Genereux Diane P, Laird Charles D
Department of Biology, Box 351800; University of Washington.
Genes Genet Syst. 2013;88(3):211-24. doi: 10.1266/ggs.88.211.
Asian and non-Asian populations have been reported to differ substantially in the distribution of fragile X alleles into the normal (< 55 CGG repeats), premutation (55-199 CGG repeats), and full-mutation (> 199 CGG repeats) size classes. Our statistical analyses of data from published general-population studies confirm that Asian populations have markedly lower frequencies of premutation alleles, reminiscent of earlier findings for expanded alleles at the Huntington's Disease locus. To examine historical and contemporary factors that may have shaped and now sustain allele-frequency differences at the fragile X locus, we develop a population-genetic/epigenetic model, and apply it to these published data. We find that founder-haplotype effects likely contribute to observed frequency differences via substantially lower mutation rates in Asian populations. By contrast, any premutation frequency differences present in founder populations would have disappeared in the several millennia since initial establishment of these groups. Differences in the reproductive fitness of female premutation carriers arising from fragile X primary ovarian insufficiency (FXPOI) and from differences in mean maternal age may also contribute to global variation in carrier frequencies.
据报道，亚洲人群和非亚洲人群在脆性X等位基因分布上有显著差异，分为正常（<55个CGG重复序列）、前突变（55 - 199个CGG重复序列）和全突变（>199个CGG重复序列）大小类别。我们对已发表的普通人群研究数据进行的统计分析证实，亚洲人群前突变等位基因的频率明显较低，这让人想起早期在亨廷顿舞蹈病基因座上关于扩增等位基因的研究结果。为了研究可能塑造并维持脆性X基因座等位基因频率差异的历史和当代因素，我们建立了一个群体遗传学/表观遗传学模型，并将其应用于这些已发表的数据。我们发现，奠基者单倍型效应可能通过亚洲人群中显著较低的突变率导致观察到的频率差异。相比之下，奠基人群体中存在的任何前突变频率差异在这些群体最初形成后的几千年里可能已经消失。由脆性X原发性卵巢功能不全（FXPOI）以及平均母亲年龄差异导致的女性前突变携带者生殖适应性差异，也可能导致携带者频率的全球差异。
