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.

概括 最近的研究已经开始表征体细胞突变的积累 一个人的终生。各种突变过程，包括细胞中的和 - 肢体， 基础这些突变（如果在关键驱动基因中发生）可能会改变细胞的适应性 并导致不利的结果。但是，需要大量工作才能充分理解功能 克隆跨组织的克隆体细胞突变的影响。特别是，组织从 祖细胞的协调迁移，分化和扩展。对于许多组织， 作为大多数上皮组织类型，在空间上粘性的克隆场作为常见的组织居民出现 祖细胞扩展。测量克隆的空间布置提供了两个关键见解 研究体突变的作用：1）克隆特异性遗传变异在空间骨料上， 在等位基因频率上建立局部优势，促进躯体突变的发现，并 2）组织需要适当的空间组织以进行功能，并具有克隆镶嵌性 外部提示可能会驱动克隆场的膨胀和/或遗传改变的克隆 重塑其周围组织以驱动组织功能障碍。因此，有一个巨大的 机会和需要空间定位克隆体细胞变体的方法。我们有 开发了一种将DNA捕获到高分辨率（10微米）的方法 数组。这种方法是幻灯片-DNA-seq，是公正的，模块化的，允许配对的测量 具有其他方式，例如转录组和表观基因组。在这里，我们试图开发 建立在幻灯片-DNA-seq的技术平台至1）大规模执行空间变体检测 人体组织，2）将这些变体与细胞类型和状态的功能变化相关联， 3）在SMAHT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