Selection and Mutation for α Thalassemia in Nonmalarial and Malarial Environments

Abstract

Summaryα thalassemia is the result of the loss of one or both copies of the two human α globin genes. α thalassemia appears to be the most common monogenic disease in the world and is in high frequency where malaria is, or has been, endemic. In nonmalarial environments, α thalassemia is rare and its frequency can be explained by a balance of deletional mutation and purifying selection. In malarial environments, the loss of one or two copies of the four α globin genes in normal diploid genotypes confers resistance (lower mortality) to malaria. Fitness estimates from data from Kenyan and Papua New Guinea populations are used to predict the increase in the −α haplotype (with one deleted gene). The frequency of double deletions (−− haplotypes) is higher in some Asian populations than that of single deletions. In this case, heterozygotes with normal αα haplotypes are expected to have the highest fitness. Overall, this population genetic examination provides an evolutionary framework for understanding the worldwide frequency of α thalassemia and the deletions that cause it in both nonmalarial and malarial environments.

Population genetics of malaria resistance in humans

“…This is true for the estimated Kenyan relative fitness values mentioned above for all values of w 1 (Hedrick, 2011b). However, for the Papua New Guinea fitness values Àa goes to fixation only when genotype ÀÀ/Àa has a fitness of 0.79 or above.…”

“…However, for the Papua New Guinea fitness values Àa goes to fixation only when genotype ÀÀ/Àa has a fitness of 0.79 or above. When w 1 is 0.78 or less, haplotype Àa does not increase in frequency and haplotypes ÀÀ and aa go to a heterozygote advantage polymorphic equilibrium, not substantially different from that observed for some Asian populations (Hedrick, 2011b).…”

“…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).…”

“…In addition, several studies have shown protection from severe malaria for individuals with a þ thalassemia, compared with individuals without thalassemia (Allen et al, 1997;Mockenhaupt et al, 2004;Williams et al, 2005b). In a large case-control study in Kenya (Williams et al, 2005b), the OR values, standardized to the normal aa/aa genotype, for a þ heterozygotes and homozygotes in Kenya are 0.623 and 0.522 for severe malaria, respectively (Hedrick, 2011b). In the other case-control study in Papua New Guinea (Allen et al 1997), the standardized OR values of a þ thalassemia heterozygotes and homozygotes are 0.781 and 0.362, respectively, for severe malaria.…”

“…Most of these have non-synonymous single-nucleotide replacements, a number of which are polymorphic. These variants range from ones that cause severe deficiency and chronic anemia to some that actually increase G6PD Table 3 The different genotypes for a-thalassemia with the number of a-globin genes and the estimated relative fitnesses of genotypes aa/aa, -a/aa and -a/-a from samples from Kenya and Papua New Guinea (Hedrick, 2011b) Genotype aa/aa -a/aa -a/-a or ÀÀ/aa ÀÀ/-a ÀÀ/ÀÀ activity. G6PD deficiency can be caused by a reduction in the number of enzyme molecules or a structural change causing enzyme instability.…”