The genetic modules that contribute to human evolution are poorly understood. Here we investigate positive selection in the Epidermal Differentiation Complex locus for skin barrier adaptation in diverse HapMap human populations (CEU, JPT/CHB, and YRI). Using Composite of Multiple Signals and iSAFE, we identify selective sweeps for LCE1A-SMCP and involucrin (IVL) haplotypes associated with human migration out-of-Africa, reaching near fixation in European populations. CEU-IVL is associated with increased IVL expression and a known epidermis-specific enhancer. CRISPR/Cas9 deletion of the orthologous mouse enhancer in vivo reveals a functional requirement for the enhancer to regulate Ivl expression in cis. Reporter assays confirm increased regulatory and additive enhancer effects of CEU-specific polymorphisms identified at predicted IRF1 and NFIC binding sites in the IVL enhancer (rs4845327) and its promoter (rs1854779). Together, our results identify a selective sweep for a cis regulatory module for CEU-IVL, highlighting human skin barrier evolution for increased IVL expression out-of-Africa.

对人类进化有贡献的基因模块知之甚少。在这里，我们研究了表皮分化复合体基因座中不同 HapMap 人群（CEU、JPT/CHB 和 YRI）皮肤屏障适应的正选择。使用复合多信号和 iSAFE，我们确定了与人类迁出非洲相关的LCE1A - SMCP和外皮蛋白 ( IVL ) 单倍型的选择性扫描，在欧洲人群中接近固定。CEU- IVL与增加的IVL表达和已知的表皮特异性增强剂有关。体内直系同源小鼠增强子的 CRISPR/Cas9 缺失揭示了增强子调节Ivl的功能要求顺式中的表达。报告基因分析证实，在IVL增强子 (rs4845327) 及其启动子 (rs1854779)中预测的 IRF1 和 NFIC 结合位点鉴定的 CEU 特异性多态性的调节和加性增强剂作用增加。总之，我们的结果确定了CEU- IVL顺式调节模块的选择性扫描，突出了人类皮肤屏障进化以增加IVL在非洲以外的表达。