Frameshift mutation

A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (insertions or deletions) of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can change the reading frame (the grouping of the codons), resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is.

A frameshift mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The framshift mutation will also alter the first stop codon ("UAA", "UGA" or "UAG") encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional.

Frameshift mutations frequently result in severe genetic diseases such as Tay-Sachs disease. A frameshift mutation is responsible for the disabling of the CCR5 HIV receptor and some types of familial hypercholesterolemia (Lewis, 2005, p. 227-228). Frameshift mutations have also been proposed a source of biological novelty, as with the alleged creation of nylonase. However, a study by Negoro et al (2006) found that a frameshift mutation was unlikely to have been the cause and that rather a two amino acid substitution in the catalytic cleft of an ancestral esterase amplified Ald-hydrolytic activity.

Frameshifting may also occur during protein translation, producing different proteins from overlapping open reading frames, such as the gag-pol-env retroviral proteins. This is fairly common in viruses and also occurs in bacteria and yeast (Farabaugh, 1996).

A frameshift mutation is not the same as a single-nucleotide polymorphism in which a nucleotide is replaced, rather than inserted or deleted.

Thermodynamics
The effects of neighboring bases and secondary structure on the frequency of frameshift mutations has been investigated in depth. Fluorescently tagged DNA, by means of base analogues, permits one to study the local changes of a DNA sequence. Studies on the effects of the length of the primer strand reveal that an equilibrium mixture of four hybridization conformations was observed when template bases looped-out as a bulge, i.e. a structure flanked on both sides by duplex DNA. In contrast, a single-loop structure with an unusual unstacked DNA conformation at its downstream edge was observed when the extruded bases were positioned at the primer–template junction, showing that misalignments can be modified by neighboring DNA secondary structure.