Original Article

Journal of Human Genetics (2000) 45, 127–132; doi:10.1007/s100380050198

Molecular analysis of alpha-thalassemia in Nepal: correlation with malaria endemicity

Yasuyoshi Sakai1, Shigeru Kobayashi2, Hiroki Shibata1, Hiroyasu Furuumi1, Toshiyasu Endo3, Supan Fucharoen4, Shinjiro Hamano5, Gopal P Acharya6, Terukazu Kawasaki7 and Yasuyuki Fukumaki1

  1. 1Division of Disease Genes, Institute of Genetic Information, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
  2. 2Department of Human Geography, Graduate School of Letters, Osaka University, Toyonaka, Japan
  3. 3Kyushu Women's College, Kitakyushu, Japan
  4. 4Department of Clinical Chemistry, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
  5. 5Department of Parasitology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
  6. 6Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
  7. 7Institute of Health Science, Kyushu University, Fukuoka, Japan

Correspondence: Yasuyuki Fukumaki, Division of Disease Genes, Institute of Genetic Information, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Fax: +81-92-632-2375. E-mail: yfukumak@gen.kyushu-u.ac.jp

Received 10 November 1999; Accepted 13 December 1999.



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 1200 m. 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 (1200 m in altitude), whereas those of the Tamang are found in malaria-free uplands. Three heterozygotes for hemoglobin (HbE) were observed in the Danuwars. We detected one type (-alpha3.7I) of alpha+-thalassemia that involves a deletion of 3.7 kb, 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.


Thalassemia, Globin, Genotype, Haplotype, Nepal, Malaria, Mitochondrial DNA