Fan Yanli, Green Jane S, Ross Alison J, Beales Philip L, Parfrey Patrick S, Davidson William S
Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6.
Hum Genet. 2005 Jan;116(1-2):62-71. doi: 10.1007/s00439-004-1184-9. Epub 2004 Oct 23.
Genetically isolated populations, such as Newfoundland, have contributed greatly to the identification of disease-causing genes. A linkage disequilibrium (LD) study involving six Newfoundland families predicted a critical interval for Bardet-Biedl syndrome 1 (BBS1) (Young et al. in Am J Hum Genet 65:1680-1687, 1999), but the subsequent identification of BBS1 revealed that it lies outside this region. This suggested that either there is another gene responsible for BBS in these families or the Newfoundland population may not be ideal for LD studies. We screened these six Newfoundland families for mutations in BBS1 and found that affected individuals in five of them were homozygous for the same M390R mutation. There was no evidence for any BBS1 mutation in the affected individual in the sixth family. Therefore, one of the criteria for LD mapping was not met; namely, there should be a single disease-causing allele in the population. Haplotype analysis of unaffected individuals from south-west Newfoundland and English BBS1 patients homozygous for M390R, revealed that a second criterion for LD mapping was violated. The M390R mutation occurred in a common haplotype and both of these chromosomes, the ancestral wild-type and disease-causing haplotypes, were introduced to Newfoundland and spread by a founder effect. Moreover, it was found that disease-associated alleles occurred at relatively high frequencies in normal haplotypes and this probably accounted for the incorrect prediction in the previous LD study. Knowing the amount of genetic variation and its distribution in the Newfoundland population would be useful to maximize its potential for mapping hereditary disorders.
基因隔离群体，如纽芬兰人群体，对致病基因的鉴定做出了巨大贡献。一项涉及六个纽芬兰家庭的连锁不平衡（LD）研究预测了巴德-比德尔综合征1（BBS1）的关键区间（Young等人，《美国人类遗传学杂志》65:1680 - 1687，1999年），但随后对BBS1的鉴定表明它位于该区域之外。这表明要么在这些家庭中有另一个基因导致BBS，要么纽芬兰人群体可能不太适合进行LD研究。我们对这六个纽芬兰家庭进行了BBS1突变筛查，发现其中五个家庭的患病个体对于相同的M390R突变是纯合的。在第六个家庭的患病个体中没有发现任何BBS1突变的证据。因此，LD定位的一个标准未得到满足；即，人群中应该只有一个致病等位基因。对来自纽芬兰西南部的未患病个体和M390R纯合的英国BBS1患者进行单倍型分析，发现LD定位的第二个标准也被违反了。M390R突变发生在一个常见的单倍型中，并且这两条染色体，即祖先野生型和致病单倍型，都被引入到了纽芬兰并通过奠基者效应传播开来。此外，还发现疾病相关等位基因在正常单倍型中出现的频率相对较高，这可能是之前LD研究中预测错误的原因。了解纽芬兰人群体中的遗传变异量及其分布，对于最大限度地发挥其在遗传性疾病定位方面的潜力将是有用的。
