Mutation can be described as a change in the nucleotide sequence of DNA. It can occur either spontaneously or is induced by the environment. These changes, if occur in gametes, are inherited from one generation to the succeeding ones. Mutations are of many types such as frameshift mutation (insertion or deletion of nucleotides), base pair substitutions (a purine or a pyrimidine is substituted by another purine or pyrimidine), and chromosomal rearrangement (inversion or translocation of multiple genes).
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A change in the DNA sequence may the alter the process of transcription and DNA replication. In addition, it can also change the structure of the proteins being synthesized and thus hamper the biological functions. In certain cases, where no phenotypical changes occur due to mutation, these changes are known as silent mutation.
Changes in the DNA sequence are usually brought about by certain biological processes such as spontaneous DNA hydrolysis, error in the DNA replication, recombination, and repair of damaged DNA. The frequency of these mutations is usually 10-9. Certain agents, however, may cause or increase the frequency the mutations. These agent are known as mutagens. A mutagen can therefore be defined as an agent that can bring about a change in the nucleotide sequence in the DNA of an organism. Mutagens cause deleterious changes in the DNA that may lead to cancer, and are known as carcinogens.
Mutagens may directly damage the DNA. Sometimes, certain agents (promutagens) are taken up by living cells to produce certain metabolites that can in turn act as a mutagen. There are three types of mutagens.
◆ Ultraviolet radiations of above 260 nm induce certain molecular lesions in the DNA known as pyrimidine dimers. In, this, adjacent thymine and cytosine bases form covalent bonds with each other. Cyclobutane pyrimidine dimers and 6,4 photoproducts are the common products formed.
◆ Ionizing radiations such as X-rays and gamma rays usually cause breakage in the DNA strand. Exposure to such radiations may have deterministic effect, in which most cells are either severely damaged or killed. Sometimes, these may have a stochastic effect, leading to cancer and may be alterations in the DNA of gametes. After exposure to ionizing radiations, it may take several years for cancer to manifest itself.
◆ Sometimes, radioactive decay may change isotopic carbon 14C to nitrogen.
Certain chemicals agents react with DNA in a number of ways to give rise to a change in the DNA sequence.
◆ Reactive oxygen species (ROS) are chemical like superoxides, hydrogen peroxide, and hydroxyl radicals. These chemicals give the formation of many base adducts, cross linkages, and nicks in the DNA.
◆ Deaminating chemicals like bisulfite and nitrous hydrolyze cytosine to uracil and release ammonia in the process.
◆ Base analogs are chemicals that are structurally similar to the nucleotide bases and are sometimes substituted in place of the nucleotide bases, 2-aminopurine and bromouracil are common examples of these chemical agents.
◆ Certain alkylating agents like N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), Ethylmethane sulfonate (EMS), and Ethylethane sulfonate (DES) transfer a methyl or an ethyl group to the bases or the phosphate groups, leading to a mismatch pairing, DNA cross linking, and nicks in the DNA.
◆ Intercalating agents like acridine orange, proflavine, and ethidium bromide get inserted in between the nitrogenous bases in the DNA and induce a frameshift mutation in the DNA.
◆ Viruses usually infect host cells and inject their genetic material into the host genome, this may sometimes cause a change in the host cells and may transform them into a cancerous cells. Examples of such viruses are Human papilloma virus, Kaposi's sarcoma-associated herpesvirus, hepatitis C virus, etc.
◆ Infection of bacteria like Helicobacter pylori has been associated with bringing about an alteration in the host genome and an increased prevalence of gastric cancer. Further, it is suspected that the metabolic derivative of the bacterial cytotoxin may directly damage the DNA.
◆ Transposons are DNA sequences that can remove or insert themselves in the genome. They are also known as jumping genes. As transposons move from one part of the DNA to the other, they tend to create some changes in the genome giving rise to mutations and alteration of the genome.
Although mutagens may have deleterious effect in nature, mutagens such as cisplatin, doxorubicin, and ionizing radiations have been applied in the destruction of cancer cells.