Quantification of the close association between DNA haplotypes and specific β-thalassaemia mutations in Mediterraneans

It has been suggested that there is a close linkage between specific restriction fragment polymorphism patterns, defined as haplotypes, in the β-globin gene cluster and specific mutations in Mediterranean people with thalassaemia¹. This association formed the basis of a strategy for the efficient characterization of β-thalassaemia mutations from the DNA sequence of one or two β-thalassaemia genes derived from each haplotype in each ethnic group. Subsequently, Robertson and Hill argued that this strategy greatly underestimates the number of mutations on haplotypes which are frequent among normal chromosomes². We have therefore now analysed the proposed association and strategy quantitatively by the use of oligonucleotide hybridization and direct restriction analysis. Our results suggest that: (1) the association of specific haplotypes with specific mutations is high, but not invariant; (2) a different β-thalassaemia mutation has arisen within each haplotype in Mediterraneans; and (3) mutation spread from one haplotype to another occurs mainly through meiotic recombination within a 9-kilobase region 5′ to the β-globin gene