title: The worldwide distribution of the VHL 598C>T mutation indicates a single founding event.
abstract: The first congenital defect of hypoxia-sensing homozygosity for VHL 598C>T mutation was recently identified in Chuvash polycythemia. Subsequently, we found this mutation in 11 unrelated individuals of diverse ethnic backgrounds. To address the question of whether the VHL 598C>T substitution occurred in a single founder or resulted from recurrent mutational events in human evolution, we performed haplotype analysis of 8 polymorphic markers covering 340 kb spanning the VHL gene on 101 subjects bearing the VHL 598C>T mutation, including 72 homozygotes (61 Chuvash and 11 non-Chuvash) and 29 heterozygotes (11 Chuvash and 18 non-Chuvash), and 447 healthy unrelated individuals from Chuvash and other ethnic groups. The differences in allele frequencies for each of the 8 markers between 447 healthy controls (598C) and 101 subjects bearing the 598T allele (P < 10(-7)) showed strong linkage disequilibrium. Haplotype analysis indicated a founder effect. We conclude that the VHL 598C>T mutation, the most common defect of congenital polycythemia yet found, was spread from a single founder 1,000 to 62,000 years ago.
authors: Baylor College of Medicine and Veterans Affairs Medical Center, Houston, TX, USA.
authors: Enli
authors: E
authors: Liu
authors: Melanie J
authors: MJ
authors: Percy
authors: Christopher I
authors: CI
authors: Amos
authors: Yongli
authors: Y
authors: Guan
authors: Sanjay
authors: S
authors: Shete
authors: David W
authors: DW
authors: Stockton
authors: Mary F
authors: MF
authors: McMullin
authors: Lydia A
authors: LA
authors: Polyakova
authors: Sonny O
authors: SO
authors: Ang
authors: Yves D
authors: YD
authors: Pastore
authors: Katerina
authors: K
authors: Jedlickova
authors: Terry R J
authors: TR
authors: Lappin
authors: Victor
authors: V
authors: Gordeuk
authors: Josef T
authors: JT
authors: Prchal
mesh_terms: D000483:Alleles; D004252:DNA Mutational Analysis; D018703:Founder Effect; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D011086:Polycythemia / Q000235:genetics*; D011110:Polymorphism, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human