'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.

项目总结