Frameshift Mutation- Definition, Causes, Mechanism, Applications, Examples

Frameshift mutation definition

A frameshift mutation is a type of genetic mutation resulting from the alteration of a number of nucleotides in DNA sequences that are not multiple of three.

  • Frameshift mutation occurs as a result of a change in the reading frame of the sequence. Since the codons for gene expression occur in the form of triplets, the difference in nucleotides results in the change in the frame.
  • As a result of the change in the reading frame, a completely different translation product will be formed.
  • The effect of the change in the reading frame depends on the position of the changed nucleotide. If the change occurs earlier in the sequence, more altered protein is produced.
  • During a frameshift mutation, the nucleotide is inserted or deleted rather than replaced. A frameshift mutation results in change once the codons are read after mutation to produce different amino acids.
  • There are cases where a stop codon might be produced during a frameshift mutation which results in an abnormally short or abnormally long non-functional protein product.
  • Even though frameshift mutations are more complex than single nucleotide polymorphism, these can, however, result from the addition or removal of a single nucleotide.
  • Frameshift mutations only occur in the coding region of the DNA sequence as the changes in the non-coding or regulatory regions of the genome produce no change in the protein.

Causes of Frameshift Mutation

  • Frameshift mutations are caused by the addition or deletion of nucleotides from a DNA sequence, resulting in the shift of frame.
  • Substitution cannot result in frameshift mutation as it requires the production of a completely different amino acid product.
  • In some cases, the mutation might be spontaneous, resulting from some mistake during the processing of the DNA.
  • The change in DNA sequence can occur either at a particular point or over a region of the sequence. The change causes a shift in the reading frame to produce a different product.
  • Besides, frameshift mutation can also occur via induced mutation in the presence of physical agents like X-ray and UV radiation.
  • Frameshift mutation might also be induced by the production of molecules like reactive oxygen species that influence DNA composition.
  • Frameshift mutations can occur in both the single-stranded and double-stranded DNA as a result of different causes.

Mechanism of Frameshift Mutation

The mechanism of frameshift mutation depends on the cause of the mutation. But the following are some of the possible mechanisms of frameshift mutation;

1. Deletion

  • Deletion of the DNA segment occurs in anaphase movement or during reorganizing of the nuclei or digestion by nucleases.
  • Deletion can either be terminal or intercalary, where the terminal deletion results from the removal of the terminal section of a chromosome.
  • The intercalary deletion occurs as a result of the loss of an intermediate section or portion of the chromosome.
  • Deletion is the more common mechanism of frameshift mutation that produces a change in the reading frame.
Frameshift Mutation
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2. Insertion

  • Insertion is the addition of nucleotides into a DNA sequence in a way that changes the reading frame of the sequence.
  • It occurs within the microsatellite regions of the DNA in the presence of DNA polymerase. The number of nucleotides and the position of insertion can be different and also determines the severity of the mutation.
  • Usually, insertion and subsequent frameshift mutation cause the active translation of a gene while producing a premature stop codon.

Applications of Frameshift Mutation

The following are some of the applications of frameshift mutations;

  1. Frameshift mutations have been associated with several diseases, thus these can be used as a method of diagnosis of such diseases.
  2. Frameshift mutation can also be induced as a form of molecular therapy to cure and prevent different hereditary and genetic diseases.
  3. Frameshift mutation can also be used as a means to target cancer cells and their proteins to prevent such diseases.
  4. Frameshift mutation, when induced under controlled conditions, can be used as a means of mutation breeding to produce new and improved crops.
  5. These can also be used in studies related to the structure, function, and stability of different proteins.
  6. Some of the frameshift mutations can be beneficial as they might increase the fitness of the organism in the ecosystem. 

Examples of Frameshift Mutation

  • An example of frameshift mutation can be observed in the case of Crohn’s disease. The disease is associated with the NOD2 gene.
  • A mutation occurs due to the insertion of the cytosine nucleotide at the 3020 position on the gene.
  • This changes the codon to a stop codon which then results in the formation of a shortened protein. 
  • The change in the structure of the protein then affects its function, which is to respond to bacterial liposaccharides.
  • The mutation doesn’t affect the gene sequence at the multiple of three, which is responsible for the frameshift mutation and the eventual disease.

References

  1. Verma PS and Agarwal VK (3005). Cell Biology, Genetics, Molecular Biology, Evolution and Ecology. Multicoloured Edition
  2. Sheetlin, Sergey L et al. “Frameshift alignment: statistics and post-genomic applications.” Bioinformatics (Oxford, England) vol. 30,24 (2014): 3575-82. doi:10.1093/bioinformatics/btu576
  3. García-Barreno, B et al. “Frame shift mutations as a novel mechanism for the generation of neutralization resistant mutants of human respiratory syncytial virus.” The EMBO journal vol. 9,12 (1990): 4181-7. doi:10.1002/j.1460-2075.1990.tb07642.x.

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