Negative epistasis between the malaria-protective effects of α+-thalassemia and the sickle cell trait

Abstract

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria¹. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and α⁺-thalassemia, a condition characterized by reduced production of the normal α-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria^2,3,4, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying α⁺-thalassemia. Negative epistasis could explain the failure of α⁺-thalassemia to reach fixation in any population in sub-Saharan Africa.