Atypical βs haplotypes are generated by diverse genetic mechanisms

The majority of the chromosomes with the b 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 as “atypical” haplotypes. In order to explore the genetic mechanisms that could generate these atypical haplotypes, we extended our analysis to other rarely studied polymorphic markers of the b S -gene cluster, in a total of 40 chromosomes with uncommon haplotypes from Brazil and Cameroon. The following polymorphisms were examined: seven restriction site polymorphisms of the «gdbcluster, the pre- G g framework sequence including the 6-bp deletion/insertion pattern, HS-2 LCR (AT)xR(AT)y and pre-b (AT)xTy repeat motifs, the GC/TT polymorphism at ˛1105‐1106 of G g-globin gene, the C/T polymorphism at ˛551 of the b-globin gene, and the intragenic b-globin gene framework. Among the Brazilian subjects, the most common atypical structure (7/16) was a Bantu 3*-subhaplotype associated with different 5*sequences, while in two chromosomes a Benin 3*-subhaplotype was associated with two different 5*-subhaplotypes. A hybrid Benin/Bantu configuration was also observed. In three chromosomes, the atypical haplotype differed from the typical one by the change of a single restriction site. In 2/134 chromosomes identified as having a typical Bantu RFLPhaplotype, a discrepant LCR repeat sequence was observed, probably owing to a crossover 5* to the «-gene. Among 80 bS chromosomes from Cameroon, 22 were associated with an atypical haplotype. The most common structure was represented by a Benin haplotype (from the LCR to the b-gene) with a non-Benin segment 3* to the b-globin gene. In two cases a Bantu LCR was associated with a Benin haplotype and a non-Benin segment 3* to the b-globin gene. In three other cases, a more complex structure was observed that can be considered as a hybrid of Benin, Bantu, Senegal, or other chromosomes was observed. These data suggest that the atypical bS haplotypes are not uncommon in America and in Africa. These haplotypes are probably generated by a variety of genetic mechanisms including (a) isolated nucleotide changes in one of the polymorphic restriction sites, (b) simple and double crossovers between two typical bS haplotypes or much more frequently between a typical b S haplotype and a different b A associated haplotype that was present in the population, and (c) gene conversions. Am.