Hemoglobin A₂ is often elevated in β-thalassemia and decreased in α-thalassemia. This might be due to hemoglobin subunit-subunit affinity variation. It has been inferred from the study of abnormal hemoglobins that the a subunits have higher affinity for β subunits than for δ subunits. However, only in one study has the affinity of α, β, and δ subunits for each other been measured. In this work we have attempted to measure the hemoglobin subunit-subunit affinity with somewhat different approach, i.e., hybridization of hemoglobin A and A₂. It is shown that hybridization and recombination of equal amounts of hemoglobins A and A₂ lead always to the formation of more hemoglobin A than A₂. Incubation of pure α, β, and δ subunits forms more hemoglobin A than A₂ as the availability of a subunits declines. It is concluded that hemoglobin a subunits have approximately four-fold higher affinity for β subunits than for the δ subunits under these experimental conditions. This subunit-subunit affinity difference, which has been attributed to the variation in molecular electrostatic charges, explains the variation of hemoglobin A₂ levels in thalassemia syndromes.

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