Nature and contribution of noncoding, regulatory mutations in neurodevelopmental disorders

神经发育障碍中非编码调节突变的性质和贡献

• 批准号: 10002303
• 负责人: Tychele Naomi Turner
• 金额: $ 24.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002303
• 关键词: Address; Advisory Committees; Affect; Algorithms; Animal Model; Architecture; Area; Award; Bachelor' s Degree; Basic Science; Biological Assay; Brain; Caliber; Cells; Cellular Assay; Chromatin; Collaborations; Complex; Consent; Coupled; DNA; Data; Data Set; Databases; Development; Disease; Doctor of Philosophy; Drosophila melanogaster; Embryo; Enhancers; Etiology; Family; Funding; Future; Genetic; Genetic Diseases; Genome; Genomics; Genotype; Goals; Human; Human Genetics; In Vitro; Individual; Inherited; Knowledge; Laboratories; Mentors; Methods; Michigan; Molecular Biology; Molecular Genetics; Mouse Cell Line; Mus; Mutation; Nature; Neurodevelopmental Disorder; Neurons; Nucleic Acid Regulatory Sequences; Other Genetics; Pathway interactions; Population; Population Genetics; Privatization; Regulation; Reporter; Research; Research Personnel; Resolution; Role; Running; Scientist; Single Nucleotide Polymorphism; Sister; Site; Structure; Supervision; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Training; Training Programs; Transposase; Universities; Untranslated RNA; Variant; Washington; Work; base; exome; exome sequencing; genetic architecture; genetic risk factor; genome sciences; genome sequencing; genomic variation; improved; in vitro testing; in vivo; in vivo evaluation; insertion/deletion mutation; insight; medical schools; mouse development; novel; promoter; skills; variant detection; whole genome

Project Summary This proposal for a Pathway to Independence Award focuses on the training of Dr. Tychele Turner to become an independent investigator of large-scale genomics and human genetics. Dr. Turner has a Bachelor's Degree from Michigan State University in Genomics and Molecular Genetics and a Ph.D. in Human Genetics and Molecular Biology from the Johns Hopkins University School of Medicine. Proposed studies will advance her genomics training into long-read based technologies and massively parallel reporter assays (MPRAs) to assess function of variants discovered in genomes from individuals with neurodevelopmental disorders (NDDs). Another essential piece will be the development of a collaboration for assessing function of these variants in vivo. The training program will consist of two years of mentored training in the laboratory of Dr. Evan Eichler and three years of funding for her independent laboratory. Specifically, the training program will center on the study of noncoding variants in NDDs by identifying these variants and assessing their function. The mentored work will take place under the supervision of the primary mentor, Dr. Evan Eichler, and the co-mentor, Dr. Jay Shendure, both at the University of Washington (UW) Department of Genome Sciences (GS). Both the mentor and co-mentor are well-established experts in the characterization of genomes and high-throughput functional assays of genomic variation, respectively. Dr. Turner will also gain advice from a formal advisory committee as well as through activities arranged by the Department of GS. This department is an optimal place for the mentored training providing the candidate with access to a number of high caliber scientists in areas ranging from basic science, model organisms, disease genomics, population genetics, development and high throughput functional assessment of genomes. While there has been considerable progress in our understanding of the genetics of NDDs through the use of exome and array technologies there still remains an appreciable gap in understanding of their genetic architecture. In proposed studies, we will assess NDDs via a genome-first strategy coupled with functional- based assays to determine the role of noncoding variation in NDDs. We will approach this by (1) calling and statistical assessment of variants from whole-genome sequencing data in 14,000 families; (2) variant prioritization via single-cell based assays identifying regulatory sites in the brain; and (3) by MPRAs of variant function coupled with in vivo functional characterization of a subset of these variants in mice. The skills learned in this proposal are on the cutting-edge and many are unique to the setting of the UW Department of GS. The candidate will amass a great amount of knowledge in new areas of genomics, which will be applicable to many diseases and critical to the candidate's future independent laboratory.

项目概要 这项独立之路奖提案的重点是培训 Tychele Turner 博士成为 大规模基因组学和人类遗传学的独立研究者。特纳博士拥有学士学位 密歇根州立大学基因组学和分子遗传学博士，博士。在人类遗传学和 约翰·霍普金斯大学医学院的分子生物学。拟议的研究将推动她 基因组学培训基于长读的技术和大规模并行报告分析（MPRA） 评估神经发育障碍 (NDD) 个体基因组中发现的变异的功能。 另一个重要部分是开发合作来评估这些变体的功能 体内。培训计划将包括在 Evan Eichler 博士的实验室进行两年的指导培训 以及为她的独立实验室提供三年的资助。 具体来说，培训计划将通过识别 NDD 中的非编码变体来研究这些变体。 变体并评估其功能。指导工作将在初级主管的监督下进行 导师 Evan Eichler 博士和联合导师 Jay Shendure 博士均来自华盛顿大学 (UW) 基因组科学系（GS）。导师和共同导师都是该领域的知名专家 分别进行基因组表征和基因组变异的高通量功能分析。博士。 特纳还将从正式的咨询委员会以及通过组织安排的活动获得建议 GS系。该部门是进行指导培训的最佳场所，为候选人提供 接触基础科学、模式生物、疾病等领域的许多高素质科学家 基因组学、群体遗传学、基因组发育和高通量功能评估。 虽然通过使用 外显子组和阵列技术对其遗传的理解仍然存在明显差距 建筑学。在拟议的研究中，我们将通过基因组优先策略与功能性相结合来评估 NDD。 基于测定法来确定 NDD 中非编码变异的作用。我们将通过 (1) 调用和 对 14,000 个家庭的全基因组测序数据的变异进行统计评估； (2) 变体 通过基于单细胞的测定确定大脑中的调节位点的优先级； (3) 通过 MPRA 变异功能与小鼠中这些变异的子集的体内功能表征相结合。 在此提案中学到的技能是最前沿的，其中许多技能是威斯康星大学所独有的 GS系。候选人将在基因组学新领域积累大量知识， 将适用于许多疾病，对候选人未来的独立实验室至关重要。