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

总结 全基因组关联研究（GWAS）已经产生了大量的候选基因和基因座，用于广泛的遗传学研究。 一系列复杂的疾病和表型性状，但往往没有导致足够的机制洞察力， 导致在预防、诊断或治疗疾病方面可操作的变化。这是一个关键的后果 潜在的遗传效应的属性，可以证明难以建模，特别是：组合 多个基因座之间的相互作用，可能在不同时间起作用的调节作用的优势， 在不同的组织或器官中，以及许多映射疾病中终身多维风险的整合 性状随着该领域的发展，其他贡献也开始在特定的地点得到承认，包括; 修改现有的孟德尔基因的影响，更复杂的基因-基因或基因-环境 相互作用和体细胞变异的作用，导致各种慢性疾病。 我们已经成功地克服了我们现有的斑马鱼GWAS社区资源中的这些挑战， 创建一个管道，利用快速可扩展性，功能相关性和基因组 保护斑马鱼模型系统，以产生超过100个基因的有用功能注释， 在过去的7年里，我们已经平行定义了多个GWAS基因座的疾病基因， 将这一领域推进到了早期的机械学研究。我们现在建议扩大这一社区资源， 继续我们现有的活动，同时增加以下方面的关键能力：a）建模基因-基因和基因环境 相互作用，以进一步探索许多常见疾病的复杂遗传学和B）确定性的 体细胞变异的建模，包括有效的移植研究，以充分了解体细胞变异的作用。 疾病的变异。这些新功能还直接解决了人类遗传学的持续要求 该资源最初开发的社区。 作为一个联合体，我们将继续推动斑马鱼作为这方面的模式生物的能力。 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 在整个提案期间。重要的是，我们将能够提供一个全面的一揽子计划， 将注释的候选基因和相互作用反馈给我们在人类遗传学社区的合作者， 增强他们的研究产生的影响和洞察力。对于此更新申请，我们提出以下建议 具体目标： 目的1 -功能分析来自血液、肝脏、心脏和血管性状的多个GWAS研究的基因座， 在斑马鱼中使用CRISPR-Cas9技术进行测定开发和基因编辑。 目的2 -定量表征基因-基因和基因-环境相互作用， 与人类遗传学有关 目的3 -模拟GWAS基因座的体细胞变异在慢性疾病中的作用