Analysis of linkage disequilibrium between the 5' and 3' haplotypes of the beta-globin gene cluster in Mexican afromestizos.

Analysis of the 5' and 3' haplotypes (Hps) of the beta-globin gene cluster was performed in 110 beta(A) chromosomes from unrelated Mexican afromestizo individuals in order to determine Hardy-Weinberg equilibrium, allelic frequencies, linkage disequilibrium (LD) and association between the 5' and 3' haplotypes. All sites were found to be in Hardy-Weinberg equilibrium (p>0.05). In the whole beta-cluster, only 12.87% of the pairs of loci exhibited significant LD (22/171) (r(2)>0.33). Within the 5'Hp, three pairs of loci were associated (epsilonHincII/(G)gammaHindIII, epsilonHincII/3'psibetaHincII and (G)gammaHindIII/3'psibetaHincII). In the 3'Hp, 19 pairs of loci showed significant LD and were distributed mostly among the -551, -340, Exon1nt6 and IVS2nt16 polymorphisms. The absence of pairs of loci significantly linked between both 5' and 3' Hps is noteworthy. The allelic combinations of the 40 studied polymorphisms (5 sites in the 5' Hp and 35 sites in the 3' Hp) displayed 69 distinct haplotypes, 22 of them belonging to group A, 27 to B, 18 to C and 2 to D, which denoted the great heterogeneity of our population. Further, 1a7A1, 1a7B1 and 1a1C1 were the most common sequences with 8, 9 and 9 chromosomes each. Association analysis between both 5' and 3' Hps revealed strong coherence with the proposed evolutionary histories for the beta-globin gene polymorphisms. 5'Hp1 (+----), which is considered to be an ancestral haplotype, was the most frequent haplotype found in our population and was linked to 24 different sequences in the 3'Hp, demonstrating great heterogeneity. A similar result was found in the 3' Hps, where older alleles (a17A1 and a7B1) were linked to a higher number of 5'Hps. This is the first time that an analysis of association among the 5' and 3' haplotypes and the LD has been performed with 40 polymorphisms distributed in the beta-globin gene cluster in the Mexican afromestizo population. The poor LD observed between and within the 5' and 3' Hps show that this region is very prone to recombination events.