DNA-GPS: A theoretical framework for optics-free spatial genomics and synthesis of current methods

While single-cell sequencing technologies provide unprecedented insights into genomic profiles at the cellular level, they lose the spatial context of cells. Over the past decade, diverse spatial transcriptomics and multi-omics technologies have been developed to analyze molecular profiles of tissues. In this article, we categorize current spatial genomics technologies into three classes: optical imaging, positional indexing, and mathematical cartography. We discuss trade-offs in resolution and scale, identify limitations, and highlight synergies between existing single-cell and spatial genomics methods. Further, we propose DNA-GPS (global positioning system), a theoretical framework for large-scale optics-free spatial genomics that combines ideas from mathematical cartography and positional indexing. DNA-GPS has the potential to achieve scalable spatial genomics for multiple measurement modalities, and by eliminating the need for optical measurement, it has the potential to position cells in three-dimensions (3D).