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

项目总结 精确的基因组医学依赖于对正常人类所有形式的遗传变异的完整理解 个人。然而，目前研究人类遗传变异的方法已经产生了一个不完整的 体细胞变异及其对健康和疾病的贡献的快照，因为目前的方法通常 对单个组织(血液)进行测序，不适合识别结构变体，重复序列中的变体 元素，或体细胞变异的功能后果。我们提出的“人类的嵌合体”的目标 组织，从端粒到端粒“是描述人类多种类型的体细胞变异 从50个捐赠者的10个组织中提取完整的人类基因组，并与SMATH网络的其他成员合作 为理解非病理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GCC将使用一条非常成功的管道，已经生产了数以万计的 高质量的人类基因组，包括有史以来第一个完整的端粒到端粒人类基因组。我们会 产生高质量的短读和长读DNA测序数据、全长转录本RNA测序数据， 单分子染色质图谱数据和来自每个供体的远程染色质构象数据。 这种方法将使我们能够产生供体特定的参考基因组组合，我们将使用它来 在起源的单倍型基因组背景下称体细胞变异体。调用独立于 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。这些地区正是 预计体细胞突变率将会提高，因为它们对细胞的内源 复制和校对机制。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重叠的表观遗传和转录基因调控模式的影响。 这位GCC汇集了三位国际公认的首席调查员(贝内特博士、艾希勒博士和 Stergacits)，在高通量基因组学、体细胞变异发现、结构 变异体鉴定、长读测序和染色质生物学。与SMAHTT的其他成员一起 网络，我们将制作最完整的体细胞变异及其基因调控影响目录- 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.