Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean.
Several human genetic disorders of hemoglobin have risen in frequency because of the protection they offer against death from malaria, sickle-cell anemia being a canonical example. Here we address the issue of why this highly protective mutant, present at high frequencies in subSaharan Africa, is uncommon in Mediterranean populations that instead harbor a diverse range of thalassemic hemoglobin disorders. We demonstrate that these contrasting profiles of malaria-protective alleles can arise and be stably maintained by two well-documented phenomena: an alleviation of the clinical severity of alpha- and beta-thalassemia in compound thalassemic genotypes and a cancellation of malaria protection when alpha-thalassemia and the sickle-cell trait are coinherited. The complex distribution of globin mutants across Africa and the Mediterranean can therefore be explained by their specific intracellular interactions.
Penman
Bridget S
BS
Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom.
Pybus
Oliver G
OG
Weatherall
David J
DJ
Gupta
Sunetra
S
D000349:Africa; D000755:Anemia, Sickle Cell / Q000235:genetics*; D004843:Epistasis, Genetic; D005787:Gene Frequency; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D008288:Malaria / Q000235:genetics; D008521:Mediterranean Islands; D013789:Thalassemia / Q000235:genetics*
D006455:Hemoglobins, Abnormal