Characterization of Human-Specific Duplicated Genes Implicated in Neurocognitive

描述(由申请者提供)：我们提出了一项培训计划，将培养一名有效的人类遗传学和神经生物学的独立研究员。这位候选人拥有与牛津大学和国立卫生研究院联合研究生项目的DPhil/博士学位，专注于人类疾病中常见的非编码变异的特征。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的测序技术和功能神经生物学分析来分析基因变异，然后是一个结构化的三年研究计划。该培训计划将促进使用测序技术和功能分析来表征人类特有的重复基因及其在神经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。艾希勒博士在基因组学和疾病遗传学领域享有盛誉，他的开创性工作是探索基因组的复杂区域。生物结构教授兼基因组科学兼职教授David Raible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，候选人将得到一个调查团队的支持，该团队致力于为她成为一名独立研究人员做好准备。华盛顿大学医学院的基因组科学系是为成为一名独立研究调查员而进行培训的理想场所。这些教师具有高度的多样性和协作性，拥有从计算生物学到使用模型系统的实验方法的各种专业知识。由节段性复制介导的大规模重复缺失和复制与自闭症、智力残疾、癫痫和精神分裂症有关。人类特有的基因驻留在这些侧翼节段性复制中，这些复制在人类参考构建中缺失或被错误注释，这加剧了我们对疾病致病机制的理解。为了全面了解这些人类特有的基因及其在疾病中的作用，我们将(1)利用为评估高序列同一性区域而开发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；以及(3)使用细胞系分析和斑马鱼对基因和已识别的变体进行功能表征。这里提出的许多方法对候选人来说都是新的，包括用来表征疾病变异的下一代测序分析和使用斑马鱼的功能神经生物学分析。实验范式将很容易扩展到表征与神经疾病有关的任何基因，并将是为候选人的独立研究计划奠定基础的关键。好了！

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. !