A Platform for Scalable Spatial Somatic Variant Profiling

可扩展的空间体细胞变异分析平台

• 批准号: 10662761
• 负责人: Jason Daniel Buenrostro
• 金额: $ 36.82万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662761
• 关键词: ATAC-seq; Aging; Bar Codes; Benchmarking; Biological Assay; Cells; Clonal Expansion; Computer software; Cues; DNA; DNA sequencing; Data; Data Set; Disease; Ensure; Epithelium; Equipment; Functional disorder; Gene Expression; Gene Frequency; Genes; Genetic; Genomics; Goals; Grouping; Individual; Measurement; Measures; Methods; Modality; Morphology; Mosaicism; Mutation; Neighborhoods; Process; Protocols documentation; Publications; Research; Resolution; Sampling; Slide; Software Tools; Somatic Mutation; Technology; Technology Transfer; Time; Tissues; Variant; Work; adverse outcome; cell type; computerized tools; data quality; epigenome; epigenomics; fitness; functional outcomes; genetic variant; human tissue; improved; insight; interest; member; migration; multiple omics; novel; progenitor; software development; stem cells; technology platform; tool; transcriptome; transcriptome sequencing; variant detection

SUMMARY Recent studies have begun to characterize the accumulation of somatic mutations over the lifetime of an individual. A variety of mutational processes, both cell-intrinsic and -extrinsic, underpin these mutations, which if occurring in key driver genes, may alter the fitness of the cell and lead to adverse outcomes. However, much work is needed to fully understand the functional effect of clonal somatic mutations across human tissues. In particular, tissues emerge from coordinated migration, differentiation and expansion of progenitor cells. For many tissues, such as most epithelial tissue types, spatially cohesive clonal fields emerge as common tissue-resident progenitors expand. Measuring the spatial arrangement of clones offers two critical insights for studying the effects of somatic mutations: 1) clone-specific genetic variants spatially aggregate, creating a local dominance in allele frequency, facilitating the discovery of somatic mutations, and 2) tissues require the proper spatial organization of cell types for function, with clonal mosaicism extrinsic cues may drive the expansion of clonal fields and/or genetically altered clones may remodel their surrounding tissue to drive tissue dysfunction. As such, there is an immense opportunity and need for methods that spatially localize clonal somatic variants. We have developed an approach to capture DNA onto high resolution (10 micron) spatially barcoded arrays. This approach, Slide-DNA-seq, is unbiased, modular, and allows for paired measurements with other modalities such as the transcriptome and epigenome. Here, we seek to develop a technology platform, built on Slide-DNA-seq, to 1) perform spatial variant detection at scale in human tissues, 2) to associate those variants with functional changes in cell-types and states, and 3) to disseminate these technologies within the SMaHT consortium.

摘要 最近的研究已经开始表征体细胞突变的积累 一个人的一生。各种突变过程，既有细胞内在的，也有外在的， 如果这些突变发生在关键驱动基因中，可能会改变细胞的适合性 并导致不良后果。然而，需要做很多工作才能完全理解功能 克隆性体细胞突变对人体组织的影响。特别是，组织从 协调祖细胞的迁移、分化和扩增。对于许多纸巾，如 与大多数上皮组织类型一样，空间内聚的克隆场以常见的组织驻留形式出现 祖细胞不断扩大。测量克隆的空间排列为以下两个关键问题提供了见解 研究体细胞突变的影响：1)克隆特有的遗传变异在空间上聚集， 在等位基因频率上创造局部优势，促进体细胞突变的发现，以及 2)组织需要适当的细胞类型的空间组织以发挥功能，具有克隆嵌合体 外部线索可能驱动克隆领域的扩展和/或基因改变的克隆可能 重塑他们周围的组织以驱动组织功能障碍。因此，有一个巨大的 对克隆体细胞变异进行空间定位方法的机会和需求。我们有 开发了一种将DNA捕获到高分辨率(10微米)空间条形码上的方法 数组。这种方法，Slide-DNA-Seq，是无偏的、模块化的，并允许配对测量 与其他方式，如转录组和表观基因组。在这里，我们寻求开发一种 建立在Slide-DNA-seq上的技术平台，用于1)在 人类组织，2)将这些变异与细胞类型和状态的功能变化联系起来， 以及3)在SMAT财团内传播这些技术。

项目成果

Slide-tags enables single-nucleus barcoding for multimodal spatial genomics.

• DOI: 10.1038/s41586-023-06837-4
• 发表时间: 2024-01
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Russell, Andrew J. C.;Weir, Jackson A.;Nadaf, Naeem M.;Shabet, Matthew;Kumar, Vipin;Kambhampati, Sandeep;Raichur, Ruth;Marrero, Giovanni J.;Liu, Sophia;Balderrama, Karol S.;Vanderburg, Charles R.;Shanmugam, Vignesh;Tian, Luyi;Iorgulescu, J. Bryan;Yoon, Charles H.;Wu, Catherine J.;Macosko, Evan Z.;Chen, Fei
• 通讯作者: Chen, Fei