The worldwide distribution of the VHL 598C>T mutation indicates a single founding event |
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Authors: | Liu Enli Percy Melanie J Amos Christopher I Guan Yongli Shete Sanjay Stockton David W McMullin Mary F Polyakova Lydia A Ang Sonny O Pastore Yves D Jedlickova Katerina Lappin Terry R J Gordeuk Victor Prchal Josef T |
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Affiliation: | Baylor College of Medicine and Veterans Affairs Medical Center, Houston, TX, USA. |
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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. |
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