Q.39 A single copy of an allele in sickle–cell heterozygous individuals reduces the
frequency and severity of malaria. The reason for this is
(A) Low oxygen binding capacity of hemoglobin
(B) Single amino acid substitution in hemoglobin deforms the red blood cells
(C) Abnormal hemoglobin is toxic for malaria parasite
(D) Malaria parasite escapes the deformed red blood cells

The correct answer is (C) Abnormal hemoglobin is toxic for malaria parasite.​

Sickle cell heterozygous individuals (HbAS) carry one normal hemoglobin gene (A) and one sickle cell allele (S), providing resistance to severe malaria without causing full sickle cell anemia. This protection arises because the abnormal sickle hemoglobin (HbS) creates conditions inside red blood cells that hinder Plasmodium falciparum growth, particularly under low oxygen levels encountered during infection.​

Option Analysis

(A) Low oxygen binding capacity of hemoglobin
HbS does bind oxygen, but deoxygenates and polymerizes faster than normal HbA under low oxygen, which indirectly affects parasite survival rather than directly reducing binding capacity as the primary mechanism. This option misrepresents the core reason for protection.​

(B) Single amino acid substitution in hemoglobin deforms the red blood cells
The Glu6Val substitution in beta-globin causes HbS polymerization and sickling under deoxygenation, but in heterozygotes, cells sickle mainly after parasite infection and sequestration in low-oxygen tissues. Sickling leads to cell removal by macrophages, interrupting parasite replication, yet the direct toxicity of HbS polymers to the parasite during growth precedes full deformation.​

(C) Abnormal hemoglobin is toxic for malaria parasite
HbS polymerization in low oxygen stalls parasites at the ring/early trophozoite stage, impairing hemoglobin digestion (needed for parasite amino acids) and DNA replication, effectively making HbS toxic to intraerythrocytic P. falciparum growth. Studies confirm restored growth with antisickling agents like carbon monoxide, proving HbS directly inhibits parasites.​

(D) Malaria parasite escapes the deformed red blood cells
Parasites do not escape; instead, infected HbAS cells sickle, get phagocytosed by spleen macrophages, or experience arrested growth, reducing parasitemia. Escape implies active parasite evasion, which contradicts evidence of growth inhibition and clearance.​

Sickle cell heterozygous malaria resistance exemplifies balanced polymorphism, where a single sickle cell allele (HbAS) confers strong protection against severe Plasmodium falciparum malaria in endemic regions. This genetic adaptation, prevalent in malaria hotspots like sub-Saharan Africa, stems from HbS creating a hostile environment for parasites without causing full sickle cell disease.​

Mechanism Details

HbAS red blood cells support initial parasite invasion but falter during intraerythrocytic development. Low oxygen in sequestered tissues triggers HbS polymerization, stalling parasites before DNA replication and blocking hemoglobin digestion essential for parasite nutrition.​

• Enhanced phagocytosis removes sickled infected cells.​

• Reduced cytoadherence limits severe complications like cerebral malaria.​

• Lower parasitemia prevents progression to life-threatening stages.​

Evolutionary Significance

Natural selection maintains the sickle allele at 10-20% frequency in malaria zones due to heterozygote advantage, offsetting homozygous sickle cell anemia risks. CSIR NET aspirants note this as classic heterozygote superiority in population genetics.​