Supplementary Material for: Genetic Differences between Five European Populations

<i>Aims:</i> We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. <i>Methods:</i> We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ² test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p &lt; 10^–45. <i>Results:</i> We found 40,593 SNPs which are genome-wide significantly (p ≤ 10^–8) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation <i>(HERC2, EXOC2, IRF4)</i>, the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, <i>FOXP2</i>, implicated in speech development. <i>Conclusion:</i> Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci.

**研究目的**：本研究旨在探究5个欧洲人群（苏格兰、爱尔兰、瑞典、保加利亚及葡萄牙人群）之间单核苷酸多态性（Single Nucleotide Polymorphism，SNP）等位基因频率的差异幅度，并识别差异最为显著的基因位点。
**研究方法**：本研究采用Affymetrix 6.0与5.0基因芯片开展基于人群的全基因组关联分析，使用4自由度卡方（χ²）检验计算每个SNP的群体分层程度。随后以P<10⁻⁴⁵这一高度保守的临界阈值，对群体分层程度最高的区域内的基因进行分析。
**研究结果**：本研究共筛选出40593个在上述人群间呈现全基因组显著差异（P≤10⁻⁸）的SNP，其群体分层特征显著。差异最为显著的位点富集于与免疫及色素沉着相关的基因本体（Gene Ontology，GO）功能类别中。部分排名靠前的差异位点所在基因已被报道存在显著群体分层：包括毛发颜色与色素沉着相关基因（HERC2、EXOC2、IRF4）、LCT基因、烟酰胺腺嘌呤二核苷酸（Nicotinamide Adenine Dinucleotide，NAD）代谢相关基因，以及免疫相关基因：人类白细胞抗原（Human Leukocyte Antigen，HLA）、Toll样受体基因TLR10、TLR1、TLR6。此外，本研究还发现多个此前未被报道在欧洲人群间存在群体分层的基因，提示这些基因可能同样受到选择优势作用：包括多个锌指基因、2个参与谷胱甘肽合成或功能调控的基因，最引人关注的是与言语发育相关的FOXP2基因。
**研究结论**：本研究分析表明，欧洲人群间存在大量呈现全基因组显著差异的SNP，且差异幅度与地理距离呈正相关。上述差异至少部分源于这些基因位点内的多态性所带来的选择优势。