Structural analysis of the 5' flanking region of the beta-globin gene in African sickle cell anemia patients: further evidence for three origins of the sickle cell mutation in Africa.

Abstract

Haplotype analysis of the ,3-globin gene cluster shows two regions of DNA characterized by nonrandom association of restriction site polymorphisms. These regions are separated by a variable segment containing the repeated sequences (ATTTT). and (AT)XTy, which might be involved in recombinational events. Studies of haplotypes linked to the sickle cell gene in Africa provide strong argument for three origins of the mutation: Benin, Senegal, and the Central African Republic. Nevertheless, the haplotype determination does not give any information about the variable segment and does not totally exclude the possibility of recombination leading to different haplotypes linked to the mutation. The structure of the variable segment in the three African populations was studied by S1 nuclease mapping of genomic DNA, which allows a comparison of several samples. A 1080-base-pair DNA segment was sequenced for one sample from each population. S1 nuclease mapping confirmed the homogeneity of each population with regard to both (ATTTT). and (AT)XTy repeats. We found three additional structures for (AT)XTy correlating with the geographic origin of the patients. Ten other nucleotide positions, 5' and 3' to the (AT)XTy copies, were found to be variable when compared to homologous sequences from human and monkey DNAs. These results allow us to propose an evolutionary scheme for the polymorphisms in the 5' flanking region of the (-globin gene. The results strongly support the hypothesis of three origins for the sickle mutation in Africa.

Genetics of kidney failure and the evolving story of APOL1

“…The frequency of sickle cell allele in hemoglobin (HbS) varies greatly, globally and within Africa, in relation to the historical endemicity of malaria. Recent evidence suggests that the allele arose independently multiple times in history, as HbS is found on several different haplotype backgrounds (55,56). The survival advantage conferred by the HbS allele (a dominant trait) caused it to increase in frequency until the recessive disease became common.…”

The Natural History of Sickle Cell Disease

“…Characterization of the DNA structure flanking the b-globin locus of HbS suggests that the mutation has arisen on at least three independent occasions in the African continent, referred to as b-globin haplotypes and named after the areas where they were first described: Benin, Senegal, and Central African Republic or Bantu (Pagnier et al 1984;Nagel et al 1985;Chebloune et al 1988). The HbC trait is believed to be a relatively recent mutation limited to West Africa where it occurs at high frequencies (.20%) in central Ghana and Burkina Faso, in only 2% in Nigeria, and does not occur, except in peoples of West African origin, in East and Central Africa.…”

BP1, a Homeodomain-Containing Isoform of DLX4, Represses the β-Globin Gene

“…There are differences in the clinical severity of SCA among the haplotypes, with the Indian-Arabo (hereafter referred to as the Indian haplotype) being the mildest and the Bantu being the most severely affected (35). A sequence polymorphism within the Ϫ530 bp binding site for BP1 in silencer I is also in linkage disequilibrium with these five SCA haplotypes (6). Using competition electrophoretic mobility shift assays (EMSAs), it was found that BP1 binds five to six times more tightly to the Indian haplotype sequence than to the normal sequence (2,15,47).…”