Rearrangements of the beta-globin gene cluster in apparently typical betaS haplotypes

Abstract

BACKGROUND AND OBJECTIVES: The majority of the chromosomes with the betaS gene have one of the five common haplotypes, designated as Benin, Bantu, Senegal, Cameroon, and Arab-Indian haplotypes. However, 5-10% of the chromosomes have less common haplotypes, usually referred to as atypical haplotypes. We have demonstrated that most atypical haplotypes are generated by recombinations. The present study was carried out in order to explore whether recombination also occurs in chromosomes with the common (or typical) haplotypes. DESIGN AND METHODS: We screened the HS-2 region of the beta-globin gene locus control region (LCR) in 244 sickle cell patients who had typical restriction fragment length polymorphism (RFLP)-defined haplotypes of the betaS-gene cluster. For 14 cases in which the expected and the observed LCR repeat-sequence sizes were discrepant, the analysis was extended to other unexplored polymorphic markers of the bS-globin gene cluster, i.e.: pre-Ggamma framework, pre-Ggamma 6-bp deletion, HS-2 LCR (AT)xR(AT)y and pre-beta(AT)xTy repeats, and the intragenic beta-globin gene framework. RESULTS: In all 14 cases (15 chromosomes) in which the LCR repeat-sequence sizes were discrepant, a recombination involving a typical 3' segment of the betaS globin gene cluster was demonstrated. In most of the cases, the recombination site was located between the beta-globin gene and the betaLCR. Nine cases involving recombination were detected among 156 Brazilian HbS homozygotes and five among 88 African patients homozygotes for the Benin haplotype. INTERPRETATION AND CONCLUSIONS. Thus, 3.1% of apparently typical haplotypes linked to the sickle cell gene involve recombinations similar to those that generate the atypical haplotypes, a finding that reinforces the picture of the beta-globin gene cluster as highly dynamic.