Pastinen T, Perola M, Ignatius J, Sabatti C, Tainola P, Levander M, Syvänen A C, Peltonen L
Department of Molecular Medicine, National Public Health Institute, Biomedicum, 00250 Helsinki, Finland.
Hum Mol Genet. 2001 Dec 15;10(26):2961-72. doi: 10.1093/hmg/10.26.2961.
Compared to mixed populations, population isolates such as Finland show distinct differences in the prevalence of disease mutations. However, little information exists of the differences on the prevalence of different disease alleles in regional populations with different history of multiple bottlenecks. We constructed a DNA-array and monitored the prevalence of 31 rare and common disease mutations underlying 27 clinical phenotypes in a large population-based study sample. Over 64 000 genotypes were assigned in 2151 samples from four geographical areas representing early and late settlement regions of Finland. Each sample was analyzed in duplicate and a total of 142 000 array-derived genotyping calls were made. On average one in three individuals was found to be a carrier of one of the 31 monitored mutations. This should remove fears of the stigmatizing effect of a carrier-screening program monitoring multiple diseases. Regional differences were found in the prevalence of mutations, providing molecular evidence for the deviating population histories of regional subisolates. The mutations introduced early into the population revealed relatively even distribution in different subregions. More recently introduced rare mutations showed local clustering of disease alleles, indicating the persistence of population subisolates and the effect of multiple bottlenecks in molding the population gene pool. Regional differences were observed also for common disease alleles. Such precise information of the carrier frequencies could form the basis for targeted genetic screens in this population. Our approach describes a general paradigm for large-scale carrier-screening programs also in other populations.
与混合人群相比，像芬兰这样的人群隔离区在疾病突变的患病率上表现出明显差异。然而，对于经历多次瓶颈事件且历史不同的区域人群中不同疾病等位基因患病率的差异，我们了解得还很少。在一项基于大规模人群的研究样本中，我们构建了一个DNA阵列，并监测了27种临床表型所对应的31种罕见和常见疾病突变的患病率。在来自代表芬兰早期和晚期定居区域的四个地理区域的2151个样本中，确定了超过64000个基因型。每个样本都进行了重复分析，总共进行了142000次基于阵列的基因分型检测。平均每三个人中就有一个被发现是所监测的31种突变之一的携带者。这应该消除了人们对监测多种疾病的携带者筛查计划会产生污名化效应的担忧。我们发现突变的患病率存在区域差异，这为区域亚隔离人群不同的人口历史提供了分子证据。早期引入人群的突变在不同亚区域呈现出相对均匀的分布。最近引入的罕见突变则显示出疾病等位基因的局部聚集，这表明人群亚隔离的持续存在以及多次瓶颈事件对塑造人群基因库的影响。常见疾病等位基因也存在区域差异。这种携带者频率的精确信息可以为该人群的靶向基因筛查奠定基础。我们的方法也为其他人群的大规模携带者筛查计划描述了一个通用范式。
