Department of Anthropology, University of Toronto at Mississauga, Mississauga, Ontario, Canada.
BMC Evol Biol. 2013 Jul 12;13:150. doi: 10.1186/1471-2148-13-150.
Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution.
Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies.
We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation.
目前，东亚人群中与正常色素变异相关的基因知之甚少。我们利用 1000 基因组计划第一阶段数据集进行了全基因组扫描，以鉴定东亚地区存在选择漂变信号的色素基因。我们应用了多种方法来检测选择信号，包括：1）用于识别位点频率谱（SFS）偏离中性预期的测试（Tajima 的 D、Fay 和 Wu 的 H、Fu 和 Li 的 D和 F）；2）专注于识别具有扩展连锁不平衡的高频单倍型的测试（iHS 和 Rsb）；3）基于群体间遗传分化的测试（LSBL）。基于对 25 kb 窗口全基因组分析的结果，我们为每个统计量在所有窗口上构建了一个经验分布，并确定了分布中的色素基因异常值。
我们的测试鉴定了 20 个与色素生物学相关的基因。其中，8 个基因（ATRN、EDAR、KLHL7、MITF、OCA2、TH、TMEM33 和 TRPM1）至少在一个统计量上为极端异常值（经验分布的前 0.1%），12 个基因（ADAM17、BNC2、CSD、DCT、EGFR、LYST、MC1R、MLPH、OPRM1、PDIA6、PMEL（SILV）和 TYRP1）至少在一个统计量上位于经验分布的前 1%。此外，其中 8 个基因（BNC2、EGFR、LYST、MC1R、OCA2、OPRM1、PMEL（SILV）和 TYRP1）已在关联研究中与色素性状相关。
我们鉴定了一些在东亚地区显示出非常特殊的遗传变异模式的候选色素基因。这些基因中的大多数在不同的测试和/或不同的群体中都是异常值，并且已经在前一次的正选择扫描中被描述过，这为最近的选择漂变在这些区域留下了信号的假设提供了强有力的支持。然而，有必要进行关联和功能研究来证明这些基因在正常色素变异中的作用。
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