Frameshift mutations, protein

The conversion of a functional into a pseudogene most frequently results from mutations such as frameshift mutations or deletions. Even though pseudogenes might still have some retained functionality such as promoter-or enhancer-like features, they are usually classified as pseudogenes upon their lack of protein-coding ability. 

For example, c-Fos is heavily phosphorylated on a series of serine residues in the C-terminal domain of the protein by several types of protein kinases. The likely functional importance of these phosphorylation sites is indicated by the fact that the difference between c-Fos (the normal cellular form of the protein) and v-Fos (the viral oncogene product) is a frameshift mutation in the v-Fos protein, which obliterates the phosphorylated serine residues. It is speculated that the loss of these phosphorylation sites removes one mechanism by which the cell can regulate the protein, thereby leading to cellular transformation. 

Two mutations were identified a splice variant that eliminated an exon and a frameshift mutation that truncated the protein. The linkage between the pseudogene polymorphism and these mutations was much stronger in Caucasians than African Americans. Thus a test for the pseudogene polymorphism in African Americans would have lower predictive values than in Caucasians. 

The answer is C. Production of a truncated protein indicates that a mutation has occurred, but this phenomenon may have arisen from a frameshift mutation (insertion or deletion) or by a nonsense mutation. The most likely possibility is a nonsense mutation because sequence analysis of the truncated protein showed that it had normal (wild-type) sequence. Insertion and deletion events often produce a stretch of garbled or abnormal protein sequence at the C-terminal end of the truncated protein arising from out-of-frame translation of the mRNA downstream of the mutation until a stop codon is encountered. 

Frameshift mutations. Insertions or deletions of genetic material that lead to a shift in the translation of the reading frame. The mutation usually leads to nonfunctional proteins. 

The loss or gain of one or two base pairs in a gene causes an incorrect reading of the DNA and is known as a frameshift mutation. This is illustrated in Figure 8.2, which shows the insertion of a single base pair into a gene. It is seen that subsequent codons are changed, which almost always means that there are nonsense codons that specify no amino acid. So either no protein or a useless protein is likely to result. 

Figure 8.2 Illustration of a frameshift mutation in which a base pair is inserted into a DNA sequence, altering the codons that code for kinds of amino acids in a protein.

Gene mutations include base pair substitutions and frameshift mutations, where base pair substitutions arise from the substitution of one or several base pairs in the DNA, and frameshift mutations arise from an insertion or deletion involving a number of base pairs that is not a multiple of three and consequently disrupts the triplet reading frame, usually leading to the creation of a premature termination (stop) codon and resulting in a truncated protein product. 

Frameshift Mutation. Deletion or insertion of a base or bases that alters the reading frame of the gene. In contrast to base substitution mutations where the mutation often has no consequence to the gene function or has only a partial effect on the gene function, a frameshift mutation completely changes the amino acid sequence downstream of the mutation site within a proteincoding gene. Thus, frameshift mutation is a severe type of mutation, which results in inactivation of the protein product most of the time. 

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. 

Studies on PAP families indicate that a wide variety of germline mutations exist >95% result in truncated proteins, either because of a nonsense mutation (30%) or by a frameshift mutation, and most are contained within the 5 -haIf of the gene. In germiine mutations there are two hot spots at codons 1061 and 1309, with the most common mutation being an AAAAG deletion at codon 1309. These mutations leave the truncated APC protein unable to regulate p-catenin. 

Frameshift mutations almost always result in destruction of protein function. 

A frameshift mutation occurs when the number of inserted or deleted nucleotides is not a multiple of three (Fig. 15.4). The reading frame shifts at the point where the insertion or deletion begins. Beyond that point, the amino acid sequence of the protein translated from the mRNA differs from the normal protein. 

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