Mutagenesis

Mutagenesis /mjuːtəˈdʒɛnɪsɪs/ is a process by which the genetic information of an organism is changed, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. In nature mutagenesis can lead to cancer and various heritable diseases, but it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century. Mutagenesis /mjuːtəˈdʒɛnɪsɪs/ is a process by which the genetic information of an organism is changed, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. In nature mutagenesis can lead to cancer and various heritable diseases, but it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century. DNA may be modified, either naturally or artificially, by a number of physical, chemical and biological agents, resulting in mutations. Hermann Muller found that 'High temperatures' have the ability to mutate genes in the early 1920s, and in 1927, demonstrated a causal link to mutation upon experimenting with an x-ray machine and noting phylogenetic changes when irradiating fruit flies with relatively high dose of X-rays. Muller observed a number of chromosome rearrangements in his experiments, and suggested mutation as a cause of cancer. The association of exposure to radiation and cancer had been observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen and radioactivity by Henri Becquerel. Muller's contemporary Lewis Stadler also showed the mutational effect of X-ray on barley in 1928, and ultraviolet (UV) radiation on maize in 1936. In 1940s, Charlotte Auerbach and J. M. Robson, found that mustard gas can also cause mutations in fruit flies. While changes to the chromosome caused by X-ray and mustard gas were readily observable to the early researchers, other changes to the DNA induced by other mutagens were not so easily observable, and the mechanism may be complex and takes longer to unravel. For example, soot was suggested to be a cause of cancer as early as 1775, and coal tar was demonstrated to cause cancer in 1915. The chemicals involved in both were later shown to be polycyclic aromatic hydrocarbons (PAH). PAHs by themselves are not carcinogenic, and it was proposed in 1950 that the carcinogenic forms of PAHs are the oxides produced as metabolites from cellular processes. The metabolic process was identified in 1960s as catalysis by cytochrome P450 which produces reactive species that can interact with the DNA to form adducts,; the mechanism by which the PAH adducts give rise to mutation, however, is still under investigation. Mammalian nuclear DNA may sustain more than 60,000 damage episodes per cell per day, as listed with references in DNA damage (naturally occurring). If left uncorrected, these adducts, after misreplication past the damaged sites, can give rise to mutations. In nature, the mutations that arise may be beneficial or deleterious—this is the driving force of evolution. An organism may acquire new traits through genetic mutation, but mutation may also result in impaired function of the genes, and in severe cases, cause the death of the organism. Mutation is also a major source for acquisition of resistance to antibiotics in bacteria and possibly to antifungal agents in yeasts. In the laboratory, however, mutagenesis is a useful technique for generating mutations that allows the functions of genes and gene products to be examined in detail, producing proteins with improved characteristics or novel functions, as well as mutant strains with useful properties. Initially, the ability of radiation and chemical mutagens to cause mutation was exploited to generate random mutations, but later techniques were developed to introduce specific mutations. Humans on average naturally pass 60 new mutations to their children but fathers pass more mutations depending on their age, transmitting an average of two new mutations with every additional year of their age to the child. DNA damage is an abnormal alteration in the structure of DNA that cannot, itself, be replicated when DNA replicates. In contrast, a mutation is a change in the nucleic acid sequence that can be replicated; hence, a mutation can be inherited from one generation to the next. Damage can occur from chemical addition (adduct), or structural disruption to a base of DNA (creating an abnormal nucleotide or nucleotide fragment), or a break in one or both DNA strands. When DNA containing damage is replicated, an incorrect base may be inserted in the new complementary strand as it is being synthesized (see DNA repair § Translesion synthesis). The incorrect insertion in the new strand will occur opposite the damaged site in the template strand, and this incorrect insertion can become a mutation (i.e. a changed base pair) in the next round of replication. Furthermore, double-strand breaks in DNA may be repaired by an inaccurate repair process, non-homologous end joining, which produces mutations. Mutations can ordinarily be avoided if accurate DNA repair systems recognize DNA damage and repair it prior to completion of the next round of replication. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in the 5 types of DNA repair processes indicated in the chart shown in the article DNA repair. Mutagenesis may occur endogenously, for example, through spontaneous hydrolysis, or through normal cellular processes that can generate reactive oxygen species and DNA adducts, or through error in replication and repair. Mutagenesis may also arise as a result of the presence of environmental mutagens that induce changes to the DNA. The mechanism by which mutation arises varies according to the causative agent, the mutagen, involved. Most mutagens act either directly, or indirectly via mutagenic metabolites, on the DNA producing lesions. Some, however, may affect the replication or chromosomal partition mechanism, and other cellular processes. Mutagenesis may also be self-induced by unicellular organisms when environmental conditions are very restrictive, for instance, in presence of toxic substances like antibiotics or, in yeasts, in presence of an antifungal agent or in absence of a nutrient Many chemical mutagens require biological activation to become mutagenic. An important group of enzymes involved in the generation of mutagenic metabolites is cytochrome P450. Other enzymes that may also produce mutagenic metabolites include glutathione S-transferase and microsomal epoxide hydrolase. Mutagens that are not mutagenic by themselves but require biological activation are called promutagens.