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.

NARRATIVE Tissues in our bodies accumulate mutations over time. We do not yet understand what the effects of these mutations are on aging and disease. Currently, we do not have good tools to study these mutations in the native context of where cells live, tissues. Here, we will develop new tools to study mutations in tissues, and in particular, assay how and if somatic variants occur in spatial groupings across different types of tissues. After discovering these spatial groupings, we will explore how the variants change the state of the cells that harbor them.