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Molecular Biology and Genetics
MBG 2040
Dennis Baker

Chapter 13: Mutation The term mutation refers to both (1) the change in the genetic material and (2) the process by which the change occurs. Mutations that involve changes at specific sites in a gene are referred to as point mutations. They include the substitution of one base pair for another or the insertion or deletion of one or a few nucleotide pairs at a specific site in a gene. Without mutation, all genes would exist in only one form no alleles Some level of mutation is essential to provide new genetic variability so populations can evolve and adapt BUT if mutations occur too frequently, they disrupt the transfer of genetic information from generation to generation. Rate of mutation is influenced by genetic factors and mechanisms have evolved that regulate the level of mutation that occurs under various environmental conditions. Point mutations are of three types: (1) transitionspurine for purine and pyrimidine for pyrimidine substitutions; (2) transversionspurine for pyrimidine and pyrimidine for purine substitutions; and (3) frameshift mutationsadditions or deletions of one or two nucleotide pairs, which alter the reading frame of the gene distal to the site of the mutation. Structures of the bases in DNA are not static. Tautomeric shifts: when Hydrogen atoms move from one position in a purine or pyrimidine to another position they are rare and of considerable importance in DNA metabolism because some alter the pairing potential of the bases. Keto forms of thymine and guanine may undergo tautomeric shifts to less stable enol forms. Amino forms of adenine and cytosine may undergo tautomeric shifts to less stable imino forms. If a base existed in the rare form at the moment that it was being replicated or incorporated into a nascent DNA chain, a mutation would result. When present in their rare imino or enol states, they can form A-C and G-T base pairs. The net effect of such an event, and the subsequent replication required to segregate the mismatched base pair, is an A:T to G:C or a G:C to A:T base-pair substitution. Transitions: mutations resulting from tautomeric shifts in the bases of DNA involve the replacement of a purine in one strand of DNA with the other purine and the replacement of a pyrimidine in the complementary strand with the other pyrimidine. Transversions: base-pair substitutions involving the replacement of a purine with a pyrimidine and vice versa There are 3 substitutionsone transition and two transversionspossible for every base pair. A total of four different transitions and eight different transversions are possible. Frameshift mutations: base-pair additions and deletions within the coding regions of genes. They alter the reading frame of all base- pair triplets (DNA triplets that specify codons in mRNA and amino acids in the polypeptide gene product) in the genes that are distal to the site at which the mutation occurs. Almost always result in the synthesis of nonfunctional protein gene products. Transitions, transversions, and frameshift mutations are all spontaneously occurring mutations. A large proportion of the spontaneous mutations studied in prokaryotes are single base-pair additions and deletions rather than base-pair substitutions. Although much remains to be learned about the causes, molecular mechanisms, and frequency of spontaneously occurring mutations, three major factors are (1) the accuracy of the DNA replication machinery, (2) the efficiency of the mechanisms that have evolved for the repair of damaged DNA, and (3) the degree of exposure to mutagenic agents present in the environment. Perturbations of the DNA replication apparatus or DNA repair systems, both of which are under genetic control, have been shown to cause large increases in mutation rates. Induced mutations: mutational dissection: can induce mutations, knockouts, and study the effects to figure ut function of wildtype. Can use X-rays as mutagens on Drosophila, plants, animals, microbes. Chemical mutagens Mutagenic to both replicating and nonreplicating DNA, such as the o Alkylating agents: chemicals that donate alkyl groups to other molecules. (Nitrogen mustard, and methyl and ethyl methane sulfonate (MMS and EMS)). Induce all types of mutations, including transitions, transversions, frameshifts, and even chromosome aberrations, with relative frequencies that depend on the reactivity of the agent involved. Alkylating agents as a class therefore exhibit less specific mutagenic effects than do base analogs, nitrous acid, or acridines. One mechanism involves the transfer of methyl or ethyl groups to the bases, resulting in altered base- pairing potentials. EMS causes ethylation of the bases in DNA at the 7-N and the 6-O positions. When 7- ethylguanine is produced, it base-pairs with T to cause G:C A:T transitions. Other base alkylation products activate error-prone DNA repair processes that introduce transitions, transversions, and frameshift mutations during the repair process. Some alkylating agents, particularly those with two reactive alkyl groups, cross-link DNA strands or molecules and induce chromosome breaks. The hydroxylating agent hydroxylamine (NH2OH) has a specific mutagenic effect. It induces only G:C A:T transitions. Because of its specificity, hydroxylamine has been very useful in classifying transition mutations. Mutations that are induced to revert to wild-type by nitrous acid or base analogs, and therefore were originally caused by transitions, can be divided into two classes on the basis of their revertibility with hydroxylamine. (1) Those with an A:T base pair at the mutant site will not be induced to revert by hydroxylamine. (2) Those with a G:C base pair at the mutant site will be induced to revert by hydroxylamine. Thus, hydroxylamine can be used to determine whether a particular mutation was an A:T G:C or a G:C A:T transition. o Nitrous acid: causes oxidative deamination of the amino groups in A, G and C. This reaction converts the amino groups to keto groups and changes the hydrogen-bonding potential of the modified bases. Induces transitions in both directions, A:T G:C. As a result, nitrous acid-induced mutations also are induced to mutate back to wild- type by nitrous acid. Adenine is deaminated to hypoxanthine, which base-pairs with C rather than T. results in A:T G:C transitions, Cytosine is converted to uracil, which base-pairs with A instead of G. produces G:C A:T transitions Deamination of guanine produces xanthine, but xanthinejust like Gbase-pairs with C. Thus, the deamination of guanine is not mutagenic. Mutagenic only to replicating DNA, o Base analogs: purines and pyrimidines with structures similar to the normal bases in DNA that are incorporated into DNA chains in the place of normal bases during replication and have mutagenic effects. Their structure is sufficiently different from the normal bases in DNA that they increase the frequency of mispairing, and thus mutation, during replication. The two most commonly used bas
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