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

项目摘要 精确的基因组医学取决于对正常人中所有形式的遗传变异的完全理解。 个体然而，目前研究人类遗传变异的方法已经产生了不完整的结果。 体细胞变异的快照及其对健康和疾病的贡献，因为目前的方法通常 对单个组织（血液）进行测序，不太适合识别结构变异、重复序列变异 元素，或体细胞变异的功能后果。我们的建议的目标“镶嵌在人类 组织，从端粒到端粒”是为了表征多种类型的人类体细胞变异， 在来自50个捐赠者的10个组织中的整个人类基因组，并与其他SMaHT网络成员合作 为理解非病理性人体组织中的体细胞变异提供了一个框架。 为了推进这些目标，我们的海湾合作委员会将使用一个非常成功的管道， 高质量的人类基因组，包括第一个完整的端粒到端粒的人类基因组。我们将 产生高质量的短和长读段DNA测序数据，全长转录物RNA测序数据， 单分子染色质分析数据和来自每个供体的长程染色质构象数据。 这种方法将使我们能够产生供体特异性参考基因组组装，我们将使用它来 在其起源的单倍型基因组背景中称为体细胞变体。调用独立于 传统上不完整的人类参考将大大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“不可映射”区域。这些地区正是 体细胞突变率预计会升高，因为它们对细胞的内源性 复制和校对机制。此外，我们的方法将使我们能够直接询问 鉴定的体细胞变异体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主要研究者（班尼特博士、Eichler博士和 Stergachis），在高通量基因组学、体细胞变异发现、结构基因组学和基因组学领域拥有数十年的专业知识， 变体鉴定、长读序测序和染色质生物学。沿着其他SMaHT成员 网络，我们将产生最完整的体细胞变异及其基因调控影响的目录- 约会

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.