Molecular evidences of single mutational events followed by recurrent crossing-overs in the common δ-globin alleles in the Mediterranean area

The human δ-globin gene (HBD) is one of the β-like globin genes expressed in adults. In the Mediterranean countries the carriers of δ-thalassemia defects or Hb A2-variants are > 1% and about 40/70 known alleles have been found in families with this ethnic origin. The scope of this study was to investigate the variability of the gene and of the chromosomal background in order to highlight the origin and spreading of the δ-globin gene alleles in the Mediterranean area. We carried out the characterization of the δ-globin gene alleles and of RFLP-haplotypes, SNPs and one microsatellite associated with them in 231 carriers originating principally from East Sicily. Seventeen alleles were identified, of which five were new. The chromosomes associated with mutated alleles from unrelated carriers were 158; the allele Hb A2-Yialousa accounted for about 75% of relative frequency, Hb A2-Mitsero for about 8%. The alleles were associated with RFLP 5'-haplotypes “− − − −” or “+ − + +”, prevalent in the Mediterranean area, except Hb A2-Mitsero associated with the 5'-haplotype “Benin” “− − − +” and the Hb A2' associated with “+ − − +”, both of African origin. Each allele showed linkage with one haplotype with these exceptions. The Hb A2-Yialousa showed heterogeneity of the 5'-haplotype in 2/58 chromosomes; the Hb A2-Mitsero showed SNPs and Aγ-microsatellite typical of a “Benin” haplotype found associated with the Hb C and Hb S chromosomes; the Hb A2-Yialousa (14/58 chromosomes), Hb A2-Mitsero, Hb A2-Pylos, Hb A2-Fitzroy showed heterogeneity in the 3'-haplotypes and β-globin gene SNPs. The Hb A2-Coburg was found associated with the haplotype “+ − + +/+ +” different from that already reported “− − − −/+ −”. With the exception of this last allele, the linkage of each mutation with a core of RFLPs or SNPs around or inside the δ-globin locus suggested the unicentric origin of the mutations followed by recurrent recombination events causing the chromosomal background heterogeneity.