Developmental and genetic mechanisms of diversity and disease

项目摘要 了解解剖变异的分子基础是生物学的一个基本挑战。在 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，全面了解多样性的一般分子机制， 更好地了解人类健康。我开创了分子发育和遗传研究， 家鸽作为一个模型的戏剧性的解剖变异。在短短几年内，我们已经取得了迅速 在发现鸽子复杂性状的分子基础方面取得了进展，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关键作用。 该项目旨在加深和扩大我们对典型和 异常变异鸽子是一个理想的系统，在其中追求这些目标，因为它的特点 单个物种内巨大的形态变异，从而促进全基因组关联 研究，传统的遗传作图和功能发育生物学。首先，我们将确定监管 控制前肢和后肢身份的机制。在某些品种的家鸽中， 作图和发育研究表明，两个基因的调节变化与 脚上的羽毛代替了鳞片。在人类中，这些相同基因的突变会导致引人注目的肢体 畸形我们将通过测试增强子来确定引起鸽子调节变化的特定突变， 在卵内构建，并使用高通量RNA测序来鉴定下游基因调控 控制肢体身份的网络。其次，我们将绘制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中的遗传作图，我们将 使用候选基因的功能测试和转录组分析来确定自由基的分子基础， 鸟嘴结构的变化。鸽子的颅面骨骼显示出品种间惊人的差异， 这些结构的异常发育占人类出生缺陷的三分之一。因此，我们认为， 理解这种变异的分子基础对于理解自然变异和 人类颅面疾病的发病机制。第三，两个经典的鸽子突变体在两个方面都表现出变异， 色素沉着和眼睛发育。现象学上的联系在色素变化 和眼睛的发育，但机械联系往往是模糊的。我们已经确定了强候选基因 对于这两种突变体，并将使用鸽子和其他典型的模式生物功能测试的影响， 他们改变的表情。 总之，这些互补的遗传、基因组和发育方法将确定 在一个创新的模型系统中惊人的变化的分子基础，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.