Atypical beta(S) haplotypes are generated by diverse genetic mechanisms

The majority of the chromosomes with the beta(S) gene have one of the five common haplotypes, designated as Benin, Bantu, Senegal, Cameroon, and Arab- Indian haplotypes. However, in every large series of sickle cell patients, 5-10% of the chromosomes have less common haplotypes, usually referred to a s "atypical" haplotypes. In order to explore the genetic mechanisms that co uld generate these atypical haplotypes, we extended our analysis to other r arely studied polymorphic markers of the beta(S)-gene cluster, in a total o f 40 chromosomes with uncommon haplotypes from Brazil and Cameroon. The fol lowing polymorphisms were examined: seven restriction site polymorphisms of the epsilon gamma delta beta-cluster, the pre-(G)gamma framework sequence including the 6-bp deletion/insertion pattern, HS-2 LCR (AT)xR(AT)y and pre -beta (AT)xTy repeat motifs, the GC/TT polymorphism at -1105-1106 of (G)gam ma-globin gene, the C/T polymorphism at -551 of the beta-globin gene, and t he intragenic beta-globin gene framework. Among the Brazilian subjects, the most common atypical structure (7/16) was a Bantu 3'-subhaplotype associat ed with different 5'-sequences, while in two chromosomes a Benin 3'-subhapl otype was associated with two different 5'-subhaplotypes, A hybrid Benin/Ba ntu configuration was also observed. In three chromosomes, the atypical hap lotype differed from the typical one by the change of a single restriction site. In 2/134 chromosomes identified as having a typical Bantu RFLP-haplot ype, a discrepant LCR repeat sequence was observed, probably owing to a cro ssover 5' to the epsilon-gene. Among 80 beta(S) chromosomes from Cameroon, 22 were associated with an atypical haplotype, The most common structure wa s represented by a Benin haplotype (from the LCR to the beta-gene) with a n on-Benin segment 3' to the beta-globin gene. In two cases a Bantu LCR was a ssociated with a Benin haplotype and a non-Benin segment 3' to the beta-glo bin gene. In three other cases, a more complex structure was observed that can be considered as a hybrid of Benin, Bantu, Senegal, or other chromosome s was observed. These data suggest that the atypical beta(S) haplotypes are not uncommon in America and in Africa. These haplotypes are probably gener ated by a variety of genetic mechanisms including (a) isolated nucleotide c hanges in one of the polymorphic restriction sites, (b) simple and double c rossovers between two typical beta(S) haplotypes or much more frequently be tween a typical beta(S) haplotype and a different beta(A)-associated haplot ype that was present in the population, and (c) gene conversions. Am. J, He matol, 63:79-84, 2000. (C) 2000 Wiley-Liss, Inc.