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To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the ß gene cluster in ßs-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the ßs gene are linked in 91% of the cases to the “Asian” (Arab-Indian) haplotype (although 25% of the haplotypes had the c polymorphic site negative, making the 5' portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high Gɿ expression (67.2 ± 5.9%) and a high percentage of Hb F (15.5 ± 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to ßs in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the ßs gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (—α) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The ßs gene linkage to a high Hb F-expressing haplotype and the high incidence of α-thalassemia predict a mild phenotypical expression of sickle cell anemia in India.