Base substitution, mutations occurring

Mutations occur by substitution, insertion, or deletion of bases. Substitution mutations are the most common types of mutation. A substitution mutation, involving the substitution of one base by another, changes one codon in mRNA. This may or may not alter the amino acid residue specified by that codon because of the degeneracy of the genetic code. 

This then leads on further replication to the replacement of the original GC pair by an AT palr-a base substitution mutation. Whether such mutations need to occur in particular regions of the DNA is not yet clear. 

Point mutations can occur when one base is substituted for another (base substitution). Substitution of another purine for a purine base or of another pyrimidine for pyrimidine is called a transition, while substitutions of purine for pyrimidine or pyrimidine for purine are called transversions. Both types of base substitution have been identified within mutated genes. These changes lead to a codon change which can cause the wrong amino acid to be inserted into the relevant polypeptide and are known as mis-sense mutations. Such polypeptides may have dramatically altered properties if the new amino acid is close to the active center of an enzyme or affects the three-dimensional makeup of an enzyme or a structural protein. These changes, in turn, can lead to change or reduction in function, which can be detected as a change in phenotype of the affected cells. 

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. 

Studies with mutated (base substitution) 30-mer synthetic oligonucleotides revealed differences for 3, 2 and 1 mismatched strands. The type of interaction that disappears and the possible new interactions that are generated when a base substitution occurs are of importance. One mismatch is detected even if it is located extreme far from the electrode, being the attenuation of the signal lower than when the substitution occurs near the electrode surface (Fig. 26.5). Moreover,... 

The 12 possible types of nucleotide substitution can be treated differently (assuming nonsymmetry of change, e.g., the frequency of A to C does not equal that for C to A) or treated equally, or any combination of these substitutions can be grouped. One obvious division of base substitutions is to treat transitions (changes of purine to purine or pyrimidine to pyrimidine) separately from transversions (change of purine to pyrimidine or vice versa). Insertion/deletion events can also be treated as a separate type of mutation. Additionally, nucleotide substitutions can be preferentially treated by a combination of position and mutation (e.g., transversions occurring in the first and second codon positions). 

Ames developed strains of bacteria that had carefully selected lethal mutations. In a test system the bacteria could survive only when its mutation had been corrected by experiencing another mutation caused by the tested material. This correction could be accomplished by causing a point mutation or frameshift mutations . Point mutations are base-pair substitutions, that is, a base change in DNA of at least one DNA base pair. In a reverse mutation test, this change in base pairs may occur at the site of the original mutation, or at a secondary site in the bacterial genome. Frameshift mutations are the addition or deletion of one or more base pairs in the DNA. Since amino acids are encoded by triplets of base pairs in sequence, any addition or deletion of 1 or 2 base pairs will dramatically alter the expressed protein from that point on. The Ames system employs strains of Salmonella typhimurium and Escherichia coli that require amino acids (histidine or tryptophan, respectively) to detect such reverse point and frameshift mutations. The reverse mutation allows the S. typhimurium or E. coli strains to restore the functional capability of the bacteria to be able to synthesize the specific amino acid on their own, independent of amino acid content in the medium. 

Among the human tumor mutations identified by sequencing, 87.2% are single base substitutions and 12.8% are complex mutations and short deletions or insertions. Missense mutations have been observed at 231 of the 393 codons, including all the codons of the DNA-binding domain except codon 123. This codon (ATC, threonine) is well conserved in evolution, but experimental mutation (to Alanine) at this codon has been shown to activate, rather than suppress DNA-binding activity (Freeman et al., 1994). The vast majority of the mutated codons are recurrent mutation sites that are likely to result in dysfunctional p53. Silent mutations represent up to 3.9% of the mutations in the database and it is possible that mutations occurring at rare... 

In a reversion assay, restoration of a mutated gene activity only occurs if the mutagen produces mutations of the same type, (base-substitution or frame-shift) as the revertible mutation carried by the indicator strain. In the Ames assay this problem is circumvented by using different indicator strains, some of which are reverted by base-substitution mutagens and others which are preferentially reverted by different types of frameshift mutagens. ... 

Reflect and Apply Consider a three-base sequence in the template of DNA 5. . . 123. .. 3, in which 1, 2, and 3 refer to the relative positions of deoxyribonucleotides. Comment on the probable effect on the resulting protein if the following point mutations (one-base substitutions) occurred. 

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