Sickle cell anaemia is the result of which type of mutation in the haemoglobin gene?

Question

Accepted Answer

The correct option is 3: Point mutation

Sickle cell anaemia (SCA) serves as a quintessential example in molecular genetics, demonstrating the profound consequences of a **point mutation**. A point mutation is a change in a single base pair of the DNA sequence, also known as a base-pair substitution. In the context of SCA, the mutation occurs in the gene responsible for synthesizing the beta-globin chain of the haemoglobin molecule. The normal DNA triplet at the sixth position of this gene is GAG, which codes for the amino acid Glutamic acid. The mutation involves the substitution of Adenine (A) by Thymine (T), changing the codon to GTG, which codes for the amino acid Valine. This single base substitution is a type of point mutation called a *missense* mutation, and this switch from a hydrophilic (water-loving) Glutamic acid to a hydrophobic (water-fearing) Valine is what drastically alters the structure of the haemoglobin and forces red blood cells into their characteristic sickle shape under low-oxygen conditions.

The incorrect option is 1: Frame shift mutation

A frame shift mutation involves the insertion or deletion of one or two nucleotides (or any number not divisible by three) into the DNA sequence. This is generally a much more severe mutation than a point mutation because it shifts the entire translational reading frame from the point of the change. This shift causes every subsequent codon to be misread, leading to a completely new and often nonsensical amino acid sequence, usually followed quickly by a premature stop codon. If a frame shift were the cause of sickle cell anaemia, the beta-globin protein would be entirely non-functional and likely very short, leading to a completely different and probably non-viable disorder, rather than the specific single-amino-acid alteration observed in SCA.

The incorrect option is 2: Deletion

Deletion refers to the complete removal of one or more base pairs from the DNA sequence. If a base deletion occurs in a number not divisible by three (e.g., one or two bases), it causes a frame shift mutation, as explained above. If a large segment is deleted, it can lead to conditions like certain forms of Thalassemia, where the *quantity* of the beta-globin chain produced is severely reduced or eliminated entirely. Sickle cell anaemia, however, is a classic *qualitative* disorder, meaning the globin chain is produced but is structurally defective, a defect precisely linked to the single base substitution that is the definition of a point mutation.

The incorrect option is 4: Duplication

Duplication is a mutational event where a segment of the gene is copied one or more times. Duplications within the coding region, much like insertions and deletions, are highly disruptive to the gene's function. The duplication of a single or small number of bases (not a multiple of three) would result in a frame shift mutation and a catastrophic change to the protein sequence. If an entire codon or larger segment were duplicated, it would lead to an expanded, structurally aberrant protein. The specific pathology of sickle cell anaemia, which relies on the change of just one amino acid (Glutamic acid to Valine) at a specific site, cannot be accounted for by the larger, repeated sequence structure that characterizes a duplication mutation.