Nature and contribution of noncoding, regulatory mutations in neurodevelopmental disorders

项目摘要 这项独立之路奖的提议重点是将泰切尔·特纳博士培养成 大规模基因组学和人类遗传学的独立研究员。特纳博士拥有学士学位 密歇根州立大学基因组和分子遗传学学士学位，人类遗传学和分子遗传学博士学位 来自约翰霍普金斯大学医学院的分子生物学。拟议的研究将促进她的进步 将基因组学培训转化为基于长时间阅读的技术和大规模平行报告分析(MPRA)，以 评估在神经发育障碍(NDDS)患者基因组中发现的变异的功能。 另一项重要工作将是发展一项合作，以评估这些变体在 活着。培训计划将包括在Evan Eichler博士的实验室进行两年的指导性培训 以及为她的独立实验室提供三年的资金。 具体地说，培训方案将重点研究NDDS中的非编码变体，方法是确定这些变体 并评估它们的功能。辅导工作将在小学生的监督下进行。 导师Evan Eichler博士和共同导师Jay Shendure博士，均在华盛顿大学(UW) 基因组科学系(GS)。导师和共同导师都是 基因组特征和高通量基因组变异功能分析。Dr。 特纳还将从一个正式的咨询委员会以及通过 美国地质调查局。这个部门是指导培训的最佳地点，为应聘者提供 接触到基础科学、模式生物、疾病等领域的一批高素质科学家 基因组学、群体遗传学、基因组的发展和高通量功能评估。 虽然在我们对NDDS的遗传学的理解上已经有了相当大的进步，通过使用 外显子组和阵列技术在理解它们的基因方面仍然存在着明显的差距 建筑。在拟议的研究中，我们将通过基因组优先的策略结合功能- 基于分析以确定非编码变异在NDDS中的作用。我们将通过(1)调用和 对14,000个家系的全基因组测序数据进行变异的统计评估；(2)变异 通过基于单细胞的分析确定大脑中的调节部位来确定优先顺序；以及(3)通过MPRAs 变异体功能与这些变异体的子集在小鼠体内的功能特征相结合。 在这份提案中学到的技能是尖端的，其中许多技能是威斯康星州大学所特有的 美国地质调查局。候选人将在基因组学的新领域积累大量知识，这些领域 将适用于许多疾病，并对候选人未来的独立实验室至关重要。

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.