Genetic diversity within the R408W phenylketonuria mutation lineages in Europe.
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.
Tighe
Orna
O
Department of Pathology and National Centre for Newborn Screening, The Children's University Hospital, Dublin, Ireland.
Dunican
Donncha
D
O'Neill
Charles
C
Bertorelle
Giorgio
G
Beattie
Diane
D
Graham
Colin
C
Zschocke
Johannes
J
Cali
Francesco
F
Romano
Valentino
V
Hrabincova
Eva
E
Kozak
Libor
L
Nechyporenko
Marina
M
Livshits
Ludmilla
L
Guldberg
Per
P
Jurkowska
Monika
M
Zekanowski
Cezary
C
Perez
Belen
B
Desviat
Lourdes Ruiz
LR
Ugarte
Magdalena
M
Kucinskas
Vaidutis
V
Knappskog
Per
P
Treacy
Eileen
E
Naughten
Eileen
E
Tyfield
Linda
L
Byck
Susan
S
Scriver
Charles R
CR
Mayne
Philip D
PD
Croke
David T
DT
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*
D014364:Tryptophan; D001120:Arginine