CellWalker2: multi-omic discovery of hierarchical cell type relationships and their associations with genomic annotations.

CellWalker2 is a graph diffusion-based method for single-cell genomics data integration. It extends the CellWalker model by incorporating hierarchical relationships between cell types, providing estimates of statistical significance, and adding data structures for analyzing multi-omics data so that gene expression and open chromatin can be jointly modeled. Our open-source software enables users to annotate cells using existing ontologies and to probabilistically match cell types between two or more contexts, including across species. CellWalker2 can also map genomic regions to cell ontologies, enabling precise annotation of elements derived from bulk data, such as enhancers, genetic variants, and sequence motifs. Through simulation studies, we show that CellWalker2 performs better than existing methods in cell type annotation and mapping. We then use data from the brain and immune system to demonstrate CellWalker2's ability to discover cell type-specific regulatory programs and both conserved and divergent cell type relationships in complex tissues.