Characterization of Human-Specific Duplicated Genes Implicated in Neurocognitive

与神经认知有关的人类特异性重复基因的表征

基本信息

批准号：
9186571
负责人：
Megan Y Dennis
金额：
$ 24.82万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186571
关键词：
Autistic Disorder Biological Biological Assay Biological Models Candidate Disease Gene Cell Line Child Complete Hydatidiform Moles Complex Computational Biology Copy Number Polymorphism Defect Development Developmental Process Diagnostic Procedure Disease Doctor of Philosophy Epilepsy Evolution Faculty Foundations Frequencies Gene Family Gene Structure Generations Genes Genetic Genetic Variation Genome Genomic Segment Genomics Goals Haploidy Health Hereditary Disease Human Human Cell Line Human Genetics Intellectual functioning disability Joints Lead Libraries Life Mediating Mentors Mentorship Messenger RNA Methodology Methods Modeling Molecular Mus Mutation Nature Nervous System Physiology Neurobiology Neurocognitive Neurodevelopmental Disorder Neurologic Nucleotides Orthologous Gene Pathway interactions Phase Pongidae Population Primates Process Proteins Reading Recurrence Research Research Personnel Resources Role Schizophrenia Science Sequence Analysis Societies Source Structure Technology Testing Time Training Training Programs Translating United States National Institutes of Health Universities Variant Washington Work Zebrafish career cohort duplicate genes experience follow-up gene function genetic variant genome sequencing human disease human reference genome improved innovation knock-down medical schools mutation screening nervous system disorder neurocognitive disorder neurodevelopment next generation sequencing novel overexpression paralogous gene professor programs reference genome skills tool trait

项目摘要

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.

描述（由申请人提供）：我们提出了一项培训计划，该计划将准备有效的人类遗传学和神经生物学领域的独立研究者。该候选人拥有与牛津大学联合研究生计划的DPHIL/PHD，以及美国国立卫生研究院的重点是表征人类疾病中常见的非编码差异。她将扩展自己的技能，包括使用新型测序技术和功能性神经生物学分析在为期两年的有组织指导和培训计划中分析遗传变异，然后是结构化的三年研究计划。该培训计划将促进测序技术和功能测定方法来表征人类特异性重复的基因及其在神经系统特征和缺陷中的作用。基因组科学教授埃文·艾希勒（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中享誉世界，并通过开创性的工作探索了基因组的复杂地区。生物结构教授兼基因组科学兼职教授David Raible博士将通过使用斑马鱼作为基因工具来指导候选人在神经发育中基因的功能表征。此外，候选人将得到一支致力于为她作为独立研究人员做好准备的调查员团队的支持。华盛顿大学医学院的基因组科学系是寻求成为独立研究研究者的理想场所。该教师具有高度多样性的，并且具有从计算生物学到使用模型系统实验方法的专业知识。分段重复介导的大规模复发缺失和重复与自闭症，智力残疾，癫痫和精神分裂症有关。人类特异性基因居住在这些侧翼节段重复的重复中，这些复制在人类参考构建中缺少或误导，这加剧了我们对促成疾病机制的理解。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）利用单倍体基因组资源来评估高序列身份区域的三个基因组区域的高质量序列；（2）在神经发育障碍病例中进行突变的筛选；（3）使用细胞系分析和斑马鱼在功能上表征基因并确定了变体。这里提出的许多方法对候选人都是新颖的，包括下一代测序分析，以使用斑马鱼来表征疾病变异和功能性神经生物学测定法。实验范式将很容易扩展，以表征与神经疾病有关的任何基因，对于为候选人的独立研究计划奠定基础至关重要。