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

Abstract

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria 1 . 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 malaria 2-4 , 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 subSaharan Africa.The mutation underlying the hemoglobin S variant (HbS) is a prototypical example of a balanced polymorphism: its frequency in populations is determined both by positive selection for heterozygosity (HbAS) 5 and negative selection for homozygosity (HbSS), which causes sickle cell disease, a debilitating condition associated with chronic anemia and premature death. Negative selection has not been shown to affect the frequency of α + -thalassemias. Perhaps as a consequence, these conditions approach fixation in a number of populations; for unknown reasons, however, frequencies remain relatively low in much of sub-Saharan Africa 1 .Despite conclusive evidence that both HbAS and α + -thalassemia protect against severe and fatal P. falciparum malaria 2-4 , the mechanisms underlying this protection are poorly 6,7 , and parasite-infected HbAS erythrocytes also seem to be targeted for premature destruction by the spleen 6,8,9 . These hypothetical mechanisms are supported by both the reduced incidence of clinical malaria and the lower parasite densities observed in children with HbAS erythrocytes when they suffer from clinical attacks 3,10 . Much less is known about α + -thalassemia. Although both heterozygosity (-α/αα) and homozygosity (-α/-α) with respect to the underlying mutation protect against severe and fatal malaria 2,4 , neither protects against uncomplicated malaria 11 or affects parasite densities during incident episodes 2,12 . We believe that a better understanding of how these conditions protect against malaria might provide insights into both the pathophysiology of severe malaria and the hostparasite relationship more generally 10 . Accordingly, we studied the effects of both HbAS and α + -thalassemia on the epidemiology of malaria in children living on the coast of Kenya.We measured the incidence of P. falciparum malaria in two cohorts of children from Kilifi District, where al...

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.…”

“…Williams et al (2005b) examined these disorders in Kenya in a population that was segregating for both variants (the same one in which we estimated relative fitnesses). In this population, they found that the protection from malaria given by each variant was lost when the two disorders were inherited together in the same individual (see also May et al, 2007).…”

Evidence for contrasting modes of selection at interacting globin genes in the European rabbit (Oryctolagus cuniculus)

“…Another possibility is that the observed patterns of a-and b-globin polymorphism reflect selection for resistance to blood-borne pathogens, as allelic variation in haemoglobin function is known to play an important role in modulating the reduction-oxidation status of red blood cells. In humans, despite the long term knowledge of the selective agent for the most common haemoglobinopathies in sub-Saharan Africa, the existence of negative epistasis between both conditions was reported only recently (Williams et al, 2005). It may therefore prove difficult to unravel the causes of the observed patterns of allele frequency variation at both globin loci in the European rabbit.…”

“…If the observed patterns of variation at the HBA and HBB genes are attributable to hitchhiking associated with selection at linked loci, in each case the true target of selection is likely to be another closely linked globin gene. In mammals and other vertebrates, haemoglobin polymorphism plays a well-documented role in adaptation to hypoxic environments (Poyart et al, 1992;Weber and Fago, 2004;Storz, 2007;Storz et al, 2007), and in humans, amino acid and deletion polymorphisms in the a-and b-globin genes have been implicated in resistance to malaria (for example, Agarwal et al, 2000;Ohashi et al, 2004;Kwiatkowski, 2005;Williams et al, 2005). In the case of the European rabbit, patterns of HBA and HBB variation across the Iberian Peninsula do not correlate with altitude or any obvious environmental factors.…”

Large scale screening for haemoglobin disorders in southern Vietnam: implications for avoidance and management

“…The remarkable variation in the gene frequency between different ethnic groups and regions of Vietnam presumably reflects the complex effects of ancient migrations, variable exposure to selection by malaria and epistatic interactions between the different haemoglobin disorders themselves (Williams et al, 2005;Penman et al, 2009). For example, the lower frequency of b thalassaemia in regions where HbE is particularly common, and vice versa, could reflect different migration patterns but could also result from the variability in the selective effect of two different alleles.…”