LINKAGE DISEQUILIBRIUM AND EXTENDED HAPLOTYPES IN THE HLA-A TO D6S105REGION - IMPLICATIONS FOR MAPPING THE HEMOCHROMATOSIS GENE (HFE)

The hemochromatosis gene (HFE) maps to 6p21.3, in close linkage with t he HLA Class I genes. Linkage disequilibrium (LD) studies were designe d to narrow down the most likely candidate region for HFE, as an alter native to traditional linkage analysis. However, both the HLA-A and D6 S105 subregions, which are situated 2-3 cM and approximately 3 Mb apar t, have been suggested to contain HFE. The present report extends our previous study based upon the analysis of a large number of HFE and no rmal chromosomes from 66families of Breton ancestry. In addition to th e previously used RFLP markers spanning the 400-kb surrounding HLA-A, we examined three microsatellites: D6S510, HLA-F, and D6S105. Our comb ined data not only confirm a peak of LD at D6S105, but also reveal a c omplex pattern of LD over the i82 to D6S105 interval. Within our ethni cally well-defined population of Brittany, the association of HFE with D6S105 is as great as that with HLA-A, while the internal markers dis play a lower LD. Fine haplotype analysis enabled us to identify two ca tegories of haplotypes segregating with HFE. In contrast to the vast m ajority of normal haplotypes, 50% of HFE haplotypes are completely con served 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 configurati on might account for the apparent inconsistencies between genetic link age and LD data, and additionally greatly complicates positional cloni ng of HFE through disequilibrium mapping.