Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans.
Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans.
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全基因组关联研究和 CRISPR/Cas9 介导的基因编辑确定了影响人类眉毛厚度的调控变异。
DOI：
10.1371/journal.pgen.1007640
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发表时间：
2018-09
期刊：
影响因子：
4.5
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Wu S;Zhang M;Yang X;Peng F;Zhang J;Tan J;Yang Y;Wang L;Hu Y;Peng Q;Li J;Liu Y;Guan Y;Chen C;Hamer MA;Nijsten T;Zeng C;Adhikari K;Gallo C;Poletti G;Schuler-Faccini L;Bortolini MC;Canizales-Quinteros S;Rothhammer F;Bedoya G;González-José R;Li H;Krutmann J;Liu F;Kayser M;Ruiz-Linares A;Tang K;Xu S;Zhang L;Jin L;Wang S
毛发在灵长类动物中起着重要的作用，并且显然受到适应性选择的影响。虽然人类已经失去了大部分面部毛发，但眉毛是一个明显的例外。眉毛的厚度是可以遗传的，并且被广泛认为是受到性选择的影响。然而，很少有基因组研究探索其遗传基础。在这里，我们对2961名汉族人的眉毛厚度进行了全基因组扫描。我们发现了两个具有全基因组意义的新位点，位于SOX 2附近的3q26.33（rs 1345417：P = 6.51×10−10）和FOXD 1附近的5q13.2（rs 12651896：P = 1.73×10−8）。我们进一步在维吾尔族、来自中国的东亚-欧洲混合人群（N = 721）、来自五个拉丁美洲国家的CANDELA队列（N = 2301）和荷兰欧洲人的鹿特丹研究队列（N = 4411）中复制了我们的研究结果。一项荟萃分析结合了来自三个完全或部分亚洲血统的队列（汉族、维吾尔族和拉丁美洲人，N = 5983）的完整GWAS结果，强调了第三个在EDAR附近的2q12.3（rs 1866188：P = 5.81×10−11）具有全基因组意义的信号。我们进行了精细映射，并优先考虑了四个变体，以供进一步的实验验证。CRISPR/Cas9介导的基因编辑提供的证据表明，rs 1345417和rs 12651896影响附近的SOX 2和FOXD 1基因的转录活性，这两个基因都参与了头发的发育。最后，适当的统计分析显示，在任何测试的群体中，没有相关的变体显示出明确的选择信号。与流行的猜测相反，我们没有发现任何证据表明眉毛厚度受到强烈的选择压力。毛发在灵长类动物中起着重要的作用，并且显然受到适应性选择的影响。虽然人类已经失去了大部分面部毛发，但眉毛是一个明显的例外。眉毛的厚度是可以遗传的，并且被广泛认为是受到性选择的影响。然而，很少有基因组研究探索其遗传基础。在这里，我们对多个民族的眉毛厚度进行了全基因组关联研究，包括汉族人，维吾尔族人，拉丁美洲人和高加索人。我们发现了确凿的证据表明，SOX 2、FOXD 1和EDAR基因附近的新遗传变异可能会影响眉毛厚度。在精细映射之后，我们优先考虑四个变体进行实验验证。CRISPR/Cas9介导的基因编辑提供了证据，证明变体rs 1345417和rs 12651896影响附近SOX 2和FOXD 1基因的转录活性。这代表了GWAS和CRISPR/Cas9技术相结合的成功例子，证明了具有调控功能的非编码变体如何在常见疾病和性状中发挥重要作用。最后，适当的统计分析表明，与流行的猜测相反，眉毛厚度不应该受到强大的选择压力，包括性别选择。
Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10−10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10−8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10−11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure. Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here we performed genome-wide association studies for eyebrow thickness in multiple ethnic groups, including Han Chinese, Uyghurs, Latin Americans, and Caucasians. We found solid evidence that novel genetic variants near the SOX2, FOXD1 and EDAR genes could affect eyebrow thickness. After fine mapping, we prioritized four variants for experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that the variants rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes. This represents a successful example of a combination of GWAS and CRISPR/Cas9 technology to demonstrate how non-coding variants with regulatory functions may play an important role in common diseases and traits. Finally, suitable statistical analyses suggest that, contrary to popular speculation, eyebrow thickness should not be subject to strong selection pressure, including sexual selection.
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