Question
Explain the genetic basis of sickle cell anemia. What type of mutation causes it? Why do carriers (heterozygous individuals) have an advantage in malaria-endemic regions? Show the inheritance pattern using a cross between two carriers.
(NCERT Class 12, Molecular Basis of Inheritance)
Solution — Step by Step
Sickle cell anemia is caused by a point mutation (single base substitution) in the gene coding for the beta-globin chain of haemoglobin:
- Normal: DNA codon GAG → mRNA codon GUG → Glutamic acid (Glu) at position 6
- Mutant: DNA codon GTG → mRNA codon GUG → Valine (Val) at position 6
Wait — let’s be precise. The normal DNA template strand reads CTC (giving mRNA codon GAG → Glu). The mutant reads CAC (giving mRNA codon GUG → Val).
This single amino acid change (Glu → Val) changes the haemoglobin from HbA (normal) to HbS (sickle). The hydrophobic valine causes HbS molecules to polymerise under low oxygen conditions, forming rigid fibres that distort the RBC into a sickle (crescent) shape.
Sickle cell anemia follows autosomal recessive inheritance. Let = normal allele and = sickle allele.
Cross between two carriers:
| (normal) | (carrier) | |
| (carrier) | (sickle cell disease) |
Ratio: 1 normal : 2 carriers : 1 affected (1:2:1 genotypic, 3:1 phenotypic if we consider carriers as unaffected)
Carriers () have a survival advantage in malaria-endemic regions (tropical Africa, parts of India). Why?
- The malaria parasite (Plasmodium falciparum) lives inside RBCs
- In carriers, infected RBCs tend to sickle more readily under low O₂
- Sickled cells are destroyed by the spleen, killing the parasite inside them
- The carrier has enough normal HbA to survive without severe anemia
This is called heterozygote advantage or balanced polymorphism. Natural selection maintains the HbS allele in the population because carriers are fitter than both homozygotes in malaria zones.
Why This Works
This is a textbook example of how a single nucleotide change can cause a devastating disease. The Glu → Val substitution changes one property: the surface of the beta-globin chain becomes hydrophobic at position 6. This causes HbS molecules to stick together (polymerise) in deoxygenated conditions, forming long fibres that stretch and deform the flexible RBC into a rigid sickle shape.
Sickled RBCs block small blood vessels (causing pain crises), are destroyed prematurely (causing anemia), and can damage organs (spleen, kidneys, lungs). Homozygous individuals () have severe disease and reduced lifespan without treatment.
The geographic correlation between sickle cell trait frequency and malaria prevalence is striking — it’s one of the best-documented examples of natural selection in humans.
Alternative Method
For quick identification of the mutation type: it’s a missense mutation (changes one amino acid to another), specifically a transversion (purine A replaced by pyrimidine T in the coding strand). This is also classified as a point mutation since only one nucleotide is affected.
NEET commonly tests: “What amino acid substitution causes sickle cell anemia?” — Glutamic acid replaced by Valine at position 6 of beta-globin. “What type of mutation?” — Point mutation / missense. “Why is HbS allele maintained in African populations?” — Heterozygote advantage against malaria. These are high-frequency questions.
Common Mistake
Students often write that sickle cell anemia is “caused by a change from Valine to Glutamic acid.” It’s the reverse — Glutamic acid (normal) is replaced BY Valine (mutant). The direction matters. Also, some students write it as a deletion or insertion mutation — it is NOT. It’s a substitution (point mutation) where one base pair is changed, not added or removed.