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

• 批准号: 8565256
• 负责人: Megan Y Dennis
• 金额: $ 9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8565256
• 关键词: Autistic Disorder; Biological; Biological Assay; Biological Models; Candidate Disease Gene; Cell Line; Child; Commit; Complete Hydatidiform Moles; Complex; Computational Biology; Defect; Development; Developmental Process; Diagnostic Procedure; Disease; Disease Association; Doctor of Philosophy; Epilepsy; Evolution; Faculty; Foundations; Frequencies; Gene Family; Gene Structure; Generations; Genes; Genetic; Genetic Variation; Genome; Genomics; Goals; Haploidy; 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; genome sequencing; human disease; improved; innovation; knock-down; medical schools; nervous system disorder; neurodevelopment; next generation sequencing; novel; overexpression; paralogous gene; professor; programs; public health relevance; skills; tool; trait

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，旨在培养人类遗传学和神经生物学方面有效的独立研究者。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学位/博士学位，该项目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以及随后的为期三年的研究计划中，使用新颖的测序技术和功能性神经生物学测定来分析遗传变异。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誉世界，在探索基因组复杂区域方面做出了开创性的工作。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进行神经发育中基因的功能表征。此外，候选人将得到一组研究人员的支持，致力于帮助她为独立研究人员的职业生涯做好准备。华盛顿大学医学院基因组科学系是接受独立研究人员培训的理想场所。教师队伍高度多元化，具有从计算生物学到使用模型系统的实验方法等专业知识。由节段重复介导的大规模重复性缺失和重复与自闭症、智力障碍、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，这些重复在人类参考构建中缺失或错误注释，这加深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) 筛查神经发育障碍病例的突变； (3) 使用细胞系分析和斑马鱼对基因进行功能表征并鉴定变异。这里提出的许多方法对候选人来说都是新颖的，包括用于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测定。该实验范式将很容易扩展到表征与神经系统疾病有关的任何基因，并且对于为候选人的独立研究计划奠定基础至关重要。 ！