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

Abstract

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, 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 alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.

Figure 1

IRRs for malaria by hemoglobin type and α⁺-thalassemia genotype. Derived from data described in Tables 1 and 2.

Figure 2

The evolutionary consequences of negative epistasis between the malaria-protective effects of HbS and α⁺-thalassemia. The equilibrium frequencies of HbS (filled diamonds) and α⁺-thalassemia (unfilled circles) are shown under various schedules of relative mortality, reflecting an increase in epistasis along the x axis. The balance between mortality rates is altered between the graphs by an additional component of non-malaria-specific mortality of (a) μ = 0.034 and (b) μ = 0.05, which we added to the suite of malaria-associated mortality values (μ₁₁ = 0.02757, μ₁₂ = 0.01578, μ₁₃ = 0.01433, μ₂₁ = 0 and μ₂₂ = 0.034, Table 2.)