Title :

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.

Authors :

Williams, T. N., Mwangi, T. W., Wambua, S., Peto, T. E., Weatherall, D. J., Gupta, S., Recker, M., Penman, B. S., Uyoga, S., Macharia, A., Mwacharo, J. K., Snow, R. W., Marsh, K.

PubMed link :

Journals :

Nat Genet