Analysis of 5′ flanking regions of the gamma globin genes from major African haplotype backgrounds associated with sickle cell disease

Abstract

There are at least three major African haplotype backgrounds on which the βs mutation arises. Sequence changes in the immediate 5′ flanking area of the γ-globin genes may account for differences in fetal hemoglobin expression among the three haplotypes. We determined the sequence from -350 to 10 bp 5′ of the Gγ and Aγ fetal globin genes from one βs-containing chromosome on each of the three major haplotype backgrounds. The Senegal chromosome had a T at -158 5′ to the Gγ gene; the Benin (BEN) chromosome had an A to G change at -309 5′ to the Gγ gene; and the Central African Republic (CAR) chromosome had a C to T change at -271 5′ to the Aγ gene. Genomic DNA from patients with sickle cell disease was analyzed using the polymerase chain reaction and radiolabeled allele-specific oligonucleotide probes. The -309 G variant 5′ to the Gγ gene is associated with BEN chromosomes, and the -271 T variant 5′ to Aγ with CAR. The -309 change was also found on βA-containing chromosomes, while the -271 change was not. The -309 change may have predated the βs mutation on the BEN chromosome.