title: The role of human demographic history in determining the distribution and frequency of transferase-deficient galactosaemia mutations.
abstract: Classical or transferase-deficient galactosaemia is an inherited metabolic disorder caused by mutation in the human Galactose-1-phosphate uridyl transferase (GALT) gene. Of some 170 causative mutations reported, fewer than 10% are observed in more than one geographic region or ethnic group. To better understand the population history of the common GALT mutations, we have established a haplotyping system for the GALT locus incorporating eight single nucleotide polymorphisms and three short tandem repeat markers. We analysed haplotypes associated with the three most frequent GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and estimated their age. Haplotype diversity, in conjunction with measures of genetic diversity and of linkage disequilibrium, indicated that Q188R and K285N are European mutations. The Q188R mutation arose in central Europe within the last 20 000 years, with its observed east-west cline of increasing relative allele frequency possibly being due to population expansion during the re-colonization of Europe by Homo sapiens in the Mesolithic age. K285N was found to be a younger mutation that originated in Eastern Europe and is probably more geographically restricted as it arose after all major European population expansions. The D2 variant was found to be an ancient mutation that originated before the expansion of Homo sapiens out of Africa.
authors.affiliation: Department of Pathology, The Children's University Hospital, Dublin, Ireland. Jonathan.Flanagan@stjude.org
authors.forename: J M
authors.initials: JM
authors.lastname: Flanagan
authors.forename: G
authors.initials: G
authors.lastname: McMahon
authors.forename: S H
authors.initials: SH
authors.lastname: Brendan Chia
authors.forename: P
authors.initials: P
authors.lastname: Fitzpatrick
authors.forename: O
authors.initials: O
authors.lastname: Tighe
authors.forename: C
authors.initials: C
authors.lastname: O'Neill
authors.forename: P
authors.initials: P
authors.lastname: Briones
authors.forename: L
authors.initials: L
authors.lastname: Gort
authors.forename: L
authors.initials: L
authors.lastname: Kozak
authors.forename: A
authors.initials: A
authors.lastname: Magee
authors.forename: E
authors.initials: E
authors.lastname: Naughten
authors.forename: B
authors.initials: B
authors.lastname: Radomyska
authors.forename: M
authors.initials: M
authors.lastname: Schwartz
authors.forename: J S
authors.initials: JS
authors.lastname: Shin
authors.forename: W M
authors.initials: WM
authors.lastname: Strobl
authors.forename: L A
authors.initials: LA
authors.lastname: Tyfield
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
authors.forename: H
authors.initials: H
authors.lastname: Russell
authors.forename: G
authors.initials: G
authors.lastname: Bertorelle
authors.forename: J K V
authors.initials: JK
authors.lastname: Reichardt
authors.forename: P D
authors.initials: PD
authors.lastname: Mayne
authors.forename: D T
authors.initials: DT
authors.lastname: Croke
mesh_terms: D005060:Europe; D005260:Female; D005693:Galactosemias / Q000201:enzymology* / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase / Q000172:deficiency / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase