Allelic stability of VNTR locus 3' alpha HVR: linkage disequilibrium with the common alpha-thalassaemia-1 deletion of South-East Asia (--SEA/)

Abstract

Variable number of tandem repeats (VNTR) loci are among the most polymorphic sequences described to date. VNTR allelic variability is a function of the high rates of de novo mutation due to intra- and inter-allelic recombination. We have assessed the allelic stability of VNTRs during recent human evolution, focusing on the relationship between an alpha-thalassaemia-1 deletion that is common among South-East Asian populations (--SEA/) and a VNTR located immediately down-stream of the alpha-globin gene cluster (3'alpha HVR). More than 50 unrelated (--SEA/) carriers were analyzed using a strategy that allowed the unambiguous assignment of a carrier's 3'alpha HVR alleles to either the normal or the (--SEA/) chromosome. The analysis revealed that 89% of the (--SEA/) chromosomes are associated with 3'alpha HVR alleles that fall within a limited size range (5,415-6,442 bp for PvuII digests). In contrast, only 4% of the carriers' normal chromosomes are associated with 3'alpha HVR alleles of this size range, and surveys of other racial and ethnic populations confirm that these 3' alpha HVR alleles are uncommon in general. Overall, these data indicate that the (--SEA/) deletion originally occurred on a chromosome marked by a rare 3'alpha HVR allele, and that this association has been relatively stable over the course of recent human evolution in South-East Asia.