Negative epistasis between the malaria-protective effects of α + - thalassemia and the sickle cell trait
Date
2005-11Author
Williams, Thomas N
Mwangi, Tabitha
Wambua, Sammy
Peto, Timothy E A
Weatherall, David J
Gupta, Sunetra
Recker, Mario
Penman, Bridget S
Uyoga, Sophie
Macharia, Alex
Mwacharo, Jedidah K
Snow, Robert W
Marsh, Kevin
Metadata
Show full item recordAbstract
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 malaria2–4, 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.