Frameshift Mutation: Definition, Causes, Mechanism, Applications & Example

Table of Contents

• Frameshift mutation definition
• Causes of Frameshift Mutation
• Mechanism of Frameshift Mutation
• Applications of Frameshift Mutation
• Examples of Frameshift Mutation
• References

Frameshift mutation definition

• A frameshift mutation is a genetic mutation caused by the insertion or deletion of nucleotides in a DNA sequence, where the number of nucleotides altered is not a multiple of three.
• This type of mutation leads to a shift in the reading frame of the genetic sequence during translation, disrupting the normal codon pattern.
• Since genetic information is read in codons (triplets of nucleotides), any change not in a multiple of three alters the grouping of the codons, which changes the downstream amino acid sequence.
• As a result of this shift in the reading frame, an entirely different polypeptide chain (translation product) is formed, often with altered or non-functional properties.
• The extent of the mutation's effect depends on the position within the sequence where the nucleotide change occurs; if the mutation happens early in the sequence, a larger portion of the resulting protein will be altered.
• Unlike point mutations, which typically involve the replacement of a nucleotide, frameshift mutations involve the insertion or deletion of nucleotides.
• These changes cause a re-reading of the codons from the point of mutation forward, leading to the production of different amino acids.
• In some instances, the frameshift mutation may introduce a premature stop codon or eliminate a natural one, which can result in a protein that is either abnormally short or excessively long and usually non-functional.
• Although frameshift mutations are generally more complex than single nucleotide polymorphisms (SNPs), they can still arise from the addition or deletion of just one nucleotide.
• Frameshift mutations only affect the coding regions of DNA; changes occurring in non-coding or regulatory regions of the genome do not result in alterations to the protein structure.

Causes of Frameshift Mutation

• Frameshift mutations occur due to the insertion or deletion of nucleotides in a DNA sequence, which causes a shift in the reading frame during translation.
• Substitution mutations do not lead to frameshift mutations because they typically replace a single nucleotide without altering the overall reading frame, and do not produce a completely different amino acid sequence.
• In some instances, frameshift mutations arise spontaneously due to errors during DNA replication or other DNA processing activities within the cell.
• The alteration in the DNA sequence can happen at a specific point (point mutation) or may span across a region, and in both cases, the resulting shift in the reading frame leads to the formation of an altered protein product.
• Induced mutations, caused by external physical agents such as X-rays and ultraviolet (UV) radiation, can also result in frameshift mutations.
• Chemical agents, including molecules like reactive oxygen species (ROS), can damage the DNA and lead to changes in nucleotide sequences, inducing frameshift mutations.
• These mutations can take place in both single-stranded and double-stranded DNA, depending on the nature and source of the damaging factor.

Mechanism of Frameshift Mutation

The mechanism of frameshift mutation varies depending on the underlying cause of the mutation, but generally involves changes in the DNA sequence that disrupt the normal triplet codon reading frame.

1. Deletion

• Deletion is one of the primary mechanisms behind frameshift mutations.
• It involves the removal of a segment of DNA, which can occur during anaphase movement, during the reorganization of nuclei, or through the digestion of DNA by nucleases.
• Deletions are categorized into two types: terminal and intercalary.
• A terminal deletion occurs when the terminal (end) section of a chromosome is removed.
• An intercalary deletion results from the loss of an intermediate section or internal portion of the chromosome.
• Among all mechanisms causing frameshift mutations, deletion is more commonly observed and typically leads to a shift in the reading frame of the DNA sequence.

2. Insertion

• Insertion is another major mechanism responsible for frameshift mutations.
• It involves the addition of one or more nucleotides into the DNA sequence in such a way that it disrupts the original reading frame.
• Insertions commonly occur within microsatellite regions of DNA, which are repetitive sequences, and are facilitated by the activity of DNA polymerase during DNA replication.
• The number of nucleotides inserted and their specific position within the sequence vary, and both factors influence the severity of the resulting mutation.
• Insertions that lead to frameshift mutations typically cause the gene to be actively translated, but they often result in the generation of a premature stop codon, which truncates the protein and usually renders it non-functional.

Applications of Frameshift Mutation

• Frameshift mutations have been linked to several diseases, making them useful as diagnostic markers for identifying such genetic conditions.
• They can be intentionally induced as a form of molecular therapy to help treat or prevent hereditary and genetic disorders.
• Frameshift mutations can also be utilized to target cancer cells and their associated proteins, offering potential strategies for cancer prevention and treatment.
• When induced under controlled conditions, frameshift mutations serve as a tool in mutation breeding, allowing for the development of new and improved crop varieties.
• They are valuable in research studies focusing on the structure, function, and stability of various proteins, contributing to a deeper understanding of protein biology.
• In certain cases, frameshift mutations can be advantageous, potentially enhancing the fitness of an organism within its ecosystem.

Examples of Frameshift Mutation

• A notable example of a frameshift mutation is seen in Crohn’s disease, which is associated with mutations in the NOD2 gene.
• In this case, the mutation involves the insertion of a cytosine nucleotide at the 3020th position of the gene sequence.
• This insertion alters the normal codon, converting it into a stop codon, which leads to the production of a shortened, incomplete protein.
• The resulting structural change in the protein impairs its normal function, which is to detect and respond to bacterial liposaccharides in the body.
• The mutation does not occur in multiples of three, which causes a shift in the reading frame—a defining characteristic of frameshift mutations—and is ultimately responsible for the onset of the disease.

References

• Verma, P. S., & Agarwal, V. K. (2005). Cell Biology, Genetics, Molecular Biology, Evolution and Ecology (Multicoloured Edition). S. Chand Publishing.
• Sheetlin, S. L., Park, Y., Frith, M. C., Spouge, J. L. (2014). Frameshift alignment: statistical analysis and applications in the post-genomic era. Bioinformatics, 30(24), 3575–3582. https://doi.org/10.1093/bioinformatics/btu576
• García-Barreno, B., Portela, A., Delgado, T., López, J. A., & Melero, J. A. (1990). Frameshift mutations as a novel mechanism for the emergence of neutralization-resistant mutants of human respiratory syncytial virus. The EMBO Journal, 9(12), 4181–4187. https://doi.org/10.1002/j.1460-2075.1990.tb07642.x