A haplotype and linkage disequilibrium analysis of the hereditary hemochromatosis gene region.

Hereditary hemochromatosis is a recessive disease of iron metabolism widely distributed among people of European descent. Most patients have inherited the causative mutation from a single ancestor. In the course of cloning the hemochromatosis gene, genotypes were generated for these samples at 43 microsatellite repeat markers that span the 6.5-Mb hemochromatosis gene region. The data used to reconstruct the ancestral haplotype across the hemochromatosis gene region are presented in this paper. Portions of the ancestral haplotype were present on 85% of patient chromosomes in this sample and ranged in size from approximately 500 kb to greater than 6.5 Mb. Only one marker, D6S2239, was identical by descent on all of the patient chromosomes containing the ancestral mutation. In contrast, only 3 of the 128 control chromosomes, or 2.3%, carried the ancestral mutation and the surrounding ancestral haplotype. To test new methods for gene finding using linkage disequilibrium we analyzed the genotypic data with a multilocus maximum likelihood method (DISMULT) and a single point method (DISLAMB), both written to analyze data generated from multi-allelic markers. The maximum value from DISLAMB analysis occurred at marker D6S2239, which is less than 20 kb from the hemochromatosis gene HFE, consistent with the haplotype analysis. The peak of the multi-point analysis was 700 kb from HFE, possibly due to the nonuniform recombination rates within this large region. The recombination rate appears to be lower than expected centromeric of the HFE gene.