Characterization of Human-Specific Duplicated Genes Implicated in Neurocognitive

描述（由申请人提供）： 我们提出了一个培训计划，将准备在人类遗传学和神经生物学有效的独立调查员。该候选人拥有牛津大学和美国国立卫生研究院联合研究生项目的哲学博士/博士学位，专注于人类疾病中常见非编码变异的表征。她将扩展自己的技能，包括在为期两年的有组织的指导和培训计划中使用新型测序技术和功能性神经生物学测定来测定遗传变异，然后进行为期三年的结构化研究计划。该培训计划将促进使用测序技术和功能测定来表征人类特异性重复基因及其在神经学特征和缺陷中的作用。基因组科学教授Evan Eichler博士将担任候选人科学发展的主要导师。Eichler博士在基因组学和疾病遗传学领域享有世界声誉，在探索基因组复杂区域方面具有开创性工作。生物结构教授和基因组科学兼职教授大卫赖布尔博士将协助指导候选人使用斑马鱼作为遗传工具对神经发育中的基因进行功能表征。此外，候选人将得到一个致力于为她作为一名独立研究员的职业生涯做准备的调查团队的支持。华盛顿大学医学院的基因组科学系是一个理想的环境，以追求成为一个独立的研究调查员的培训。教师是高度多样化和协作的专业知识，从计算生物学到使用模型系统的实验方法。由片段重复介导的大规模复发性缺失和重复与自闭症、智力残疾、癫痫和精神分裂症有关。人类特异性基因存在于这些侧翼片段重复中，这些片段重复在人类参考构建中缺失或被错误注释，这加剧了我们对导致疾病的机制的理解。为了充分表征这些人类特异性基因及其在疾病中的作用，我们将（1）利用开发用于评估高序列同一性区域的单倍体基因组资源生成与神经发育障碍相关的三个基因组区域的高质量序列;（2）筛选神经发育障碍病例中的突变;（3）使用细胞系测定和斑马鱼功能性表征基因和鉴定的变体。这里提出的许多方法对候选人来说都是新颖的，包括下一代测序分析来表征疾病变异和使用斑马鱼的功能性神经生物学测定。该实验范式将很容易扩展到表征任何与神经系统疾病有关的基因，并将为候选人的独立研究计划奠定基础。!

DESCRIPTION (provided by applicant): We propose a training program that will prepare an effective independent investigator in human genetics and neurobiology. The candidate has a DPhil/PhD from a joint graduate program with the University of Oxford and the National Institutes of Health focused on the characterization of common noncoding variation in human disease. She will extend her skills to include assaying genetic variation using novel sequencing technologies and functional neurobiological assays during a two-year program of organized mentorship and training followed by a structured three-year research program. The training program will promote use of sequencing technologies and functional assays to characterize human-specific duplicated genes and their roles in neurological traits and defects. Dr. Evan Eichler, Professor of Genome Sciences, will act as the primary mentor towards the scientific development of the candidate. Dr. Eichler is world-renowned in the field of genomics and disease genetics with pioneering work exploring complex regions of the genome. Dr. David Raible, Professor of Biological Structure and Adjunct Professor of Genome Sciences, will assist in mentoring the candidate in functional characterization of genes in neural development using zebrafish as a genetic tool. Additionally, the candidate will be supported by a team of investigators committed to preparing her for a career as an independent researcher. The Department of Genome Sciences at the University of Washington School of Medicine is an ideal setting to pursue training towards becoming an independent research investigator. The faculty is highly diverse and collaborative with expertise ranging from computational biology to experimental methods using model systems. Large-scale recurrent deletions and duplications mediated by segmental duplications are associated with autism, intellectual disability, epilepsy, and schizophrenia. Human-specific genes reside within these flanking segmental duplications that are missing or misannotated in the human reference build that exacerbate our understanding of the mechanisms that contribute to disease. To fully characterize these human-specific genes and their role in disease, we will (1) generate high-quality sequence of three genomic regions associated with neurodevelopmental disorders utilizing a haploid-genomic resource developed to assess regions of high sequence identity; (2) screen for mutations in cases with neurodevelopmental disorders; and (3) functionally characterize genes and identified variants using cell line assays and zebrafish. Many of the methodologies proposed here are novel to the candidate, including next-generation sequencing analysis to characterize disease variants and functional neurobiology assays using zebrafish. The experimental paradigm will be easily extended to characterize any gene implicated in neurological disease and will be essential in laying the foundation for the candidate's independent research program. !