Using CRISPR technology to study the function of paralogous genes

果蝇等模式生物中的基因注释对我们理解 人类基因的功能，包括人类疾病相关基因。旁系同源，它们有一个共同的 祖先，提出了一个具有挑战性的情况下，在模式生物的基因功能的鉴定，因为在某些情况下， 一方的功能丧失被另一方的补偿功能所掩盖，这样，只有当双方 将观察到信息表型。在其他情况下，冗余是部分的，例如 一个基因敲除具有当组中多于一个成员时观察到的表型子集 同时被破坏。我们小组和其他人最近在CRISPR技术方面取得的进展使得现在 有可能系统地敲除果蝇中的paradox对，包括在阶段和组织特异性 方式我们将利用现有的基础设施进行基于生物信息学的直系同源物鉴定， 旁系同源物，高效大规模生产蝇类，以及蝇类和数据共享以开发资源 可用于旁系同源物的双重敲低。我们对基因信号的初步表征 转导和神经变性，以及社区的深入分析，将揭示功能， 旁系同源基因，有助于缩小“表型差距”（缺乏相关的功能丧失表型）， 目前存在于这个重要的遗传模型系统中的所有基因的近一半。其结果将是一个苍蝇股票 果蝇专家进一步研究的资源，生物信息学管道和方法，可应用于 其他模型系统，以及为苍蝇和人类基因注释提供信息的数据资源

Gene annotations in model organisms such as Drosophila are important contributors to our understanding of the functions of human genes, including human disease-associated genes. Paralogs, which share a common ancestor, present a challenging case for identification of gene function in model organisms as in some cases, loss of function of one paralog is masked by compensatory function of the other(s), such that only when both are disrupted will informative phenotypes be observed. In other cases, redundancy is partial, such that knockout of one paralog has a subset of the phenotypes observed when more than one member of the group is disrupted simultaneously. Recent advances in CRISPR technology by our group and others makes it now possible to systematically knockout paralog pairs in Drosophila, including in a stage- and tissue-specific manner. We will use our existing infrastructure for bioinformatics-based identification of orthologs and paralogs, efficient large-scale production of fly stocks, and fly stock and data sharing to develop a resource useful for double-knockdown of paralogs. Our initial characterization of the genes with regards to signal transduction and neurodegeneration, as well as in-depth analyses by the community, will uncover function for paralogous genes, helping to close the ‘phenotype gap’ (lack of associated loss-of-function phenotypes) that currently exists for nearly half of all genes in this important genetic model system. The result will be a fly stock resource for further study by Drosophila experts, a bioinformatics pipeline and methods that can be applied to other model systems, and a data resource that will inform annotation of fly and human genes