Thalassemia is a prevalent hereditary disorder characterized by impaired synthesis of
globin chains. It has been suggested that the high frequency of
thalassemia might reflect heterozygote advantage due to reduced susceptibility to
malaria. In Nepal,
malaria has often occurred in places below the altitude of 1,200m. We carried out a microepidemiological study on
thalassemia in two neighboring populations in Nepal, the Danuwar and the Tamang. Settlements of the Danuwar are located below the limit of the malarial zone (1,200m in altitude), whereas those of the Tamang are found in
malaria-free uplands. Three heterozygotes for
hemoglobin E (HbE) were observed in the Danuwars. We detected one type (-alpha3.71) of
alpha+-thalassemia that involves a deletion of 3.7kb, leading to a loss of one of two
alpha-globin genes, in the Danuwars, at a high gene frequency of 63%, while the gene frequency in the Tamangs was only 5%. Analysis of the
alpha-globin gene cluster revealed that four different haplotypes were associated with the type of
alpha+-thalassemia in the Danuwars. Nucleotide sequences of the D-loop region in the
mitochondrial DNA of the two populations indicated a similar
nucleotide diversity in each population. The fixation index, FST, representing the degree of genetic differentiation estimated from
mitochondrial DNA diversities (FST, 0.05), was smaller than that obtained from the gene frequencies of
alpha-thalassemia (FST, 0.55). If we assume neutral molecular evolution in the D-loop region of
mitochondrial DNA, these results suggest that the high frequency of
alpha+-thalassemia may be due to biological adaptation to the malarial environment rather than to events such as a bottleneck.