Biophysically interpretable inference of cell types from multimodal sequencing data

Multimodal, single-cell genomics technologies enable simultaneous measurement of multiple facets of DNA and RNA processing in the cell. This creates opportunities for transcriptome-wide, mechanistic studies of cellular processing in heterogeneous cell populations, such as regulation of cell fate by transcriptional stochasticity or tumor proliferation through aberrant splicing dynamics. However, current methods for determining cell types or ‘clusters’ in multimodal data often rely on ad hoc approaches to balance or integrate measurements, and assumptions ignoring inherent properties of the data. To enable interpretable and consistent cell cluster determination, we present meK-means (mechanistic K-means) which integrates modalities through a unifying model of transcription to learn underlying, shared biophysical states. With meK-means we can cluster cells with nascent and mature mRNA measurements, utilizing the causal, physical relationships between these modalities. This identifies shared transcription dynamics across cells, which induce the observed molecule counts, and provides an alternative definition for ‘clusters’ through the governing parameters of cellular processes. MeK-means clusters single-cell multimodal data by linking modalities through their biophysical relationships. We redefine clusters through transcription kinetics to reveal how RNA production and processing drive cellular diversity and disease.