Global distribution of fatal familial insomnia: founder or recurrent mutations.
Global distribution of fatal familial insomnia: founder or recurrent mutations.
复制标题
致命性家族性失眠的全球分布：创始人或复发突变。
DOI：
10.1007/s10048-008-0135-3
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发表时间：
2008
期刊：
影响因子：
2.2
通讯作者：
Goldfarb,LG
中科院分区：
文献类型：
--
作者：
Lee,H-S;Goldfarb,LG
遗传性疾病通过主要奠基者效应或主要复发性突变事件的地理传播机制不仅具有历史意义，而且对于理解疾病传播的分子机制非常重要，并可能最终影响疾病预防方法的选择。正如最近一期《日刊》所报道的那样，罗德里格斯-马丁内斯等人。[1]通过使用7个单核苷酸多态性（SNPs）对发生在三个欧洲国家的38例（27个先证者）的疾病单倍型进行鉴定，对与致死性家族性失眠（FFI）相关的PRNP D178 N遗传变异进行单倍型分析。该研究报告了两种FFI单倍型。所有西班牙病例和来自意大利托斯卡纳地区的一个家族共享一个共同的单倍型，所有9名德国患者和来自韦内托地区的一个意大利家族共享第二个单倍型。似然G拟合优度检验显示西班牙FFI病例和西班牙对照之间单倍型频率分布的差异。基于这些结果，作者得出结论，两个独立的古代PRNP D178 N突变事件是欧洲目前大多数FFI病例的原因。我们发现了一些严重的问题，与作者用来得出结论的方法和数据解释有关。G检验仅评估患者中观察到的单倍型频率是否偏离对照中的频率的一般假设。G检验的综合性质不允许评价其他情况，如FFI患者中存在两个或更多创始者突变。在确定携带D178 N的染色体时缺乏特异性尤其令人不安，因为本研究中鉴定的单倍型在背景人群中很常见（17%和43%），而FFI是一种罕见疾病。由Rodriguez-Martinez等人选择的七个SNPs作为单体型分析单位仅产生非常有限的信息量。这七个SNP的单倍型多样性值为0.75（根据表3计算），相当于仅一个微卫星标记。作者正确地指出，SNPs作为确定古代创始人效应的方法学比微卫星具有固有的优势（它们更稳定，并且有大量的SNPs可用）。但是，只有当SNP和单倍型被仔细选择来代表遗传的基因组时，这种论点才有效。Stacey等人最近的一项研究很好地说明了这种方法。[2]在BARD 1 C557 S携带者中，乳腺癌风险7-SNP单倍型频率为53/53，而在对照组中为0/1197。我们认为，Rodriguez-Martinez等人未能提供确凿的证据来支持只有两种创始单倍型与欧洲人群中所有已知的FFI病例相关的假设。因此，D178 N应被认为是一种主要的复发性突变，如先前基于微卫星检测得出的结论[3]，直到获得有效数据以得出其他结论。基于SNP的祖先单倍型分析比微卫星分析优越上级，但是为了利用基于SNP的分析的所有优点，产生的单倍型应该代表创始者疾病相关染色体的唯一性。
The mechanisms of geographic spread of hereditary disorders through predominantly founder effect or predominantly recurrent mutational events is not only of historic significance; it is important for understanding molecular mechanisms of disease spread and may ultimately influence the selection of methods for disease prevention. As reported in the recent issue of the Journal, Rodriguez-Martinez et al.[1] carried out a haplotype analysis of the PRNP D178N genetic variant associated with Fatal familial insomnia (FFI) by using seven single nucleotide polymorphisms (SNPs) for identification of disease haplotypes in 38 cases (27 probands) that occurred in three European countries. The study reports two founder FFI haplotypes. All Spanish cases and one family from the Tuscany region in Italy share a common haplotype, and all nine German patients and an Italian family from Veneto region share the second haplotype. The likelihood G goodness-of-fit test shows a difference in haplotype frequency distribution between Spanish FFI cases and Spanish controls. Based on these results, the authors conclude that two independent ancient PRNP D178N mutational events are responsible for most of the current FFI cases in Europe. We find a number of serious issues related to the methodology and data interpretation that the authors used for drawing their conclusions. The G test merely evaluates a general hypothesis of whether observed haplotype frequency among patients deviates from the frequency in controls. The omnibus nature of the G test does not allow evaluating other scenarios like the presence of two or more founder mutations in the FFI patients. This lack of specificity in determining the D178N-carrying chromosomes is especially troubling because the haplotypes identified in this study are common in the background population (17% and 43%), while FFI is a rare disease. The seven SNPs selected by Rodriguez-Martinez et al. only yield very limited amount of information as a haplotyping unit. The haplotype diversity value of these seven SNPs is 0.75 (calculated from their Table 3), which is equivalent to only one microsatellite marker. The authors rightfully indicate that SNPs have inherent advantage over microsatellites as a methodology for determining ancient founder effects (they are more stable, and a large number of SNPs are available). But, this argument is valid only when SNPs and haplotypes are carefully selected to represent a genome being inherited. A good illustration of such approach is a recent study by Stacey et al.[2], in which the breast cancer risk seven-SNP haplotype frequency was 53 of 53 among the BARD1 C557S carriers, while it was 0 of 1,197 in controls.In our view, Rodriguez-Martinez et al. failed to provide conclusive evidence to support the hypothesis that only two founder haplotypes are associated with all known FFI cases in the European populations. Therefore, D178N should be considered a predominantly recurrent mutation, as previously concluded based on microsatellite testing [3], until valid data are obtained to conclude otherwise. Ancestral haplotype analysis based on SNPs is superior to microsatellites, but to use all advantages of SNP-based analysis, the generated haplotype should represent the uniqueness of the founder disease-associated chromosome.