Core B - Technical Services

核心 B - 技术服务

• 批准号: 10613364
• 负责人: MICHAEL E TALKOWSKI
• 金额: $ 61.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613364
• 关键词: 3-Dimensional; Alleles; Bayesian Modeling; Biological Assay; Catalogs; Categories; Cell Line; Cell model; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Communities; Complex; Copy Number Polymorphism; Data; Data Analyses; Data Set; Disease; Engineering; Family; Female; Fertilization; GNRH1 gene; Gene Expression Profile; Gene Expression Profiling; General Hospitals; Genes; Genome; Genomic medicine; Genomics; Human; Idiopathic Hypogonadotropic Hypogonadism; Individual; Infertility; Joints; Kallmann Syndrome; Massachusetts; Methods; Modeling; Molecular; Mutation; Neurodevelopmental Disorder; Neurons; Pathogenicity; Pathway interactions; Patients; Phenotype; Point Mutation; Population; Process; Reagent; Reproductive Medicine; Research; Resources; Risk; Sampling; Scoring Method; Series; Services; System; Technology; Untranslated RNA; Variant; aggregation database; biobank; case control; cloud based; cohort; computerized data processing; computerized tools; de novo mutation; dosage; exome; exome sequencing; follow-up; functional genomics; gene discovery; genetic architecture; genome resource; genome sequencing; genomic data; genomic variation; human disease; induced pluripotent stem cell; insertion/deletion mutation; insight; loss of function; loss of function mutation; male; multidisciplinary; novel; prime editing; progenitor; programs; rare variant; trait; transcriptome; transcriptome sequencing; transmission process; variant detection; whole genome

PROJECT ABSTRACT The Center for Reproductive Medicine (CRM) represents a multi-disciplinary program to explore the genetic architecture of infertility. The CRM Genomics Core (GC) described herein envisages providing a centralized and catalytic resource for genomic variation, statistical association, and functional perturbations for all components of this overarching CRM program. This genomics hub will specifically catalyze discoveries by providing expertise in the data and methods that will be leveraged for deeper insights into rare and common forms of infertility in Projects 1 and 2, respectively. The GC will also serve as the focal point for cross-fertilization of data, analyses, and functional modeling across the program. Over the last several years, we have developed a compendium of computational tools, statistical approaches, and functional genomics methods to interrogate the mutational spectrum of variation in human diseases. Our methods incorporate joint analyses of short variants (SNVs, indels) and structural variants (SVs), including canonical balanced SVs and copy number variants (CNVs), as well as a diverse catalog of complex SVs that are surprisingly abundant and associated with an array of human disease. These studies have required methods to uniformly generate, process, and rigorously analyze genomics datasets for association studies. In the GC, we will discover and annotate variation, interpret association against population-scale datasets in excess of 1,000,000 genomes from our related studies, and perform scalable engineering to generate an allelic series of perturbations in genes associated with rare and common forms of infertility using human induced pluripotent stem cell (hiPSC) derived GnRH models. Overall, we will support the CRM by completing three objectives related to providing datasets, methods, and functional resources. Objective 1 will develop a comprehensive genomics resource from exome, genome and long-read sequencing, and uniform data processing of the CRM cohorts. Objective 2 will perform integrated rare variant association and interpretation of these datasets by jointly analyzing CRM cohorts with population-scale datasets generated in our genome aggregation database (gnomAD) project and complex disease consortia studies. Objective 3 will then perform scalable CRISPR perturbation of infertility genes in GnRH neuronal models by engineering loss-of-function mutations and an allelic series for select infertility genes. Transcriptional profiling in the genomics core will identify signatures associated with perturbation of these infertility genes, and will seek convergence of these signatures on a small number of infertility relevant pathways. All CRISPR-engineered models will be distributed relevant projects for further functional assays, and all data and models will be made openly available for distribution to the community. These objectives in the genomics hub of the CRM will thus provide datasets, gene discoveries, and CRISPR-engineered isogenic models to facilitate new insights into infertility within the CRM and the broader research community.

项目摘要 生殖医学中心（CRM）代表了探索遗传的多学科计划 不育的建筑。本文所述的CRM基因组核心（GC）设想提供集中式和 所有组件的基因组变异，统计关联和功能扰动的催化资源 这个总体CRM计划。该基因组学枢纽将通过提供专业知识来特别催化发现 在将利用的数据和方法中，可以更深入地了解罕见和常见的不育形式 项目1和2分别。 GC还将成为数据交叉施用，分析， 和整个程序的功能建模。在过去的几年中，我们开发了 计算工具，统计方法和功能基因组学方法来审问突变 人类疾病变异的频谱。我们的方法结合了短变体（SNV，Indels）的关节分析 和结构变体（SVS），包括规范平衡的SV和拷贝数变体（CNV）以及一个 复杂的SV的各种目录，它们具有惊人的丰富且与一系列人类疾病相关的目录。 这些研究需要均匀生成，过程和严格分析基因组学数据集的方法 进行关联研究。在GC中，我们将发现并注释变化，解释关联反对 来自我们相关研究的人口尺度数据集超过1,000,000个基因组，并执行可扩展的数据集 工程学以与稀有和常见形式相关的基因产生一系列等位基因扰动 使用人类诱导多能干细胞（HIPSC）衍生的GNRH模型的不孕症。总体而言，我们将支持 CRM通过完成与提供数据集，方法和功能资源有关的三个目标。 目标1将从外显子，基因组和长阅读中开发全面的基因组学资源 CRM队列的测序和统一的数据处理。目标2将执行综合稀有变体 通过与人口规模共同分析CRM队列，对这些数据集的关联和解释 在我们的基因组聚集数据库（GNOMAD）项目和复杂疾病联盟中产生的数据集 研究。然后，目标3将执行GNRH神经元中不育基因的可扩展CRISPR扰动 通过工程功能丧失突变和选择的不孕基因的等位基因系列模型。 基因组学核心中的转录分析将识别与这些扰动相关的特征 不孕基因，并将在少数不育相关途径上寻求这些特征的收敛。 所有CRISPR工程模型都将分发相关项目，以进行进一步的功能测定，所有数据 并将公开向社区分发模型。基因组学中的这些目标 因此 促进对CRM和更广泛的研究社区内不孕症的新见解。