SCOUT: Ornstein-Uhlenbeck modelling of gene expression evolution on single-cell lineage trees.

Understanding the evolutionary dynamics of clonal populations is essential for uncovering the principles of development, disease progression, and therapeutic resistance. Recent advances in single-cell lineage tracing and transcriptomics enable such analyses by combining heritable barcodes with cell-state information. Here, we present SCOUT (single-cell Ornstein-Uhlenbeck trees), a framework that models gene expression dynamics along single-cell lineage trees using Ornstein-Uhlenbeck processes to distinguish neutral drift from selective pressure. Using simulations, we demonstrate that SCOUT accurately classifies genes based on their underlying evolutionary models. We further validate SCOUT in Caenorhabditis elegans development, identifying biological processes under selection across distinct developmental contexts. Finally, we apply SCOUT to a lung adenocarcinoma xenograft model, revealing key regulators of metastatic progression and tumor microenvironmental adaptation. By integrating lineage and transcriptomic data, SCOUT provides a powerful evolutionary lens for dissecting the forces that shape cell fate.