Genetic diversity within the R408W phenylketonuria mutation lineages in Europe

Orna Tighe, Donncha Dunican, Charles O'Neill, Giorgio Bertorelle, Diane Beattie, Colin Graham, Johannes Zschocke, Francesco Cali, Valentino Romano, Eva Hrabincova, Libor Kozak, Marina Nechyporenko, Ludmilla Livshits, Per Guldberg, Monika Jurkowska, Cezary Zekanowski, Belen Perez, Lourdes Ruiz Desviat, Magdalena Ugarte, Vaidutis KučinskasPer Knappskog, Eileen Treacy, Eileen Naughten, Linda Tyfield, Susan Byck, Charles R. Scriver, Philip D. Mayne, David T. Croke

Research output: Contribution to journalArticlepeer-review


The R408W phenylketonuria mutation in Europe has arisen by recurrent mutation in the human phenylalanine hydroxylase (PAH) locus and is associated with two major PAH haplotypes. R408W-2.3 exhibits a west-to-east cline of relative frequency reaching its maximum in the Balto-Slavic region, while R408W-1.8 exhibits an east-to-west cline peaking in Connacht, the most westerly province of Ireland. Spatial autocorrelation analysis has demonstrated that the R408W-2.3 cline, like that of R408W-1.8, is consistent with a pattern likely to have been established by human dispersal. Genetic diversity within wild-type and R408W chromosomes in Europe was assessed through variable number tandem repeat (VNTR) nucleotide sequence variation and tetranucleotide short tandem repeat (STR) allelic associations. Wild-type VNTR-8 chromosomes exhibited two major cassette sequence organizations: (a1)5-b3-b2-c1 and (a1)5-b5-b2-c1. R408W-1.8 was predominantly associated with (a1)5-b5-b2-c1. Both wild-type VNTR-3 and R408W-2.3 chromosomes exhibited a single invariant cassette sequence organization, a2-b2-c1. STR allele distributions associated with the cassette variants were consistent with greater diversity in the wild-type VNTR-8 lineage and were suggestive of different levels of diversity between R408W-1.8 and R408W-2.3. The finding of greater genetic diversity within the wild-type VNTR-8 lineage compared to VNTR-3 suggests that VNTR-8 may be older within the European population. However, in the absence of a more extensive STR data-set, no such conclusions are possible for the respective R408W mutant lineages.

Original languageEnglish
Pages (from-to)387-393
Number of pages7
JournalHuman Mutation
Issue number4
Publication statusPublished - 2003


  • Europe
  • PAH
  • Phenylalanine hydroxylase
  • Phenylketonuria
  • PKU
  • Population genetics
  • STR
  • VNTR

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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