frameshift mutation

A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels, ie. insertion or deletion 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 disrupt the reading frame, or 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 causes the reading of all codons after the mutation to code for different amino acids (with a few exceptions due to redundancy). Furthermore, the stop codon ("UAA", "UGA" or "UAG") will not be read or a stop codon could be created at an earlier or later site. The protein being created could be abnormally short, abnormally long, and/or contain the wrong amino acids. It 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 can also be beneficial. For example, a frameshift mutation was responsible for the creation of nylonase.

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 of Frameshift Mutations

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. ^[1] 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.^[2]

See also

Frameshift

References

• Farabaugh, P. J. (1996), "Programmed translational frameshifting", Microbiol. Rev. 60: 103-104 
• Lewis, R. (2005), Human Genetics: Concepts and Applications (6th ed.), New York: McGraw Hill 
• Nylonase Enzymes, 04-2004, http://www.talkorigins.org/origins/postmonth/apr04.html, retrieved 02-06-2009 

External links

• MeSH Frameshift+Mutation
• NCBI dbSNP database — "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"
• Wise2 - aligns a protein against a DNA sequence allowing frameshifts and introns
• FastY - compare a DNA sequence to a protein sequence database, allowing gaps and frameshifts
• Path - tool that compares two frameshift proteins (back-translation principle)