Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley CA, United States of America.
PLoS Genet. 2018 Jun 14;14(6):e1007449. doi: 10.1371/journal.pgen.1007449. eCollection 2018 Jun.
Threespine stickleback fish offer a powerful system to dissect the genetic basis of morphological evolution in nature. Marine sticklebacks have repeatedly invaded and adapted to numerous freshwater environments throughout the Northern hemisphere. In response to new diets in freshwater habitats, changes in craniofacial morphology, including heritable increases in tooth number, have evolved in derived freshwater populations. Using a combination of quantitative genetics and genome resequencing, here we fine-mapped a quantitative trait locus (QTL) regulating evolved tooth gain to a cluster of ten QTL-associated single nucleotide variants, all within intron four of Bone Morphogenetic Protein 6 (Bmp6). Transgenic reporter assays revealed this intronic region contains a tooth enhancer. We induced mutations in Bmp6, revealing required roles for survival, growth, and tooth patterning. Transcriptional profiling of Bmp6 mutant dental tissues identified significant downregulation of a set of genes whose orthologs were previously shown to be expressed in quiescent mouse hair stem cells. Collectively these data support a model where mutations within a Bmp6 intronic tooth enhancer contribute to evolved tooth gain, and suggest that ancient shared genetic circuitry regulates the regeneration of diverse vertebrate epithelial appendages including mammalian hair and fish teeth.
三刺鱼为解析自然界中形态进化的遗传基础提供了一个强有力的系统。海洋棘鱼多次入侵并适应了北半球众多的淡水环境。为了应对淡水生境中的新食物，包括牙齿数量遗传性增加在内的颅面形态发生了变化，这在衍生的淡水种群中进化而来。在这里，我们使用定量遗传学和基因组重测序的组合，将一个调节进化牙齿获得的数量性状基因座（QTL）精细映射到一组十个与 QTL 相关的单核苷酸变异体簇上，所有这些变异体都位于骨形态发生蛋白 6（Bmp6）的内含子 4 中。转基因报告基因检测揭示了这个内含子区域包含一个牙齿增强子。我们诱导了 Bmp6 的突变，揭示了其在存活、生长和牙齿模式形成中所必需的作用。对 Bmp6 突变体牙组织的转录谱分析鉴定出一组基因的显著下调，这些基因的同源物以前被证明在静止的小鼠毛囊干细胞中表达。这些数据共同支持了这样一个模型，即 Bmp6 内含子牙齿增强子中的突变有助于进化中的牙齿获得，并表明古老的共享遗传电路调节了包括哺乳动物毛发和鱼类牙齿在内的多种脊椎动物上皮附属物的再生。
