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

In the present study we report the sequence haplotypes associated with 22 b-globin gene mutations present in Turkey. Nine nucleotide polymorphisms and an (AT)xTy motif located at the 5¢ end of the b-globin gene form the sequence haplotypes that were investigated in 204 unrelated b- thalassemia and wild-type chromosomes from Turkey. Twelve sequence haplotypes were observed in the chromosomes analyzed and haplotypic heterogeneity was found in the wild-type b-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 b-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 b-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) b- globin 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 b- thalassemia 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 b-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

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

Abstract 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) x T y motif located at the 5′ end of the β-globin gene form the sequence haplotypes that were investigated in 204 unrelated β-thalassemia 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) β-globin 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 β-thalassemia 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 hemoglobi

Origin and History of the IVS-I-110 and Codon 39 β-Thalassemia Mutations in the Lebanese Population

Using restriction fragment length polymorphisms (RFLPs) and sequence haplotype analysis, we studied the chromosomal background of the β-globin gene in 31 unrelated Lebanese IVS-I-110 or codon 39 (Cd39) subjects, and five normal βA/βA individuals. Our results are compared with those from similar studies in other parts of the Mediterranean in an attempt to provide insights into historical patterns of selection and disease. The great majority of the Lebanese chromosomes with the IVS-I-110 mutation are associated with the RFLP haplotype I and sequence haplotype HT1, which is probably the ancestral structure on which the mutation first emerged. The remainder of the IVS-I-110 alleles are linked to the 5′-subhaplotype 12 RFLP haplotype and/or HTR sequence haplotype. In contrast, in Turkey, IVS-I-110 is associated with six distinct sequence haplotypes and four distinct RFLP haplotypes, suggesting that the mutation probably emerged there. The diversity of sequence haplotypes described in Turkey was probably generated through recombination or gene conversion events with the most frequent βA autochthonous structures. Our data on Lebanese βA chromosomes and Algerian βA chromosomes, along with previously described Turkish βA chromosomes, strengthen this hypothesis. Following its emergence in Turkey, the IVS-I-110 mutation was probably introduced to Lebanon later, by migration or settlements. Cd39 demonstrates a remarkable level of sequence and RFLP haplotype heterogeneity in Algeria, in contrast to its relative homogeneity in Turkish samples. However, its rarity in the Near East, and more specifically in Lebanon, does not allow us to draw any conclusions concerning its origin and gene flow

Hérodote

Recoupant d’emblée les champs qui seront ceux de la géographie, de l’ethnographie, de l’histoire et même de la philosophie de l’histoire, fascinée à la fois par l’altérité et par la diversité des peuples et des coutumes, l’Enquête hérodotéenne dialogue sans cesse avec les autres genres et les autres modes de pensée que l’Antiquité nous a légués. Après d’autres travaux, individuels et collectifs, ce recueil d’essais a cherché à cerner les modalités et les enjeux de ce dialogue, mais en y ajoutant celui qui s’est instauré entre Hérodote et ses lecteurs, admiratifs ou critiques, de l’Antiquité jusqu’à nos jours. L’Enquête est donc ici mise en rapport avec l’épopée, la pensée ionienne, le théâtre athénien, mais aussi confrontée à des lectures aussi différentes que celles de Lucien dans l’Antiquité, de Montaigne à la Renaissance et, tout près de nous, de Ryszard Kapuściński ou de Claude Lévi-Strauss. Qu’il s’agisse des grandes questions anthropologiques posées par tout effort de compréhension et de représentation de l’autre ou des choix narratifs qu’implique toute tentative d’écrire l’histoire, cet éclairage pluriel témoigne de l’actualité sans cesse renouvelée de l’entreprise hérodotéenne

Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules.

International audienceHypoxia has been suspected to trigger transdifferentiation of renal tubular cells into myofibroblasts in an epithelial-to-mesenchymal transition (EMT) process. To determine the functional networks potentially altered by hypoxia, rat renal tubule suspensions were incubated under three conditions of oxygenation ranging from normoxia (lactate uptake) to severe hypoxia (lactate production). Transcriptome changes after 4 h were analyzed on a high scale by restriction fragment differential display. Among 1,533 transcripts found, 42% were maximally expressed under severe hypoxia and 8% under mild hypoxia (Po(2) = 48 mmHg), suggesting two different levels of oxygen sensing. Normoxia was required for full expression of the proximal tubule-specific transcripts 25-hydroxyvitamin D 1-hydroxylase (Cyp27b1) and l-pyruvate kinase (Pklr), transcripts involved in tissue cohesion such as fibronectin (Fn1) and N-cadherin (Cdh2), and non-muscle-type myosin transcripts. Mild hypoxia increased myogenin transcript level. Conversely, severe hypoxia increased transcripts involved in extracellular matrix remodeling, those of muscle-type myosins, and others involved in creatine phosphate synthesis and lactate transport (Slc16a7). Accordingly, microscopy showed loss of tubule aggregation under hypoxia, without tubular disruption. Hypoxia also increased the levels of kidney-specific transcripts normally restricted to the less oxygenated medullary zone and others specific for the distal part of the nephron. We conclude that extensive oxygen supply to the kidney tubule favors expression of its differentiated functions specifically in the proximal tubule, whose embryonic origin is mesenchymal. The phenotype changes could potentially permit transient adaptation to hypoxia but also favor pathological processes such as tissue invasion