Broad Institute Mendelian Genomic Research Center

布罗德研究所孟德尔基因组研究中心

• 批准号: 10614593
• 负责人: Anne O'Donnell-Luria
• 金额: $ 249.82万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614593
• 关键词: Acceleration; Admission activity; Adopted; Biological; Blood; Candidate Disease Gene; Catalogs; Cell Line; Childhood; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Communities; Country; Data; Data Aggregation; Data Analyses; Data Set; Development; Diagnosis; Disease; Dissection; Embryo; Emerging Technologies; Family; Genes; Genetic; Genetic Diseases; Genomics; Goals; Haplotypes; In Vitro; Investments; Joints; Kidney; Mendelian disorder; Methods; Mitochondria; Modeling; Mus; Mutation; National Human Genome Research Institute; Patients; Pediatrics; Phenotype; Process; Productivity; Rare Diseases; Research; Research Personnel; Retina; Sampling; Statistical Models; Technology; Tissues; Untranslated RNA; Variant; analytical method; analytical tool; clinical sequencing; cohort; data sharing; disease phenotype; empowerment; epigenetic profiling; exome sequencing; follow-up; gene discovery; genetic disorder diagnosis; genome sequencing; genomic data; improved; in vitro Model; in vivo; in vivo Model; induced pluripotent stem cell; infant death; insight; large scale data; method development; mosaic variant; neuromuscular; novel; novel sequencing technology; parallelization; prime editing; recruit; single-cell RNA sequencing; statistics; therapeutic development; therapeutic target; therapeutically effective; timeline; tool; transcriptome sequencing

Project Summary Despite significant progress toward deciphering the genetic cause of many rare disease phenotypes in the NHGRI Centers for Mendelian Genetics (CMG), more than half of the genes underlying Mendelian diseases remain undiscovered. However, remarkable developments in genomics technologies and the aggregation of massive reference datasets are poised to advance Mendelian gene discovery, provided these technologies can be exploited using sophisticated analytic tools in large and diverse cohorts. Importantly, these methods and datasets can only catalyze gene discovery if they are rapidly shared with the community, and enabling this goal has been a primary focus of our Broad Institute CMG. Here, we bring together an extraordinary team of investigators with diverse expertise, complementary technologies, novel analytic methods, an established recruitment network, and platforms that we have developed for data sharing to explore the genetic underpinnings of Mendelian disease, and to further enable therapeutic development for rare diseases. The Broad Institute Mendelian Genomics Research Center (MGRC) builds upon the world-class track record of Mendelian gene discovery, methods development, and data sharing set by the Broad CMG. Our team has invested considerable effort to develop widely adopted tools and platforms empowering variant analysis, such as GATK, gnomAD, and seqr, and to facilitate open sharing of variants, data, and analysis tools. Over the last four years, we have generated and shared data for over 15,000 samples from 7,600 families. In the process, we have uncovered 256 novel disease-gene relationships, with 473 additional genes undergoing follow-up. Our MGRC roadmap will rely on exome sequencing and rapid data sharing as the most efficient frontline approach, given that the vast majority of CMG discoveries are derived from coding variants, followed by genome sequencing on unsolved cases (Aim 1). Complementary approaches to discover variation not captured by conventional methods will include emerging sequencing technologies, reference-free assembly, improved annotation of evolutionary constraint, large-scale data aggregation, and novel analytic methods. Transcriptome sequencing, epigenetic profiling, and CRISPR editing, as well as in vitro and in vivo functional modeling, will then inform functional interpretation and mechanistic dissection (Aim 2). Finally, we will use our platforms to create new tools and approaches for transformative data sharing across the MGRCs and the broader community (Aim 3). At their conclusion, these studies will significantly contribute to completing the catalog of genes underlying Mendelian disease, providing new biological insights into their functional mechanisms, and openly sharing the data, tools, and discoveries that we produce.

项目摘要 尽管在破译许多罕见疾病表型的遗传原因方面取得了重大进展， NHGRI孟德尔遗传学中心（CMG），超过一半的孟德尔疾病相关基因 仍然未被发现。然而，基因组学技术的显著发展和 大量的参考数据集准备推进孟德尔基因的发现，只要这些技术可以 利用复杂的分析工具，在大量不同的群体中加以利用。这些方法和 数据集只有在与社区快速共享时才能促进基因发现，并实现这一目标 一直是我们Broad Institute CMG的主要关注点。在这里，我们汇集了一个非凡的团队， 研究人员拥有不同的专业知识，互补的技术，新颖的分析方法， 招募网络，以及我们为探索基因基础而开发的数据共享平台 孟德尔氏病，并进一步使罕见疾病的治疗发展。 布罗德研究所孟德尔基因组学研究中心（MGRC）建立在世界一流的跟踪记录， 孟德尔基因发现，方法开发和数据共享由Broad CMG设置。我们的团队已被 投入了大量的精力来开发广泛采用的工具和平台，使变异分析， GATK、gnomAD和seqr，并促进变体、数据和分析工具的开放共享。在过去 四年来，我们已经生成并分享了来自7 600个家庭的15 000多个样本的数据。在这个过程中我们 已经发现了256个新的疾病基因关系，还有473个基因正在接受随访。 我们的MGRC路线图将依赖外显子组测序和快速数据共享作为最有效的前线 方法，鉴于绝大多数CMG发现来自编码变体，其次是基因组 未解决案件的排序（目标1）。发现未被捕获的变异的补充方法 传统的方法将包括新兴的测序技术，无参考组装，改进的 演化约束的注释、大规模数据聚合和新颖的分析方法。转录组 测序、表观遗传学分析和CRISPR编辑，以及体外和体内功能建模， 通知功能解释和机械解剖（目标2）。最后，我们将利用我们的平台， 在MGRC和更广泛的社区之间进行变革性数据共享的新工具和方法（Aim 3）。在他们的结论，这些研究将大大有助于完成基因目录的基础 孟德尔疾病，提供了新的生物学见解，其功能机制，并公开分享 数据、工具和发现。