Types of Mutations

Mutations can be categorized in several ways. One system is based on the nature of the change, specifically on the number of bases changed. Thus, we distinguish a point mutation, in which a single base pair is changed from a multiple mutation, in which two or more base pairs differ from the wild-type sequence. A point mutation may be a base substitution, a base insertion, or a base deletion, but the term most frequently refers to a base substitution. 

A second system is based on the consequence of the change in terms of the amino acid sequence that is affected. For example, if there is an amino acid substitution, the mutation is a missense mutation. If the substitution produces a protein that is active at one temperature (typically 30°C) and inactive at a higher temperature (usually 

Two mechanisms of 5-bromouracil (BU)-induced mutagenesis, (a) During replication, BU in its usual keto form substitutes for T, and the replica of an initial A-T pair becomes an A-BU pair. In the first mutagenic round of replication, BU in its rare enol form pairs with G. In the next round of replication, the G pairs with a C, completing the transition from an A-T pair to a G-C pair, (b) During replication of a G-C pair, a BU in its rare enol form pairs with a G. In the next round of replication, the BU is again in the common keto form and it pairs with A, so the initial G-C pair becomes all A-T pair. The replica of the A-BU pair produced in the next round of replication is another A-T pair. 

40-42°C), the mutation is cdX cd temperature-sensitive (Ts) mutation. Sometimes no amino acid corresponds to a new base sequence (Chapter 25) in that case, termination of synthesis of the protein occurs at that point, and the mutation is called a chain termination mutation or nonsense mutation. These mutations generate one of the three nonsense codons UAA, UAG, or UGA (Chapter 25). 

Replication errors can be introduced by base analogues that can be added to a replicating DNA molecule. Such a base analogue must be able to pair with the base on the complementary strand being copied, or the 3 5  

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Both types of mutations have been made in T4 lysozyme. The chosen mutations were Gly 77-Ala, which caused an increase in Tm of 1 °C, and Ala 82-Pro, which increased Tm by 2 °C. The three-dimensional structures of these mutant enzymes were also determined the Ala 82-Pro mutant had a structure essentially identical to the wild type except for the side chain of residue 82 this strongly indicates that the effect on Tm of Ala 82-Pro is indeed due to entropy changes. Such effects are expected to be additive, so even though each mutation makes only a small contribution to increased stability, the combined effect of a number of such mutations should significantly increase a protein s stability. 

Viruses that contain amino acid substitutions in the sialidase that impart resistance to the developed inhibitors have been isolated from serial passage of virus in the presence of drug in cell culture and from the clinical setting (reviewed in McKimm-Breschkin 2000 Zambon and Hayden 2001 Cinatl et al. 2007a Reece 2007). In addition, influenza B virus variants with reduced drug sensitivity have been isolated from previously untreated patients (Hurt et al. 2006 Hatakeyama et al. 2007). The types of mutations that are observed are sub-type specific. The mutations present in variants isolated from clinical samples are shown in Table 1, and their locations within the sialidase active site are shown diagrammatically in Fig. 9. 

Mutations may be produced in many ways. Bases may be deleted or new ones may be inserted more frequently an existing base may be chemically modified so that on replication, improper base pairing will cause a different base to appear at the modified position. The latter type of mutation is called a replacement. When a purine is replaced by another purine or a pyrimidine by a different pyrimidine, the change is called a transition. A transversion is a change from pyrimidine to purine or purine to pyrimidine. 

Heath KE, Gudnason V, Humphries SE, Seed M. The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. Atherosclerosis 1999 143 41-54. 

Both types of mutation result in an altered polypeptide, which, in turn, can have a marked effect on the phenotype of the affected cell. Much use of phenotypic changes is made in mutagenicity tests. 

Base substitutions and frameshift changes occur spontaneously and can be induced by radiation and chemical mutagens. It is apparent that the molecular mechanisms resulting in these changes are different in each case, but the potential hazards associated with mutagens capable of inducing the different types of mutation are equivalent. 

Gene mutations occur in two ways they can be inherited from a parent or acquired during a person s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person s life in virtually every cell in the body. 

Missense mutation This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene. 

Duplication A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein. 

Repeat expansion Nudeotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinudeotide repeat is made up of 3-base-pair sequences, and a tetranudeotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. 

Frameshift A type of mutation which causes out-of-phase transcription of the base sequence such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH]... 

Frameshift Mutation A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH]... 

All these techniques create genetic diversity by recombination and point mutations and are well developed. However, insertions and deletions (indels) are also important types of mutation which are probably underrepresented in many conventional mutagenesis strategies. Methods for incorporation of indels in predefined positions in a combinatorial manner have been developed.Although there are some published studies on their use in the directed evolution of biocatalysts,the full potential of these newer methods of gene mutation for enzyme improvement are yet to be demonstrated. 

A very common type of mutation is a single base alteration or point mutation. 

Table 1-4-1. Effect of Some Common Types of Mutations on Protein Structure...

Several inherited cancer syndromes are also known to result from mutations in proto-oncogenes. An example is given by the RET proto-oncogene. Depending on the type of mutation and on which part of the gene is affected, RET mutations can lead to multiple endocrine neoplasia 2A or 2B or familial medullary thyroid carcinoma. These familial cancers are inherited in autosomal dominant fashion. A second example is the CDK4 proto-oncogene, which when mutated can cause familial melanoma. 

Finally, mouse studies have confirmed the hypothesis that RUNXl mutations are initiating events - but require secondary mutations for acute leukemia induction. A major emphasis of current work is to determine what type of mutations collaborate with RUNXl mutations to induce an acute leukemia. Screening of patient samples have underlined the importance of mutations in receptor tyrosine kinases (RTK) in these leukemia. Interestingly, mutations in the KIT receptor are relative rare in AML, but reach an incidence of circa 45% in AML with CBF mutations, perhaps reflecting high levels of KIT expression... 

PAH bind to the Ah receptor, this effect is not the only effect that determines the carcinogenic potency of PAH. DNA binding and induction of mutations are other significant effects in the carcinogenesis of PAH, and there is no indication that different PAH are activated via the same metabolic route, binds DNA in the same positions, and induce the same types of mutations in the same organs or tissues. In fact, the study by Culp et al. (1998) showed that a coal-tar mixture of PAH also produced tumors in other tissues and organs than those affected by benzo[a]pyrene alone, and that the additional PAH in the mixture did not significantly contribute to the incidence of stomach tumors observed after benz[a]pyrene alone. 

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

This amino acid substitution arose from what type of mutation ... 

Nucleotide Type of mutations Alteration of amino acid... 

The molecular basis of medium chain acyl-CoA dehydrogenase deficiency survey and evolution of 985A—G transition, and identification of five rare types of mutation within the medium chain acyl-CoA dehydrogenase gene. 

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