Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa.

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Abstract
Previous studies of the Hpa I cleavage site-sickle cell Hb gene linkage in various African populations suggested that the sickle gene arose independently more than once. Restriction endonuclease haplotype analysis for the .beta.-globin-like gene cluster from 4 separate geographic areas in Africa, all of which possess the sickle gene was performed. In Benin (Central West Africa) and Algeria (Arab North Africa) all chromosomes carrying the sickle gene possess an identical haplotype as defined by 11 different polymorphic restriction endonuclease sites within the 60-kilobase region of the .beta.-globin-like gene cluster. In the Central African Republic (Bantu-speaking Africa) and in Senegal (Atlantic West Africa) a very large proportion of the sickle gene chromosomes were associated with a haplotype specific for country. Thus, 3 different haplotypes are shown to be associated with the sickle gene in Africa, and each is present at a very high frequency in geographically separate regions. Since the 3 haplotypes differ from each other by at least 3 sites residing both 5'' and 3'' to a putative hot spot for recombination, it is most likely that the sickle gene arose at least 3 times on separate preexisting chromosomal haplotypes. This may have implications for a better understanding of the variable nature of the expression of sickle cell anemia, because clinically relevant sequences (e.g., .gamma.-globin gene regulatory sequences responsive to anemia) might be linked polymorphically to these haplotypes.