Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations

Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylket onuria (PKU), PAH was studied for normal polymorphisms and linkage disequil ibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-fre quency variation exists between some regions of the world. In European popu lations, linkage disequilibrium generally was found not to exist between RF LPs at opposite ends of the gene but was found to exist among the RFLPs clu stered at each end. We have now undertaken the first global survey of norma l variation and disequilibrium across the PAH gene. Four well-mapped single -nucleotide polymorphisms (SNPs) spanning similar to 75 kb, two near each e nd of the gene, were selected to allow linkage disequilibrium across most o f the gene to be examined. These SNPs were studied as PCR-RFLP markers in s amples of, on average, 50 individuals for each of 29 populations, including , for the first time, multiple populations from Africa and from the America s. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies >5% somewhere in the world , no haplotype was seen in all populations. Overall linkage disequilibrium is highly significant in all populations, but disequilibrium between the op posite ends is significant only in Native American populations and in one A frican population. This study demonstrates that the physical extent of link age disequilibrium can differ substantially among populations from differen t regions of the world, because of both ancient genetic drift in the ancest or common to a large regional group of modern populations and recent geneti c drift affecting individual populations.