Genetic diversity within the R408W phenylketonuria mutation lineages in Europe

Abstract

For the PKU Special IssueThe 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. Hum Mutat 21:387-393,

PAHdb 2003: What a locus-specific knowledgebase can do

“…Several PAH mutations, identical by state in their nucleotide change, occur on two or more different haplotype backgrounds. For example R408W, the most prevalent pathogenic PAH allele, occurs prominently on haplotypes 1 and 2 in European-derived populations [John et al, 1990;Treacy et al, 1993;Eisensmith et al, 1995;Tighe et al, 2003]. Because a CpG dinucleotide is involved, R408W has the potential to be a recurrent mutation and identical only by state on haplotypes 1 and 2 [Byck et al, 1994;Tighe et al, 2003].…”

Left ventricular structure in relation to the human SAH gene in the European Project on Genes in Hypertension

“…In the latter study, 18 Slavic compared with Italian subjects also had higher LVMI. Other investigators reported ethnic diversity between western European and Slavic populations in various genetic polymorphisms, [19][20][21] which is probably due to differing genetic evolution along the migration patterns when Europe started to be populated from the Middle East and North Africa. [22][23][24] Research into the SAH gene found its roots in studies of genes, which are overexpressed in genetically hypertensive rats.…”

The role of human demographic history in determining the distribution and frequency of transferase-deficient galactosaemia mutations

“…Control DNA samples (n ¼ 60) from individuals of Irish ethnicity were obtained with informed consent and local ethical approval; these were used to analyse the extent of polymorphism of candidate SNP and STR markers. In addition, a set of anonymized singleton DNA samples from 15 European populations (n ¼ 117) was used to assess the level of wild-type GALT haplotype diversity; these were obtained previously in the context of a study of PAH gene VNTR sequence diversity (Tighe et al, 2003) and included: Republic of Ireland (n ¼ 72), Northern Ireland (n ¼ 10), Scotland (n ¼ 8), Spain (n ¼ 5), Germany (n ¼ 7), Denmark (n ¼ 4) and Poland (n ¼ 11).…”