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Deciphering the Genetics of Synapse Development by Whole Genome Sequencing

通过全基因组测序解读突触发育的遗传学

基本信息

批准号：
8269869
负责人：
Brian D McCabe
金额：
$ 20万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269869
关键词：
Bacterial Artificial Chromosomes Biological Models Caenorhabditis elegans Candidate Disease Gene Chemicals Chromosome Mapping Cloning Collection Complement Development Disease Drosophila genus Elements Employment Epitopes Future Gene Expression Profile Generations Genes Genetic Genetic Screening Genome Genomics Goals Human Insulator Elements Integrase Label Learning Lesion Methods Modeling Molecular Morphology Mutagenesis Mutate Mutation Nervous system structure Neurobiology Neuromuscular Junction Orthologous Gene Phenotype Play Point Mutation Process Proteins Publishing Recruitment Activity Regulation Regulatory Pathway Reproducibility Role Screening procedure Series Structure Synapses Techniques Technology Time Transgenes Transgenic Animals Transgenic Organisms Validation base candidate identification cost effective genome sequencing high throughput analysis human disease mutant nervous system development nervous system disorder neurodevelopment neurogenetics neuromuscular novel red fluorescent protein vector

项目摘要

DESCRIPTION (provided by applicant): Screening for mutants that disrupt neurodevelopmental processes in model systems such as Drosophila and the subsequent identification of the causative molecules have been central to understanding of the genetic basis of nervous system development. However, the full promise of forward genetic screening to discern the total complement of genes required for a neurobiological process is rarely realized, in part due to the time and labor required to identify the disrupted genes through conventional genetic mapping techniques. Recent years have seen proof-of-principle studies on the use of Whole Genome Sequencing (WGS) to identify causative point mutations in chemically mutagenized C.elegans or Drosophila strains. In both cases, the strategy was fast and cost-effective. We propose to recruit WGS technology to identify the molecular lesions in a large collection of Drosophila neuromuscular junction (NMJ) synapse mutants we have generated in preliminary studies. Using conventional genetic mapping techniques, we have previously identified the disrupted genes in subset of these mutants and subsequently characterized both novel synaptic regulatory pathways as well mutations in the Drosophila orthologs of human disease relevant proteins. We will determine the causative genetic defect in an additional forty selected synaptic structure mutants with the goal to both increase our understanding of the molecular regulation of synapse development and provide a guide for future, in-depth analysis of the uncovered loci. Furthermore, the repeated, routine application of Whole Genome Sequencing will supply valuable information on the reproducibility and reliability of this approach and establish the technology as a state-of-the-art cloning technique for nervous system mutants in Drosophila and other neurogenetic model systems.

描述（由申请人提供）：在模型系统（如果蝇）中筛选破坏神经发育过程的突变体以及随后鉴定致病分子对于理解神经系统发育的遗传基础至关重要。然而，前向遗传筛选的全部承诺，以辨别神经生物学过程所需的基因的总补体很少实现，部分原因是由于通过传统的遗传作图技术来识别被破坏的基因所需的时间和劳动力。近年来，人们对使用全基因组测序（WGS）来鉴定化学诱变的秀丽隐杆线虫或果蝇菌株中的致病点突变进行了原理验证研究。在这两种情况下，该战略都是快速和具有成本效益的。我们建议招募WGS技术，以确定我们在初步研究中产生的大量果蝇神经肌肉接头（NMJ）突触突变体的分子病变。使用传统的遗传作图技术，我们以前已经确定了这些突变体的子集中的破坏基因，并随后表征了新的突触调控途径以及人类疾病相关蛋白质在果蝇直系同源物中的突变。我们将在另外40个选定的突触结构突变体中确定致病性遗传缺陷，目的是增加我们对突触发育的分子调控的理解，并为未来对未发现的基因座的深入分析提供指导。此外，全基因组测序的重复、常规应用将为这种方法的可重复性和可靠性提供有价值的信息，并将该技术确立为果蝇和其他神经遗传模型系统中神经系统突变体的最先进的克隆技术。