The zinc finger-containing transcription factor Gli3 is a key mediator of Hedgehog (Hh) signaling pathway. In vertebrates, Gli3 has widespread expression pattern during early embryonic development. Along the anteroposterior axes of the central nervous system (CNS), dorsoventral neural pattern elaboration is achieved through Hh mediated spatio-temporal deployment of Gli3 transcripts. Previously, we and others uncovered a set of enhancers that mediate many of the known aspects of Gli3 expression during neurogenesis. However, the potential role of Gli3 associated enhancers in trait evolution has not yet received any significant attention. Here, we investigate the evolutionary patterns of Gli3 associated CNS-specific enhancers that have been reported so far. A subset of these enhancers has undergone an accelerated rate of molecular evolution in the human lineage in comparison to other primates/mammals. These fast-evolving enhancers have acquired human-specific changes in transcription factor binding sites (TFBSs). These human-unique changes within subset of Gli3 associated CNS-specific enhancers were further validated as single nucleotide polymorphisms through 1000 Genome Project Phase 3 data. This work not only infers the molecular evolutionary patterns of Gli3 associated enhancers but also provides clues for putative genetic basis of the population-specificity of gene expression regulation.

含锌指的转录因子 Gli3 是 Hedgehog (Hh) 信号通路的关键介质。在脊椎动物中，Gli3 在早期胚胎发育过程中具有广泛的表达模式。沿着中枢神经系统 (CNS) 的前后轴，背腹神经模式的细化是通过 Hh 介导的Gli3转录本的时空部署来实现的。以前，我们和其他人发现了一组在神经发生过程中介导 Gli3 表达的许多已知方面的增强子。然而，Gli3相关增强子在性状进化中的潜在作用尚未受到任何重大关注。在这里，我们研究了Gli3的进化模式迄今为止已报道的相关 CNS 特异性增强剂。与其他灵长类动物/哺乳动物相比，这些增强子的一个子集在人类谱系中经历了加速的分子进化。这些快速进化的增强子已经在转录因子结合位点 (TFBS) 中获得了人类特异性的变化。Gli3相关的 CNS 特异性增强子子集中的这些人类独特变化通过 1000 基因组计划第 3 阶段数据进一步验证为单核苷酸多态性。这项工作不仅推断了Gli3相关增强子的分子进化模式，而且还为基因表达调控的群体特异性的假定遗传基础提供了线索。