Simultaneous mapping of somatic mosaicism and kb-resolution 3D genome in single cells.

单细胞中体细胞嵌合体和 kb 分辨率 3D 基因组的同时作图。

• 批准号: 10660575
• 负责人: Fulai Jin
• 金额: $ 40.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660575
• 关键词: 3-Dimensional; ATAC-seq; Address; Affect; Benchmarking; Biotin; Catalogs; Cell Line; Cell division; Cell model; Cell physiology; Cells; ChIP-seq; Clonal Expansion; Complex; Copy Number Polymorphism; DNA; DNA Methylation; DNA Sequence Alteration; DNA sequencing; Data; Detection; Development; Disease; Funding; Genetic; Genome; Genome Mappings; Genomics; Genotype; Hi-C; Human; Islet Cell; Islets of Langerhans; Joints; Lead; Libraries; Ligation; Malignant Neoplasms; Maps; Methods; Molecular; Mosaicism; Mutation; Names; Nature; Neurons; Normal Cell; Paper; Phase; Play; Population; Positioning Attribute; Protocols documentation; Publishing; Research; Resolution; Role; Scanning; Shotguns; Single Nucleotide Polymorphism; Somatic Cell; Somatic Mutation; Technology; Testing; Time; Tissue Sample; Tissues; Variant; autism spectrum disorder; bisulfite sequencing; cell type; deep learning; epigenome; epigenomics; experimental study; feasibility testing; genome sequencing; human tissue; improved; multiple omics; novel; scale up; tool; transcriptomics; whole genome

Project Abstract In early development and over the lifetime of a human, the genome of every somatic cell will eventually accumulate hundreds of mutations during multiple cell divisions. Although most somatic mutations are predicted to be non-functional, it is known for a long time that some of the somatic mutations, including single nucleotide variants (SNVs), copy number variants (CNVs), translocations, etc., may cause serious diseases like cancer. In the past decade, more and more studies suggested that somatic mutations may also play important roles in milder complex diseases, such as autism. However, although single-cell or ultra-deep whole genome sequencing (WGS) technologies can now identify many rare somatic mutations, these technologies tell little about the consequences or mechanisms of somatic mutations. In fact, unless a somatic mutation causes significant clonal expansion, characterizing the molecular functions of a somatic mutation in its native tissue context is extremely challenging. In general, WGS protocol precludes most of the commonly pursued epigenomic technologies such as ATAC-seq and ChIP-seq. We recent demonstrated that using a novel deep-learning-based pipeline named DeepLoop, we can upgrade the super sparse single cell Hi-C maps to kilobase resolution, which may serve as a robust readout of genome activity. This motivates us to optimize a technology named Dip-C to simultaneously map somatic mutations and 3D genome from single cells. If successful, the project will deliver a long needed multi- OMIC tool for SMaHT network. We will test Dip-C in both model cell line and human tissues and verify its unique capability to resolve how somatic mutations may affect a small number of cells in large population or complex tissue.

项目摘要 在人类的早期发育和一生中，每个体细胞的基因组最终都会 在多次细胞分裂过程中积累数百种突变。尽管大多数体细胞突变 预测为非功能性的，长期以来已知一些体细胞突变，包括 单核苷酸变体（SNV）、拷贝数变体（CNV）、易位等，可能造成严重 比如癌症在过去的十年里，越来越多的研究表明，体细胞突变可能 也在较轻的复杂疾病中发挥重要作用，如自闭症。虽然单细胞或 超深全基因组测序（WGS）技术现在可以鉴定许多罕见的体细胞突变， 这些技术对体细胞突变的后果或机制知之甚少。事实上，除非 一个体细胞突变引起显着的克隆扩增，表征的分子功能， 在其天然组织环境中的体细胞突变是极其具有挑战性的。一般来说，WGS协议排除了 大多数常用的表观基因组技术，如ATAC-seq和ChIP-seq。我们最近 演示了使用一种名为DeepLoop的新型基于深度学习的管道，我们可以升级 超稀疏的单细胞Hi-C映射到酶的分辨率，这可以作为一个强大的读出， 基因组活性这促使我们优化一种名为Dip-C的技术， 突变和3D基因组。如果成功，该项目将提供一个长期需要的多- 用于SMaHT网络的OMIC工具。我们将在模型细胞系和人体组织中测试Dip-C，并验证 其独特的能力，以解决如何体细胞突变可能会影响少数细胞在大 群体或复杂组织。