic defects.

The mechanisms by which mutations are induced by mutagens are only poorly understood. A number of model systems (e.g., bacteria, fungi, insects, mammalian cells in culture) are suitable to study particular aspects of mutagenesis in prokaryotic and eukaryotic (nucleosomal) chromosomes.

In wild-type cells the induced frequency of a given type of mutation is the result of a complex interaction between normal DNA replication, error-free and error-prone DNA repair activities, and recombinational events. In some cases, in which the genetic control of the crucial steps is known (e.g., the rec-lex-dependent error-prone repair in E. coli), detailed and experimentally testable models could be worked out. In other cases (e.g., the induction of sister chromatid exchanges or chromosomal aberrations in eukaryotes) the models are less detailed. Some reasons for this are: the low number of suitable mutants available; multiple types of mutations induced by one particular mutagen; and difficulty in identifying the premutational lesion(s), particularly because of the insensitivity of the available biochemical assays. The complexity of the chemical mutagenesis is also reflected in the observation that differnt mechanisms can lead to the same type of mutation, e.g., the induction of chromosome aberrations is dependent on the normal S-phase DNA-synthesis with some agents but not with others. In addition, not only primary DNA damage (such as strand breaks, covalently bound mutagens, intercalations) but also non-DNA damage (e.g., effects of metals on the enzymes of DNA-synthesis, or interaction of spindle poisons with the polymerization of microtubules, or nucleotide pool imbalances) can lead to mutations.

A discussion of some models of the productions of different types of mutation illustrates our present knowledge on basic mutation mechanisms in pro- and eukaryotes. The importance of the knowledge of these mechanisms for genetic toxicology has to be stressed. Vfe can learn more about the types of lesions for which we should look in mutagenicity screening tests, and we can approach the construction of better defined and more sensitive test systems and test batteries.