Population specific patterns of novel haplotype groups at the PAH locus

The phenylalanine hydroxylase (PAH) gene is of particular interest for population genetic studies because the distribution patterns of well-defined henylketonuria (PKU [MIM 261600]) mutations can be linked with distinct SNP haplotypes for the assessment of ancient migration. Through family segregation analysis and molecular haplotyping with long-range PCR in PKU patients (232 PAH mutant alleles) and controls (157 PAH normal alleles) from various European countries we identified five major haplotypes n the distal 15 kb region of the PAH ene. Haplotypes differ by 3-16 specific SNPs each and have been quite stable over the last millennia. The 29 common European PKU mutations can be linked to specific haplotypes with little evidence of recombination in the PAH gene. The results were compared to available sequencing data of Africans, East Asians, Europeans, and Admixed Americans from the 1000 Genomes Project. Additional data from chimpanzee, orangutan, and macaque, as well as high coverage sequences of Neandertal and Denisova, were used in conjunction with these data to establish a possible evolutionary tree of haplotype emergence. There are five major distal PAH haplotypes that can be found in all continental populations, but at different relative frequencies.