'Mosaicism in Human Tissues, from Telomere to Telomere to RFA-22-013: "Somatic Mosaicism across Human Tissues Program: Genome Characterization Centers."

“人体组织中的镶嵌现象，从端粒到端粒再到 RFA-22-013：“人体组织中的体细胞镶嵌现象：基因组表征中心。”

• 批准号: 10662071
• 负责人: JAMES T BENNETT
• 金额: $ 250万
• 依托单位: SEATTLE CHILDREN'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: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662071
• 关键词: Address; Alleles; Area; Autopsy; Benchmarking; Biology; Blood; Cancer cell line; Catalogs; Cell Line; Cells; Chromatin; Collaborations; Complex; DNA Sequence; DNA sequencing; Data; Data Analyses; Data Set; Detection; Disease; Elements; Epigenetic Process; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genomic Segment; Genomics; Goals; Haplotypes; Health; Hi-C; Human; Human Genetics; Human Genome; Individual; International; Knowledge; Large-Scale Sequencing; Length; Location; Methods; Methylation; Molecular Conformation; Mosaicism; Mutate; Normal Cell; Nucleotides; Pattern; Phase; Play; Principal Investigator; RNA; Regulator Genes; Role; Sampling; Somatic Mutation; Structure; Tissues; Transcript; Validation; Variant; Vision; Work; cost; design; genetic variant; genome-wide; genomic locus; human disease; human reference genome; human tissue; improved; member; nanopore; precision genomic medicine; programs; reference genome; scaffold; single molecule; telomere; transcription factor; transcriptome sequencing; whole genome

PROJECT SUMMARY Precision genomic medicine depends on a complete understanding of all forms of genetic variation in normal individuals. However, current approaches for studying genetic variation in humans have yielded an incomplete snapshot of somatic variation and its contribution to health and disease, as current approaches typically sequence a single tissue (blood) and are not well suited for identifying structural variants, variants in repeat elements, or the functional consequences of somatic variants. The goal of our proposal “Mosaicism in Human Tissues, from Telomere to Telomere” is to characterize multiple types of human somatic variation across the entire human genome in a set of 10 tissues from 50 donors, and to work with other SMaHT network members towards producing a framework for understanding somatic variation in non-pathological human tissues. To advance these goals, our GCC will use a highly successful pipeline that has produced tens of thousands of high-quality human genomes, including the first ever complete telomere-to-telomere human genome. We will produce high quality short and long-read DNA sequencing data, full length transcript RNA sequencing data, single-molecule chromatin profiling data, and long-range chromatin conformation data from each donor. This approach will enable us to generate donor-specific reference genome assemblies, which we will use to call somatic variants in their originating haplotype genomic context. Calling variants independent of traditionally incomplete human references will vastly improve our ability to accurately identify somatic variants in complex repeat regions and other “unmappable” areas. These regions are precisely the locations where somatic mutation rate is expected to be elevated because they are challenging for the cell’s endogenous replication and proofreading mechanisms. Additionally, our approach will enable us to directly interrogate the impact of identified somatic variants on overlying epigenetic and transcriptional gene regulatory patterns. This GCC brings together three internationally recognized Principal Investigators (Drs. Bennett, Eichler, and Stergachis), with decades of expertise in high-throughput genomics, somatic variant discovery, structural variant identification, long-read sequencing and chromatin biology. Along with other members of the SMaHT network, we will produce the most complete catalogue of somatic variation and its gene regulatory impact to- date.

项目概要 精准基因组医学依赖于对正常人所有形式遗传变异的完整理解 然而，目前研究人类遗传变异的方法并不完整。 体细胞变异的快照及其对健康和疾病的贡献，目前的方法通常 对单个组织（血液）进行测序，不太适合识别结构变异、重复变异 我们提案“人类镶嵌现象”的目标。 组织，从端粒到端粒”旨在表征多种类型的人类体细胞变异 来自 50 位捐赠者的 10 个组织中的完整人类基因组，并与其他 SMaHT 网络成员合作 建立一个理解非病理性人体组织体细胞变异的框架。 为了推进这些目标，我们的海湾合作委员会将使用一条非常成功的管道，该管道已生产了数以万计的产品 高质量的人类基因组，包括第一个完整的端粒到端粒人类基因组。 产生高质量的短读长和长读 DNA 测序数据、全长转录本 RNA 测序数据、 来自每个供体的单分子染色质分析数据和长程染色质构象数据。 这种方法将使我们能够生成供体特定的参考基因组组件，我们将用它来 在其原始单倍型基因组环境中调用体细胞变体。 传统上不完整的人类参考将极大地提高我们准确识别体细胞变异的能力 在复杂的重复区域和其他“无法映射”的区域中，这些区域正是其中的位置。 体细胞突变率预计会升高，因为它们对细胞的内源性具有挑战性 此外，我们的方法将使我们能够直接询问 已识别的体细胞变异对表观遗传和转录基因调控模式的影响。 该 GCC 汇集了三位国际公认的首席研究员（Bennett 博士、Eichler 博士和 Stergachis），在高通量基因组学、体细胞变异发现、结构 与 SMaHT 的其他成员一起进行变异鉴定、长读长测序和染色质生物学。 网络，我们将制作最完整的体细胞变异目录及其基因调控影响—— 日期。