A genetic mutation is a change in the DNA sequence, the instruction manual for all living organisms. A frameshift mutation is a type of genetic modification involving the addition or deletion of nucleotide bases within the DNA. This alters how genetic information is interpreted, causing a “shift” in the reading frame of the genetic code and leading to significant effects.
Understanding the Genetic Code
To grasp the implications of a frameshift mutation, it is helpful to understand the genetic code. DNA contains the instructions for building proteins, which perform most of the work in cells. These instructions are first copied into a messenger molecule called messenger RNA (mRNA) through a process called transcription. The mRNA then travels to cellular machinery where its sequence is translated into a chain of amino acids, which fold into functional proteins.
The genetic information on mRNA is read in specific units called codons. Each codon consists of a sequence of three nucleotide bases, such as adenine (A), guanine (G), cytosine (C), and uracil (U). Most codons specify a particular amino acid, the building blocks of proteins. The sequence of these amino acids determines the protein’s unique structure and function. The cell reads the mRNA sequence in a precise, non-overlapping manner, three bases at a time, establishing what is known as the “reading frame.”
How Frameshift Mutations Occur
Frameshift mutations involve the insertion or deletion of one or more nucleotide bases within a DNA sequence. An insertion adds extra bases, while a deletion removes them. If these insertions or deletions do not occur in multiples of three bases, they shift the entire reading frame of the genetic code downstream from the mutation point.
Imagine a sentence made of three-letter words, like “THE BIG DOG ATE.” If you insert a single letter, for example, “T” after “THE,” the sentence becomes “THE TBI GDO GAT E.” The original meaning is lost because all subsequent “words” are now incorrectly grouped. Similarly, in DNA, if a single base is added or removed, every codon after that point will be misread, leading to a completely different sequence of amino acids being incorporated into the protein.
The Profound Consequences
The molecular consequences of a frameshift mutation are substantial. Because the reading frame shifts, every codon downstream from the mutation is altered, leading to a different sequence of amino acids. This change means the resulting protein will differ from its original form. Such altered proteins are often non-functional or impaired in their cellular roles.
A common outcome is the introduction of a premature stop codon. If the shifted reading frame generates a new stop signal, protein synthesis terminates much earlier than normal. This results in a truncated protein, which is significantly shorter than the original and almost always non-functional. Cells often recognize these altered proteins as abnormal and degrade them, preventing harm.
Real-World Impact and Associated Conditions
Frameshift mutations are linked to numerous human genetic conditions because the non-functional or truncated proteins they produce disrupt normal bodily processes. For instance, some forms of Crohn’s disease are associated with a frameshift mutation in the NOD2 gene. This mutation leads to a shortened NOD2 protein, unable to properly respond to bacterial liposaccharides, contributing to the inflammatory bowel condition.
Tay-Sachs disease, a severe neurodegenerative disorder, is also caused by frameshift mutations in the HEXA gene, which codes for the enzyme beta-N-acetylhexosaminidase A. The absence of this functional enzyme leads to the abnormal accumulation of lipids in brain neurons, causing lethal damage. Certain cancers, such as colorectal, breast, ovarian, and gastric cancers, have also been linked to frameshift mutations in genes like APC, BRCA2, and MLH1. The severity of these conditions often depends on the specific gene affected and the mutation’s precise location.