Developmental and genetic mechanisms of diversity and disease

项目总结 了解解剖学变异的分子基础是生物学中的一个基本挑战。在……里面 在某些情况下，控制人类解剖缺陷的基因是其他物种正常变异的基础； 因此，对多样性的一般分子机制的全面理解可以保证 更好地了解人类健康。我开创了分子发育和遗传学研究的先河 家鸽作为戏剧性解剖变异的模型。在短短几年内，我们取得了迅速的进展 发现鸽子复杂性状的分子基础的进展，包括发现 人类遗传性疾病和癌症的潜在基因也在动物多样性中发挥着关键作用。 这个项目试图加深和扩大我们对典型和非典型分子基础的理解。 异常变异。鸽子是追求这些目标的理想系统，因为它的特点是 单个物种内巨大的形态变异，从而促进了全基因组的关联 研究、传统基因图谱和功能发育生物学。首先，我们将确定监管机构 控制前肢和后肢认同感的机制。在某些品种的家鸽中，我们的基因 图谱和发育研究表明，两个基因的调节变化与 用脚上的羽毛代替鳞片。在人类中，这些基因的突变会导致肢体瘫痪。 畸形。我们将通过测试增强子来识别导致鸽子调控变化的特定突变 在OVO中构建，并使用高通量RNA测序来鉴定下游调控基因 控制肢体身份的网络。第二，我们将定位控制颅面主要变化的基因 通过全基因组关联扫描和实验室杂交的遗传图谱来确定大小和形状。我们会 使用候选基因的功能测试和转录组图谱来确定自由基的分子基础 喙结构的变异。鸽子的头面部骨骼在不同品种之间表现出惊人的差异， 这些结构的异常发育占人类出生缺陷的三分之一。因此， 了解这种变异的分子基础对于理解自然变异和 人类头面部疾病的发病机制。第三，两个经典的鸽子突变体在这两个方面都表现出了变异。 色素沉着和眼睛发育。现象学上的联系在颜料变异之间建立得很好 和眼睛发育，但机械性的联系往往是模棱两可的。我们已经确定了强有力的候选基因 并将使用鸽子和其他典型的模式生物来从功能上测试 他们改变了的表情。 这些互补的遗传、基因组和发育方法将共同识别 创新模型系统中惊人变化的分子基础，从而开辟了新的途径 了解特定基因在脊椎动物正常和疾病变异中的保守作用。

PROJECT SUMMARY Understanding the molecular basis of anatomical variation is a fundamental challenge in biology. In some cases, the genes that control anatomical defects in humans underlie normal variation in other species; therefore, a comprehensive understanding of the general molecular mechanisms of diversity promises a greater understanding of human health. I have pioneered molecular developmental and genetic studies of domestic pigeons as a model for dramatic anatomical variation. In just a few years, we have made rapid progress to discover the molecular underpinnings of complex traits in pigeons, including the discovery that genes underlying hereditary disease and cancer in humans also play key roles in animal diversity. This project seeks to deepen and broader our understanding of the molecular basis of typical and abnormal variation. The pigeon is an ideal system in which to pursue these goals because it features tremendous morphological variation within a single species, thereby facilitating genome-wide association studies, traditional genetic mapping, and functional developmental biology. First, we will identify the regulatory mechanisms that control forelimb and hindlimb identity. In certain breeds of domestic pigeon, our genetic mapping and developmental studies show that regulatory changes in two genes are associated with the replacement of scales by feathers on the feet. In humans, mutations in these same genes cause striking limb malformations. We will identify specific mutations causing regulatory changes in pigeons by testing enhancer constructs in ovo, and use high-throughput RNA sequencing to identity the downstream gene regulatory networks that control limb identity. Second, we will map the genes controlling major changes in craniofacial size and shape through genome-wide association scans and genetic mapping in laboratory crosses. We will use functional testing of candidate genes and transcriptome profiling to identify the molecular basis of radical variation in beak structures. The craniofacial skeleton of pigeons shows spectacular variation among breeds, and abnormal development of these same structures accounts for one-third of human birth defects. Therefore, understanding the molecular basis of this variation is critical to understanding of both natural variation and pathogenesis of human craniofacial disorders. Third, two classical pigeon mutants exhibit variation in both pigmentation and eye development. Phenomenological links are well established between pigment variation and eye development, but mechanistic links are often ambiguous. We have identified strong candidate genes for both mutants, and will use pigeons and other canonical model organisms to functionally test the impact of their altered expression. Together, these complementary genetic, genomic, and developmental approaches will identify the molecular basis of astonishing variation in an innovative model system, thereby opening new avenues to understand the conserved roles of specific genes in normal and disease variation among vertebrates.