Develop accurate high-coverage and high-throughput single-cell Duplex-seq chemistry and multi-omics platforms for simultaneous profiling of somatic mutation and the transcriptome in single human cells

开发准确的高覆盖率和高通量单细胞 Duplex-seq 化学和多组学平台,用于同时分析单个人类细胞中的体细胞突变和转录组

基本信息

  • 批准号:
    10662693
  • 负责人:
  • 金额:
    $ 39.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

SUMMARY Here in this UG3/UH3 proposal, we aim to develop a new single-cell whole-genome amplification chemistry that allows high-accuracy and high-coverage detection of somatic mutations in single cells and the dual-omics assay that combines the high-accuracy and high-coverage genome profiling assay with the single-cell transcriptome assay (UG3). And in the UH3, we aim to scale up the throughput of the scDuplex-seq assay and the related dual-omics assay on the picoinjection-based droplet platform and validate this platform for different tissue types that are going to be profiled for somatic mosaicism by SMaTH program at the large scale. Understanding the heterogeneity of the blueprint of life at single-cell resolution is critical for our understanding of many fundamental biological processes such as aging and human diseases such as cancer and neurodegeneration. Hence, the successful development of the proposed single-cell method is important for reaching the goals of profiling somatic mosaicism set by the SMaHT program considering that somatic mutations, to our knowledge, are the most frequently occurred type of somatic variants. With the successful method development, we can determine the overall somatic mutation burdens in single cells and the variations among them. Going beyond characterizing the levels of somatic mutations, we can also effectively construct a lineage tree for all the sequenced single cells. And we expect that there will be phenotypic differences between different branches of the lineage tree, which correspond to different clones in our body, as recently observed in the regional dissection-based studies. Upon identifying the different branches/clones, we can characterize those phenotypic differences between them. The proposed dual-omics assay will provide the exact tool for this characterization. In terms of our major strategy in developing an accurate high-coverage genome profiling method, we will apply specialized transposition chemistry to genomic DNA, which results in duplex-DNA with very uniform fragment size, maximizing the recovery of these fragments in the downstream chemistry. Our major technical specialty in scaling up the throughput is the picoinjection droplet system that essentially allows the implementation of complicated chemistry onto the droplet system. The collaborative experience between Zong lab and Weitz lab has also been proven to be productive in the development of the droplet scTotalRNA-seq. Our ultimate goal of this proposal is to produce a lineage tree with a large number of cells (³1000) with both accurate characterizations of somatic mutations and the transcriptome in single cells, hence providing the proof of concept picture for future large-scale profiling by Genome Characterization Centers of the SMaHT program.
摘要 在这个UG3/UH3提案中,我们的目标是开发一种新的单细胞全基因组扩增 允许高精度和高覆盖率检测单个细胞突变的化学 细胞和结合高精度和高覆盖率基因组的双重组学分析 单细胞转录组分析(UG3)。在UH3中,我们的目标是扩大 提高scDuplex-seq分析和相关的双重组学分析的吞吐量 基于微微注射的微滴平台,并验证该平台适用于不同组织类型 将被Smath计划大规模地描述为体细胞嵌合体。理解 生命蓝图在单细胞分辨率下的异质性对于我们理解 许多基本的生物过程,如衰老和人类疾病,如癌症和 神经退行性变。因此,所提出的单细胞方法的成功发展是 对实现SMAHTT计划设定的体细胞嵌合体轮廓的目标很重要 考虑到,据我们所知,体细胞突变是最常见的 体细胞变异体。随着方法的成功开发,我们可以确定整体的体细胞 单细胞中的突变负荷以及它们之间的变异。超越了对 体细胞突变的水平,我们还可以有效地构建所有已测序的谱系树 单细胞。我们预计不同的分支机构之间会有表型差异 与我们身体中的不同克隆人相对应,正如最近在 基于区域解剖的研究。在确定不同的分支/克隆后,我们可以 描述它们之间的表型差异。拟议的双重组学分析将 为该角色化提供准确的工具。就我们发展可持续发展的主要战略而言 准确的高覆盖率基因组图谱方法,我们将应用专门的转座 化学作用于基因组DNA,从而产生具有非常均匀片段大小的双链DNA, 最大限度地回收下游化学中的这些片段。我们的主要技术 在扩大吞吐量方面的专长是微微注射液滴系统,基本上允许 在液滴系统上实现复杂的化学。协作 Zong Lab和Weitz Lab之间的经验也被证明在 滴状scTotalRNA-seq.我们这项提议的最终目标是产生一个 具有大量细胞的谱系树(³1000),同时具有准确的体细胞特征 突变和转录组,从而提供了概念图的证据 SMAHTT计划基因组特征中心未来的大规模图谱分析。

项目成果

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Chenghang Zong其他文献

Chenghang Zong的其他文献

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{{ truncateString('Chenghang Zong', 18)}}的其他基金

Detecting the onset of genome heterogeneity in tumor at single cell resolution
以单细胞分辨率检测肿瘤中基因组异质性的发生
  • 批准号:
    8754910
  • 财政年份:
    2014
  • 资助金额:
    $ 39.78万
  • 项目类别:

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