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

斑马鱼种系和体细胞遗传疾病模型的社区资源

• 批准号: 10723158
• 负责人: Wolfram Goessling
• 金额: $ 89.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723158
• 关键词: ATAC-seq; Address; Alleles; Animal Model; Animals; Area; Back; Bar Codes; Biological Assay; Biological Models; Biology; Blood; CRISPR/Cas technology; Candidate Disease Gene; Cell Lineage; ChIP-seq; Chemicals; Chronic Disease; Clonality; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Communities; Companions; Complex; DNA methylation profiling; Diagnosis; Dimensions; Disease; Disease model; Drops; Evaluation; Event; Exons; Fishes; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Recombination; Genetic study; Genomics; Genotype; Heart; Hematopoiesis; Hematopoietic; Human; Human Genetics; Kidney; Liver; Maps; Modeling; Modification; Mutagenesis; Organ; Outcome; Pathogenesis; Phenotype; Physiological; Play; Prevention; Regulatory Element; Reproducibility; Research Personnel; Resolution; Resources; Risk; Role; Somatic Mutation; System; Techniques; Technology; Testing; Time; Tissues; Toxicology; Translating; Transplantation; Untranslated RNA; Validation; Variant; Work; Zebrafish; assay development; causal variant; cell type; combinatorial; cost; design; experience; gene environment interaction; gene interaction; genome wide association study; genomic locus; human disease; insight; model organism; mosaic; new technology; programs; role model; stem cells; tool; trait; transcriptome sequencing; zebrafish genome

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

概括 全基因组关联研究 (GWAS) 已产生大量候选基因和基因座，用于广泛的研究。 一系列复杂的疾病和表型特征，但通常没有产生足够的机制洞察力 导致疾病的预防、诊断或治疗方面发生可操作的变化。这是关键的结果 潜在遗传效应的属性可能难以建模，特别是：组合 多个位点之间的相互作用，可能在不同时间和不同时间发挥作用的优势调节效应 在不同的组织或器官中，以及许多绘制的疾病中终生多维风险的整合 特征。随着该领域的发展，其他贡献已开始在特定位点得到认可，包括： 修改现有孟德尔基因、更复杂的基因-基因或基因-环境的影响 相互作用以及体细胞变异在多种慢性疾病中的作用。 我们在现有的斑马鱼 GWAS 社区资源中成功克服了这些挑战 创建一个利用快速可扩展性、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 多个基因的有用功能注释 过去7年的监管位点。我们平行定义了多个 GWAS 位点的疾病基因， 将该领域推进到早期的机制研究。我们现在建议扩展此社区资源， 继续我们现有的活动，同时增加以下方面的关键功能：a) 基因-基因和基因环境建模 相互作用，以进一步探索许多常见疾病的复杂遗传学和 b) 明确的 体细胞变异建模，包括有效的移植研究，以充分了解体细胞的作用 疾病的变异。这些新功能还直接满足人类遗传学的持续要求 资源最初开发的社区。 作为一个联盟，我们将继续推动斑马鱼作为模式生物的能力 随着成本的下降，我们能够进行功能注释的疾病/位点的数量只会增加 在提案有效期内。重要的是，我们将能够提供全面的一揽子服务 注释候选基因和相互作用返回给我们在人类遗传学界的合作者 增强研究的影响力和洞察力。对于本次续展申请，我们提出以下建议 具体目标： 目标 1 - 对血液、肝脏、心脏和血管特征的多项 GWAS 研究的基因座进行功能分析，优化 使用 CRISPR-Cas9 技术在斑马鱼中进行检测开发和基因编辑。 目标 2 - 定量描述基因-基因和基因-环境相互作用 与人类遗传学有关 目标 3 - 模拟 GWAS 位点体细胞变异在慢性疾病中的作用