title: Genetic diversity within the R408W phenylketonuria mutation lineages in Europe.
abstract: 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.
authors.affiliation: Department of Pathology and National Centre for Newborn Screening, The Children's University Hospital, Dublin, Ireland.
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.forename: Donncha
authors.initials: D
authors.lastname: Dunican
authors.forename: Charles
authors.initials: C
authors.lastname: O'Neill
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bertorelle
authors.forename: Diane
authors.initials: D
authors.lastname: Beattie
authors.forename: Colin
authors.initials: C
authors.lastname: Graham
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Francesco
authors.initials: F
authors.lastname: Cali
authors.forename: Valentino
authors.initials: V
authors.lastname: Romano
authors.forename: Eva
authors.initials: E
authors.lastname: Hrabincova
authors.forename: Libor
authors.initials: L
authors.lastname: Kozak
authors.forename: Marina
authors.initials: M
authors.lastname: Nechyporenko
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Livshits
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.forename: Monika
authors.initials: M
authors.lastname: Jurkowska
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
authors.forename: Belen
authors.initials: B
authors.lastname: Perez
authors.forename: Lourdes Ruiz
authors.initials: LR
authors.lastname: Desviat
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Vaidutis
authors.initials: V
authors.lastname: Kucinskas
authors.forename: Per
authors.initials: P
authors.lastname: Knappskog
authors.forename: Eileen
authors.initials: E
authors.lastname: Treacy
authors.forename: Eileen
authors.initials: E
authors.lastname: Naughten
authors.forename: Linda
authors.initials: L
authors.lastname: Tyfield
authors.forename: Susan
authors.initials: S
authors.lastname: Byck
authors.forename: Charles R
authors.initials: CR
authors.lastname: Scriver
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mayne
authors.forename: David T
authors.initials: DT
authors.lastname: Croke
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D001120:Arginine / Q000235:genetics*; D005060:Europe; D018703:Founder Effect; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D018598:Minisatellite Repeats / Q000235:genetics; D009154:Mutation; D010661:Phenylketonurias / Q000201:enzymology / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics*
chemical_list: D014364:Tryptophan; D001120:Arginine