Haplotype Analysis of -α^3.7 Chromosomes in Israeli Ethnic Groups Reveals Unexpected Heterogeneity and Demonstrates Ashkenazi Founder Groups in Carriers of α-Thalassemia.

α-thalassemia (α-thal) is among the world’s most common single gene disorders, whose prevalence in the “malaria belt” is attributed to a selective advantage of carriers. Our previous studies demonstrated a high frequency of deletional α-thal (nearly all heterozygotes or homozygotes for -α^3.7) in Ashkenazi Jews (carrier frequency of 7.9%, allele frequency of 0.04) (Rund et al, 2004). Ashkenazim resided in temperate climates for centuries and were not subject to malarial selection pressure, and their carriership for β-thalassemia is very low (estimated <0.1%). To elucidate the genetic mechanism(s) responsible for this high frequency of α-thal, we performed α-globin haplotype analysis on 170 chromosomes (chromos) of 85 homozygotes for -α^3.7. We compared chromos of several ethnic groups: Jews (Ashkenazim: 54 chromos, Yemenites: 54 chromos, Iraqis: 14 chromos, others: 14 chromos), Arabs (28 chromos), and Druze (6 chromos). Using PCR and digestion with ApaI and RsaI, it was determined that all but three of the chromos are of the -α^3.7I type. Haplotype analysis was performed for polymorphic sites identified by Higgs (1986), using PCR and restriction enzyme digestion. Altogether, 13 haplotypes were found. Unexpectedly, at least 5 haplotypes were found among the Ashkenazim with a large number of chromos carrying unknown haplotypes. Interestingly, 26/54 of Ashkenazi chromos carried haplotype IIIb which is found rarely in Europe and Saudi Arabia but most commonly in Melanesia and Papua New Guinea (Flint, 1992). In contrast, only 3/116 nonAshkenazi chromos carried haplotype IIIb. Interestingly there was little overlap in haplotypes between Ashkenazim and the various ethnic groups studied including the other Jewish groups, with 2 exceptions. First, Arabs and Yemenite Jews each were found to have around 50% chromos which carried haplotype Ia. Additionally, 10% of Ashkenazim and 20% of Yemenites had chromos carrying haplotype IIh, which is a haplotype originally described in an Australiam Aboriginal tribe (Roberts-Thomson, 1996). There was no overlap between Arabs and Druze. In conclusion, α-globin haplotype analysis demonstrates diversity within an apparently homogeneous ethnic group (Ashkenazim homozygous for -α^3.7) and demonstrates founder effects in Ashkenazim carrying α-globin gene rearrangements.