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Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE)

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Abstract

The hemochromatosis gene (HFE) maps to 6p21.3, in close linkage with the HLA Class I genes. Linkage disequilibrium (LD) studies were designed to narrow down the most likely candidate region for HFE, as an alternative to traditional linkage analysis. However, both the HLA-A and D6S105 subregions, which are situated 2–3 cM and approximately 3 Mb apart, have been suggested to contain HFE. The present report extends our previous study based upon the analysis of a large number of HFE and normal chromosomes from 66families of Breton ancestry. In addition to the previously used RFLP markers spanning the 400-kb surrounding HLA-A, we examined three microsatellites: D6S510, HLA-F, and D6S105. Our combined data not only confirm a peak of LD at D6S105, but also reveal a complex pattern of LD over the i82 to D6S105 interval. Within our ethnically well-defined population of Brittany, the association of HFE with D6S105 is as great as that with HLA-A, while the internal markers display a lower LD. Fine haplotype analysis enabled us to identify two categories of haplotypes segregating with HFE. In contrast to the vast majority of normal haplotypes, 50% of HFE haplotypes are completely conserved over the HLA-A to D6S105 interval. These haplotypes could have been conserved through recombination suppression, selective forces and/or other evolutionary factors. This particular haplotypic configuration might account for the apparent inconsistencies between genetic linkage and LD data, and additionally greatly complicates positional cloning of HFE through disequilibrium mapping.

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  1. Jacqueline Yaouanq

    Present address: UPR 41 CNRS, Faculté de Médecine, 2, Avenue du Pr Léon Bernard, 35043, Rennes Cedex, France

Authors and Affiliations

  1. UPR 41 CNRS “Recombinaisons Génétiques”, Faculté de Médecine, 35043, Rennes, France

    Gwenola Gandon, Anne Marie Jouanolle, Bruno Chauvel, Valérie Mauvieux, André Le Treut, Jean Yves Le Gall & Véronique David

  2. Unité INSERM 155 d'Epidémiologie Génétique, 75016, Paris, France

    Josué Feingold

  3. Service d'Epidémiologie et Hygiène Hospitalière, CHU, 35033, Rennes, France

    Jacqueline Yaouanq

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  1. Gwenola Gandon
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  2. Anne Marie Jouanolle
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  3. Bruno Chauvel
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  4. Valérie Mauvieux
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  7. Jean Yves Le Gall
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  8. Véronique David
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  9. Jacqueline Yaouanq
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Gandon, G., Jouanolle, A.M., Chauvel, B. et al. Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE). Hum Genet 97, 103–113 (1996). https://doi.org/10.1007/BF00218843

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