Developmental and genetic mechanisms of diversity and disease

多样性和疾病的发育和遗传机制

• 批准号: 10582045
• 负责人: Michael David Shapiro
• 金额: $ 4.85万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582045
• 关键词: Affect; Anatomy; Animal Model; Animals; Beak; Biological Models; Biology; Candidate Disease Gene; Chromosome Mapping; Columbidae; Complex; Congenital Abnormality; DNA Sequence; Defect; Development; Developmental Biology; Disease; Enhancers; Equipment; Exhibits; Eye; Eye Development; Face; Feathers; Forelimb; Funding; Gene Mutation; Genes; Genetic; Genetic study; Genomics; Goals; Health; Hereditary Disease; Hereditary Malignant Neoplasm; High-Throughput RNA Sequencing; Hindlimb; Human; Laboratories; Limb Development; Limb structure; Link; Maps; Modeling; Molecular; Morphology; Mutation; Pathogenesis; Pigmentation physiologic function; Pigments; Play; Research; Rock Pigeons; Role; Shapes; Skeleton; Skin; Structure; System; Testing; Variant; Vertebrates; Work; craniofacial; craniofacial disorder; developmental genetics; foot; gene discovery; gene regulatory network; genome wide association study; hereditary blindness; innovation; malformation; mutant; skin color; trait; transcriptome

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.

项目概要 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有望 对人类健康有更深入的了解。我开创了分子发育和遗传学研究 家鸽作为显着解剖变异的模型。短短几年时间，我们取得了飞速的发展 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基因也在动物多样性中发挥着关键作用。 该项目旨在加深和拓宽我们对典型和 异常变异。鸽子是追求这些目标的理想系统，因为它具有 单个物种内巨大的形态变异，从而促进全基因组关联 研究、传统遗传图谱和功能发育生物学。首先我们要明确监管 控制前肢和后肢身份的机制。在某些品种的家鸽中，我们的遗传基因 绘图和发育研究表明，两个基因的调控变化与 脚上的羽毛取代了鳞片。在人类中，这些相同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监管变化的特定突变 在卵内构建，并使用高通量 RNA 测序来识别下游基因调控 控制肢体身份的网络。其次，我们将绘制控制颅面部主要变化的基因图谱 通过全基因组关联扫描和实验室杂交中的遗传图谱来确定大小和形状。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 喙结构的变化。鸽子的颅面骨骼在不同品种之间表现出惊人的差异， 这些相同结构的异常发育占人类出生缺陷的三分之一。所以， 了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。色素变化之间的现象学联系已得到充分确立 和眼睛发育，但机制联系往往是模糊的。我们已经确定了强大的候选基因 对于这两种突变体，并将使用鸽子和其他典型模型生物来功能测试 他们的表情改变了。 总之，这些互补的遗传、基因组和发育方法将确定 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。