The phenylalanine hydroxylase locus: a marker for the history of phenylketonuria and human genetic diversity. PAH Mutation Analysis Consortium.

Disease-producing allelic variation describes one aspect of human genetic diversity. Phenylketonuria, the major type of hyperphenylalaninaemia and formerly a functional genetic lethal, has a 2% carrier frequency in temperate-zone populations. Newborn screening for hyperphenylalaninaemia (incidence of 1 in 10000) has made it one of the most widely ascertained human Mendelian traits; 99% of hyperphenylalaninaemia mutations map to the PAH (phenylalanine hydroxylase) gene on 12q24.1, and most cause phenylketonuria. The gene is well characterized. Analysis of 3986 mutant chromosomes by 81 investigators in 26 countries has identified 243 different mutations in 788 different associations (with polymorphic intragenic haplotypes [seven diallelic sites, one short tandem repeat, one variable number of tandem repeats], populations and regions). These data are compiled on a database accessible on the World-Wide Web or as a stand-alone software package. A few phenylketonuria alleles occur at high relative frequencies in particular populations on one or only a few haplotypes, suggesting positive selection in the past. Additional mechanisms (founder effect, drift and recurrent mutation) can explain frequencies and distributions of particular alleles. Allele stratification in Europeans and Orientals implies that mechanism(s) accounting for distribution and high frequencies of PAH alleles were acting before and during demic expansion in Europe and after the European and Oriental radiations.