Protection against malaria morbidity - near-fixation of the alpha-thalassemia gene in a Nepalese population

We have previously reported that the Tharu people of the Terai region in southern Nepal have an incidence of malaria about sevenfold lower than that of synpatric non-Tharu people. In order to find out whether this marked resistance against malaria has a genetic basis, we have now determined in these populations the prevalence of candidate protective genes and have performed in-vitro cultures of Plasmodium falciparum in both Tharu and non-Tharu red cells. We have found significant but relatively low and variable frequencies of beta-thal, beta-s, G6PD (-), and Duffy (a-b-) in different parts of the Terai region. The average in-vitro rate of invasion and of parasite multiplication did not differ significantly in red cells from Tharus versus those from non-Tharu controls. By contrast, the frequency of alpha-thalassemia is uniformly high in Tharus, with the majority of them having the homozygous alpha-/alpha-genotype and an overall alpha-thal gene (alpha-) frequency of .8. We suggest that holoendemic malaria has caused preferential survival of subjects with alpha-thal and that this genetic factor has enabled the Tharus as a population to survive for centuries in a malaria-holoendemic area. From our data we estimate that the alpha-thal homozygous state decreases morbidity from malaria by about 10-fold. This is an example of selection evolution toward fixation of an otherwise abnormal gene.