Learning dynamics by computational integration of single cell genomic and lineage information

A goal of single cell genome-wide profiling is to reconstruct dynamic transitions during cell differentiation, disease onset, and drug response. Single cell assays have recently been integrated with lineage tracing, a set of methods that identify cells of common ancestry to establish bona fide dynamic relationships between cell states. These integrated methods have revealed unappreciated cell dynamics, but their analysis faces recurrent challenges arising from noisy, dispersed lineage data. Here, we develop coherent, sparse optimization (CoSpar) as a robust computational approach to infer cell dynamics from single-cell genomics integrated with lineage tracing. CoSpar is robust to severe down-sampling and dispersion of lineage data, which enables simpler, lower-cost experimental designs and requires less calibration. In datasets representing hematopoiesis, reprogramming, and directed differentiation, CoSpar identifies fate biases not previously detected, predicting transcription factors and receptors implicated in fate choice. Documentation and detailed examples for common experimental designs are available at https://cospar.readthedocs.io/.