A HAPLOTYPE AND LINKAGE DISEQUILIBRIUM ANALYSIS OF THE HEREDITARY HEMOCHROMATOSIS GENE REGION

Hereditary hemochromatosis is a recessive disease of iron metabolism w idely distributed among people of European descent. Most patients have inherited the causative mutation from a single ancestor. In the cours e of cloning the hemochromatosis gene, genotypes were generated for th ese samples at 43 microsatellite repeat markers that span the 6.5-Mb h emochromatosis gene region. The data used to reconstruct the ancestral haplotype across the hemochromatosis gene region are presented in thi s paper. Portions of the ancestral haplotype were present on 85% of pa tient chromosomes in this sample and ranged in size from approximately 500 kb to greater than 6.5 Mb. Only one marker, D6S2239, was identica l by descent on all of the patient chromosomes containing the ancestra l mutation. In contrast, only 3 of the 128 control chromosomes, or 2.3 %, carried the ancestral mutation and the surrounding ancestral haplot ype. To test new methods for gene finding using linkage disequilibrium we analyzed the genotypic data with a multilocus maximum likelihood m ethod (DISMULT) and a single point method (DISLAMB), both written to a nalyze data generated from multi-allelic markers. The maximum value fr om DISLAMB analysis occurred at marker D6S2239, which is less than 20 kb from the hemochromatosis gene HFE, consistent with the haplotype an alysis. The peak of the multi-point analysis was 700 kb from HFE, poss ibly due to the nonuniform recombination rates within this large regio n. The recombination rate appears to be lower than expected centromeri c of the HFE gene.