Broad Institute Mendelian Genomic Research Center

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 仍未被发现。然而，基因组学技术的显著发展和人类基因组 海量参考数据集有望推动孟德尔基因发现，前提是这些技术可以 在大量不同的队列中使用复杂的分析工具加以利用。重要的是，这些方法和 数据集只有在迅速与社区共享并实现这一目标的情况下才能催化基因发现 一直是我们远大研究院CMG的主要关注点。在这里，我们汇聚了一支非凡的团队 调查人员具有不同的专业知识，互补的技术，新颖的分析方法，以及 招聘网络，以及我们为探索遗传基础而开发的数据共享平台 孟德尔病，并进一步开发罕见疾病的治疗方法。 布罗德研究所孟德尔基因组研究中心(MGRC)建立在世界一流的 孟德尔基因发现、方法开发和数据共享由远大CMG建立。我们队有 投入大量精力开发被广泛采用的工具和平台，以增强变体分析的能力，如 作为GATK、gnomAD和seqr，并促进变量、数据和分析工具的开放共享。在过去的几年里 四年来，我们生成并共享了来自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个额外的基因正在进行后续研究。 我们的MGRC路线图将依靠外显子组测序和快速数据共享作为最有效的前线 方法，因为绝大多数CMG发现来自编码变体，其次是基因组 未破案件排序(目标1)。发现未被捕获的变化的互补方法 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，然后将 告知功能解释和机械解剖(目标2)。最后，我们将使用我们的平台来创建 在MGRC和更广泛的社区(AIM)之间实现变革性数据共享的新工具和方法 3)。在他们的结论中，这些研究将对完成相关基因目录做出重大贡献。 孟德尔病，为其作用机制提供了新的生物学见解，并公开分享了 我们生产的数据、工具和发现。

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.