A community resource for germline and somatic genetic disease modeling in zebrafish

摘要 全基因组关联研究已经产生了大量的候选基因和基因座 一系列复杂的疾病和表型特征，但往往没有导致足够的机械洞察力 在疾病的预防、诊断或治疗方面导致可操作的变化。这是关键的结果 可能难以建模的潜在遗传效应的属性，具体地说：组合 多个基因座之间的相互作用，可能在不同的时间和在 在不同的组织或器官中，整合了终身多维的风险，在许多疾病中映射 特征。随着这个领域的发展，其他的贡献已经开始在特定的基因座被认识到，包括； 对现有孟德尔基因、更复杂的基因-基因或基因-环境的影响的修饰 相互作用和躯体变异在各种慢性病中的作用。 我们在我们现有的斑马鱼社区资源中成功地克服了这些挑战 创建一条利用快速可伸缩性、功能相关性和基因组优势的管道 保护斑马鱼模型系统，以生成100多个基因和 过去7年的监管地点。我们已经定义了多个GWA基因座的致病基因(S)并 将这一领域向前推进到早期的机械研究。我们现在提议扩展这一社区资源， 继续我们现有的活动，同时增加a)基因-基因和基因环境建模的关键能力 进一步探索许多常见疾病的复杂遗传学的相互作用和b)决定性的 体细胞变异的建模，包括有效的移植研究，以充分理解体细胞的作用 疾病的变异。这些新能力也直接解决了来自人类遗传学的持续请求。 最初为其开发资源的社区。 作为一个联盟，我们将继续推动斑马鱼作为模式生物在 随着成本的下降，我们能够在功能上注释的疾病/位置的数量只会增加 通过提案的持续时间。重要的是，我们将能够提供全面的一揽子 带注释的候选基因和相互作用返回给我们在人类遗传学社区的合作者 增强他们的研究的影响力和洞察力。对于本次续期申请，我们提出如下建议 具体目标： 目标1-从功能上分析血液、肝脏、心脏和血管特征的多个GWAS研究中的基因座，优化 利用CRISPR-Cas9技术对斑马鱼进行检测和基因编辑。 目标2-定量描述基因-基因和基因-环境之间的相互作用 与人类遗传学有关 目标3--模拟Gwas基因座的体细胞变异在慢性病中的作用

Summary Genome wide associations studies (GWAS) have produced a multitude of candidate genes and loci for a wide range of complex disease and phenotypic traits, but often have not resulted in sufficient mechanistic insight to lead to actionable changes in prevention, diagnosis, or treatment of disease. This is a consequence of key attributes of the underlying genetic effects which can prove difficult to model, specifically: combinatorial interactions between multiple loci, a preponderance of regulatory effects which may act at different times and in in different tissues or organs, and the integration of lifelong multidimensional risk in many of the mapped disease traits. As the field evolves, so other contributions have begun to be recognized at specific loci including; modification of the effects of existing Mendelian genes, more complex gene-gene or gene-environment interactions and a role for somatic variation contributing to diverse chronic diseases. We have successfully overcome these challenges in our existing Zebrafish GWAS Community Resource by creating a pipeline which exploits the strengths of rapid scalability, functional relevance and genomic conservation of the zebrafish model system to generate useful functional annotation of over 100 genes and regulatory loci over the last 7 years. We have defined the disease gene(s) for multiple GWAS loci in parallel and moved the field forward to early mechanistic studies. We now propose to extend this Community Resource, continuing our existing activities while adding key capabilities in a) modeling gene-gene and gene environment interactions to further explore the complex genetics of numerous common diseases and the b) definitive modeling of somatic variation including efficient transplantation studies to fully understand the role of somatic variation in disease. These new capabilities also directly address ongoing requests from the human genetics community for which the resource was originally developed. As a consortium, we will continue to push forward the capabilities of the zebrafish as a model organism in this field and as costs drop, the number of diseases/loci that we will be able to functionally annotate will only grow through the duration of the proposal. Importantly, we will be able to deliver a comprehensive package of annotated candidate genes and interactions back to our collaborators in the human genetics community to enhance the impact and insight derived from their studies. For this renewal application, we propose the following Specific Aims: Aim 1 - Functionally analyze loci from multiple GWAS studies on blood, liver, heart and vessel traits, optimizing assay development and gene editing using CRISPR-Cas9 technology in zebrafish. Aim 2 - Quantitatively characterize gene-gene and gene-environment interactions where these have been implicated in human genetics Aim 3 - Modeling the role of somatic variation at GWAS loci in chronic disease