Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean

Abstract

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 ␣-and ␤-thalassemia in compound thalassemic genotypes and a cancellation of malaria protection when ␣-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.epistasis ͉ host genetics ͉ malaria ͉ thalassemia ͉ human evolution

Population genetics of malaria resistance in humans

“…Here, I will use a traditional population genetics approach and show that the results are generally consistent with their findings, using an epidemiological model. An important caveat is that although most general properties discussed here are enlightening and significant, some conclusions can depend on rather small differences in estimated values (Williams et al, 2005a;Penman et al, 2009;Hedrick, 2011b).…”

“…Unbalanced production of a and b chains is a major cause of thalassemia, but if both are low, then the severity of anemia can be less. As a result, a-thalassemia can modify the phenotype of b-thalassemia such that it is not as extreme, a potential example of positive epistasis (Penman et al, 2009). In addition, the sickle-cell anemia can be ameliorated by an increase in the production of fetal hemoglobin (Flint et al, 1998), suggesting positive interaction between these genes.…”

“…They suggested that this negative epistasis could be the reason why a þ -thalassemia has not been fixed in any population in sub-Saharan Africa. This situation has been examined theoretically by Williams et al (2005a) and Penman et al (2009), using an epidemiological approach. Here, I will use a traditional population genetics approach and show that the results are generally consistent with their findings, using an epidemiological model.…”

Selection and Mutation for α Thalassemia in Nonmalarial and Malarial Environments

“…They suggested that this negative epistasis could be the reason why α + thalassemia has not been fixed in any population in sub-Saharan Africa. This situation has been examined theoretically by Williams et al (2005b) and Penman et al (2009) using an epidemiological approach and Hedrick (2011a), using a traditional population genetics approach, found generally similar results. In other words, the single-locus analysis used here may have to be expanded to multiple loci to understand the overall impact on genes conferring resistance to malaria.…”

A Journey in Science: Early Lessons from the Hemoglobin Field

“…Work carried out by the Oxford group in Africa has shown that, while those who are heterozygous for the sickle cell gene or for α + thalassemia are protected against P. falciparum malaria (36,37), in individuals who inherit both of these mutations, the protective effect is completely lost and they are equally prone to malaria as individuals who have neither trait (38). As well as providing further evidence about the mechanisms of protection, these findings have important implications for providing further information about the regional variation in the frequency of the different hemoglobin mutations in different populations (39). There seems little doubt that epistatic interactions of this type will not be restricted to the hemoglobin field and may have important implications for the distribution and pathophysiology of many monogenic diseases.…”