Recurrent composite markers of cell types and states.

Determining concise sets of genomic markers that identify cell types and states within tissue ecosystems remains challenging. To address this challenge, we developed Recurrent Composite Markers for Biological Identities with Neighborhood Enrichment (RECOMBINE). Validations of RECOMBINE with simulation and transcriptomics data in bulk, single-cell and spatial resolutions demonstrated the method's ability for unbiased selection of composite markers that characterize biological subpopulations. RECOMBINE captured markers of mouse visual cortex from single-cell RNA sequencing data and provided a gene panel for targeted spatial transcriptomics profiling. RECOMBINE identified composite markers of CD8 T cell states including GZMK HAVCR2 effector memory cells associated with anti-PD1 therapy response. The method outperformed differential gene expression analysis in characterizing a rare cell subpopulation within mouse intestine. Using RECOMBINE, we uncovered hierarchical gene programs of inter- and intra-tumoral heterogeneity in breast and skin tumors. In conclusion, RECOMBINE offers a data-driven approach for unbiased selection of composite markers, resulting in improved interpretation, discovery, and validation of cell types and states.