History and Origin of β-Thalassemia in Turkey: Sequence Haplotype Diversity of β-Globin Genes

In the present study we report the sequence haplotypes associated with 22 β-globin gene mutations present in Turkey. Nine nucleotide polymorphisms and an (AT)xTy motif located at the 5′ end of the β-globin gene form the sequence haplotypes that were investigated in 204 unrelated βthalassemia and wild-type chromosomes from Turkey. Twelve sequence haplotypes were observed in the chromosomes analyzed and haplotypic heterogeneity was found in the wild-type β-globin genes. Samples from the Black Sea region demonstrated a remarkable level of haplotypic heterogeneity in contrast to the homogeneity present in Central Anatolian samples. Of the 22 β-globin mutations analyzed, 18 were related with single sequence haplotypes. This simple association led to the attempt to determine the origin of these mutations by comparing their frequencies in Turkey with those in other countries and/or the world distribution of the haplotypes carrying them. However, the presence of several exceptions for the “one haplotype/one mutation” rule showed that the β-globin gene cluster is far from static. Each of the IVS-I-110 (G→A), Cd 39 (C→T), IVS-I-6 (T→C), and –30 (T→A) βglobin mutations was associated with a minimum of two sequence haplotypes. This fact is best explained by the likelihood of strong recombination mechanisms taking place, rather than by assuming multiple origins for each of these alleles. According to our results, malarial selection for the oldest βthalassemia allele in Anatolia (i.e., IVS-I-110 G→A) may have occurred between 6500 and 2000 b.c. From that date on, most of the common β-thalassemia mutations in Turkey were established, and by the 13th century a.d. most of them were brought to frequencies close to those observed at present. β-thalassemia is an autosomal recessive disorder characterized by microcytosis and hemolytic anemia resulting from a variety of molecular defects that intervene with the normal synthesis of the β-globin chains of hemoglobin (Weatherall and Clegg 1981). β-thalassemia constitutes one of the most serious health problems Boğaziçi University, Department of Molecular Biology and Genetics, Istanbul, Turkey. Institut Pasteur, Unité de Biologie Moléculaire du Gène, Département d’Immunologie, Paris, France. Université Claude-Bernard, Lyon I, Centre de Génétique Moléculaire et Cellulaire, Villeurbanne, France. Human Biology, October 2001, v. 73, no. 5, pp. 661–674. Copyright © 2001 Wayne State University Press, Detroit, Michigan 48201-1309