Kryukov Gregory V, Shpunt Alexander, Stamatoyannopoulos John A, Sunyaev Shamil R
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3871-6. doi: 10.1073/pnas.0812824106. Epub 2009 Feb 6.
The ability to sequence cost-effectively all of the coding regions of a given individual genome is rapidly approaching, with the potential for whole-genome resequencing not far behind. Initiatives are currently underway to phenotype hundreds of thousands of individuals for major human traits. Here, we determine the power for de novo discovery of genes related to human traits by resequencing all human exons in a clinical population. We analyze the potential of the gene discovery strategy that combines multiple rare variants from the same gene and treats genes, rather than individual alleles, as the units for the association test. By using computer simulations based on deep resequencing data for the European population, we show that genes meaningfully affecting a human trait can be identified in an unbiased fashion, although large sample sizes would be required to achieve substantial power.
以具有成本效益的方式对给定个体基因组的所有编码区域进行测序的能力正在迅速实现，全基因组重测序的潜力也不远了。目前正在开展一些计划，对数以十万计的个体进行主要人类性状表型分析。在此，我们通过对临床人群中的所有人类外显子进行重测序，确定从头发现与人类性状相关基因的能力。我们分析了一种基因发现策略的潜力，该策略结合来自同一基因的多个罕见变异，并将基因而非单个等位基因作为关联测试的单位。通过基于欧洲人群深度重测序数据的计算机模拟，我们表明，虽然需要大样本量才能获得足够的效力，但可以以无偏倚的方式鉴定出对人类性状有显著影响的基因。
