A Platform for Scalable Spatial Somatic Variant Profiling

可扩展的空间体细胞变异分析平台

基本信息

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
项目类别：
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

项目摘要

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描述体细胞突变的累积特征一个人的一生。各种突变过程，包括细胞内在的和外在的，这些突变是这些突变的基础，如果发生在关键驱动基因中，可能会改变细胞的适应性并导致不良后果。然而，要充分理解功能性还需要做很多工作克隆体细胞突变对人体组织的影响。特别是，组织出现于祖细胞的协调迁移、分化和扩增。对于许多组织来说，例如与大多数上皮组织类型一样，空间内聚的克隆域作为常见的组织驻留出现祖细胞扩张。测量克隆的空间排列提供了两个重要的见解研究体细胞突变的影响：1）克隆特异性遗传变异在空间上聚集，在等位基因频率中创造局部优势，促进体细胞突变的发现，以及 2) 组织需要细胞类型的适当空间组织才能发挥功能，并具有克隆嵌合体外在线索可能会驱动克隆领域的扩展和/或基因改变的克隆可能会重塑周围组织以驱动组织功能障碍。如此一来，就有一个巨大的对克隆体细胞变异进行空间定位的方法的机会和需求。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。这种名为 Slide-DNA-seq 的方法是无偏的、模块化的，并且允许配对测量与其他模式，如转录组和表观基因组。在这里，我们寻求开发一个基于 Slide-DNA-seq 的技术平台，1) 大规模执行空间变异检测人体组织，2) 将这些变异与细胞类型和状态的功能变化联系起来， 3) 在 SMaHT 联盟内传播这些技术。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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