Nat Genet. 2014 Aug;46(8):818-25. doi: 10.1038/ng.3021. Epub 2014 Jun 29.
Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage (∼13×) and trio design enabled extensive characterization of structural variation, including midsize events (30-500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.
全基因组测序能够全面描述遗传变异，但稀有等位基因的地理聚类要求研究许多不同的人群。在这里，我们描述了荷兰基因组（GoNL）计划，我们对 250 个荷兰亲子家庭的全基因组进行了测序，并构建了 2040 万个单核苷酸变体和 120 万个插入和缺失的单倍型图谱。中间覆盖率（约 13×）和 trio 设计使我们能够广泛地描述结构变异，包括以前很少记录的中大型事件（30-500bp）和从头突变。我们证明，单倍型的质量可以提高独立样本中的推断准确性，尤其是对于较低频率的等位基因。群体遗传分析表明，整个国家都存在细微的结构，并且支持多次古代迁徙，这与海平面和洪水的历史变化一致。GoNL 项目说明了单人群全基因组测序如何能够详细描述遗传变异，并可能指导未来的群体研究设计。
