Identifying Selected Regions from Heterozygosity and Divergence Using a Light-Coverage Genomic Dataset from Two Human Populations

When a selective sweep occurs in the chromosomal region around a target gene in two populations that have recently separated, it produces three dramatic genomic consequences: 1) decreased multi-locus heterozygosity in the region; 2) elevated or diminished genetic divergence (FST) of multiple polymorphic variants adjacent to the selected locus between the divergent populations, due to the alternative fixation of alleles; and 3) a consequent regional increase in the variance of FST (S2FST) for the same clustered variants, due to the increased alternative fixation of alleles in the loci surrounding the selection target. In the first part of our study, to search for potential targets of directional selection, we developed and validated a resampling-based computational approach; we then scanned an array of 31 different-sized moving windows of SNP variants (5�C65 SNPs) across the human genome in a set of European and African American population samples with 183,997 SNP loci after correcting for the recombination rate variation. The analysis revealed 180 regions of recent selection with very strong evidence in either population or both. In the second part of our study, we compared the newly discovered putative regions to those sites previously postulated in the literature, using methods based on inspecting patterns of linkage disequilibrium, population divergence and other methodologies. The newly found regions were cross-validated with those found in nine other studies that have searched for selection signals. Our study was replicated especially well in those regions confirmed by three or more studies. These validated regions were independently verified, using a combination of different methods and different databases in other studies, and should include fewer false positives. The main strength of our analysis method compared to others is that it does not require dense genotyping and therefore can be used with data from population-based genome SNP scans from smaller studies of humans or other species.

当两个近期分化的人类人群中，靶基因周围的染色体区域发生选择性清除（selective sweep）时，会产生三种显著的基因组特征：1）该区域内多位点杂合性降低；2）由于等位基因的交替固定，分化人群间邻近选择位点的多个多态变异的遗传分化（FST）升高或降低；3）由于选择靶标周围位点的等位基因交替固定程度增加，同一聚类变异的FST方差（S2FST）随之区域性升高。
在本研究第一部分，为搜寻定向选择的潜在靶标，我们开发并验证了一种基于重抽样的计算方法；随后我们针对包含183997个单核苷酸多态性（SNP）位点的欧洲裔与非裔美国人群样本，在全基因组范围内扫描了31个不同尺度的滑动SNP变异窗口（5~65个SNP），并校正了重组率变异。该分析在单个人群或两个人群中均鉴定出180个具有强选择信号的近期选择区域。
在本研究第二部分，我们将新发现的候选区域与此前文献中提出的位点进行比对，采用的方法包括连锁不平衡模式解析、种群分化分析及其他相关手段；同时将新发现的区域与另外9项搜寻选择信号的研究结果进行交叉验证。我们的研究结果在被3项及以上研究证实的区域中重现性尤为优异。这些经过验证的区域通过不同方法与其他研究中的不同数据库完成了独立验证，因此假阳性率更低。
相较于其他分析方法，本研究的分析方法核心优势在于无需高密度基因分型，因此可应用于来自规模较小的人类或其他物种种群研究的基于人群的基因组SNP扫描数据。