DETECTION OF LINKAGE DISEQUILIBRIUM IN AFRICAN AMERICANS NEAR THE FY GENE

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Linkage disequilibrium can be produced by the admixture of previously separated populations containing polymorphic loci with different allele frequencies between the groups. This is the basis of the method for mapping disease loci called mapping by admixture linkage disequilibrium (MALD). African Americans (AAs) are a suitable population for MALD studies since they have an estimated 15% - 30% Caucasian ancestry. To obtain parameters that will be useful for the design of future MALD studies, an investigation was initiated to determine the extent of linkage disequilibrium in AAs in the vicinity of the FY locus. In essence, most AAs and all Africans have a point mutation in the FY promoter that is absent in Caucasians. A high-throughput converted restriction fragment length polymorphism assay was developed for this mutation and performed on a panel of DNAs from 2,268 individuals. Of the 790 AAs included in this analysis, 31 were found to be homozygous for the Caucasian allele, 248 were heterozygous, and the remainder were homozygous for the African allele. The map location of FY relative to chromosome 1 markers D1S2635 and SPTA1 was confirmed by analysis of yeast artificial chromosomes (YACs) and radiation hybrid mapping. Two separate YACs contain all three of these markers, indicating that they reside within a 1.7 megabase segment of DNA. In addition, a panel containing 22 fluorescent dye-labeled microsatellite markers was devised to detect potential linkage disequilibrium at distances up to 30 centiMorgans on each side of FY. The marker density is greatest in the immediate vicinity of that gene. These markers were shown to amplify products of the expected size in a panel of DNAs established to optimize polymerase chain reaction conditions. These markers will be typed on DNAs from the 31 AAs homozygous for the Caucasian FY allele as well as about 70 samples each from heterozygous AAs and AAs homozygous for the African allele. Statistical tests will be performed to determine if the allele distribution for the flanking markers is significantly different among these three groups. These results will help elucidate the distance that MALD will be effective in establishing linkage between disease loci and microsatellite markers in genome-wide surveys.