Nature and contribution of noncoding, regulatory mutations in neurodevelopmental disorders

项目摘要 这一独立之路奖的建议侧重于培训Tychele Turner博士， 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人类遗传学和 来自约翰霍普金斯大学医学院的分子生物学。建议的研究将促进她 将基因组学培训纳入基于长读码的技术和大规模并行报告基因分析（MPRA）， 评估神经发育障碍（NDD）个体基因组中发现的变异体的功能。 另一个重要的部分将是开发一种合作，以评估这些变体在 vivo.培训计划将包括在Evan Eichler博士实验室进行为期两年的指导培训 并为她的独立实验室提供了三年的资金。 具体来说，培训计划将集中在NDD中的非编码变体的研究上， 变异并评估其功能。指导工作将在主要负责人的监督下进行 导师Evan Eichler博士和共同导师Jay Shendure博士都在华盛顿大学（UW） 基因组科学系（GS）。指导者和共同指导者都是 基因组的表征和基因组变异的高通量功能测定。博士 特纳还将从一个正式的咨询委员会以及通过由 GS部门。该部门是指导培训的最佳场所，为候选人提供 接触到许多高素质的科学家，从基础科学，模式生物，疾病， 基因组学、群体遗传学、基因组的开发和高通量功能评估。 虽然我们通过使用基因组学方法对NDD遗传学的理解已经取得了相当大的进展， 外显子组和阵列技术，在理解它们的遗传特性方面仍然存在明显的差距。 架构在拟议的研究中，我们将通过基因组优先策略结合功能性 基于分析，以确定非编码变异在NDD中的作用。我们将通过（1）调用和 对14，000个家庭全基因组测序数据中的变异进行统计评估;（2）变异 通过基于单细胞的测定确定脑中的调节位点的优先化;以及（3）通过以下的MPRA 变异体功能，以及这些变异体在小鼠中的亚组的体内功能表征。 在这项建议中学到的技能是最前沿的，许多是华盛顿大学独有的 GS部门。候选人将在基因组学的新领域积累大量的知识， 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.