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When clinical geneticists think about phenylalanine hydroxylase (PAH), they think about mutations in the gene causing phenylketonuria (PKU) and the other metabolic diseases of phenylalanine hydroxylase deficiency, their diagnosis, and their treatment. When biochemical geneticists think about PAH, they think about metabolic pathways, enzyme activity levels, and metabolic substrates and products. When population geneticists think about PAH, they think about allele frequencies of disease-causing mutations and normal polymorphisms in different populations, the patterns of these variations in the populations, and what these frequencies and patterns mean in terms of disease gene and, more broadly, human evolution. We are population geneticists, and thus we will describe our studies of normal variation in the PAH gene in populations around the world.


Soon after the PAH cDNA was cloned, it was used as a probe to detect restriction fragment length polymorphisms (RFLPs) by Southern blotting (Lidsky et al,45; Woo et al,63). The linkage between PKU and PAH was, of course, very strong. In the effort to discover the mutation(s) leading to the hyperphenylalanemias, searching for a nonrandom association of disease with alleles of normal polymorphisms [linkage disequilibrium (LD)] in the PAH gene was a strategy to consider. The use of this strategy has now reached epidemic proportions in human genetics, especially for complex diseases (Capon et al,6; Horikawa et al,32; Kim et al,41; Myers et al,47; Sawcer et al,52; Scapoli et al,53; Vaessen et al,60), but often has low power unless there is strong prior support for a specific gene. In the case of PAH and PKU there was no question that the disorder is biochemically a deficiency of the enzyme and genetically inherited at (or very close to) the PAH gene. This is the very circumstance in which LD should be at its most powerful. Nevertheless, the simple version of this strategy did not work in the case of PKU because there was not a single etiologically crucial mutation, but, rather, many different PKU-causing mutations distributed across the approximately 90 kb of the gene. Recourse was to haplotypes. A haplotype is the combination of alleles at two or more polymorphisms close enough to one another on a chromosome that the alleles at the polymorphisms are usually transmitted through generations as an intact stretch of DNA. That is, recombination does not disrupt or scramble the combinations of alleles in the haplotype regions. The term is derived from haploid genotype (Ceppellini et al,7) and can refer to a specific combination of the variants at multiple sites or can refer to the entire system.

Although PKU showed no significant association with any single RFLP, in a sample of Danish families certain haplotypes were found to be disproportionately associated with the disease-causing mutations. This finding led to the identification of the first ...

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