LineageOT is a unified framework for lineage tracing and trajectory inference

Understanding the genetic and epigenetic programs that control differentiation during development is a fundamental challenge, with broad impacts across biology and medicine. Measurement technologies like single-cell RNA-sequencing and CRISPR-based lineage tracing have opened new windows on these processes, through computational trajectory inference and lineage reconstruction. While these two mathematical problems are deeply related, methods for trajectory inference are not typically designed to leverage information from lineage tracing and vice versa. Here, we present LineageOT, a unified framework for lineage tracing and trajectory inference. Specifically, we leverage mathematical tools from graphical models and optimal transport to reconstruct developmental trajectories from time courses with snapshots of both cell states and lineages. We find that lineage data helps disentangle complex state transitions with increased accuracy using fewer measured time points. Moreover, integrating lineage tracing with trajectory inference in this way could enable accurate reconstruction of developmental pathways that are impossible to recover with state-based methods alone. Lineage tracing and snapshots of transcriptional state at the single-cell level are powerful, complementary tools for studying development. Here, the authors propose a mathematical method combining lineage tracing with trajectory inference to improve our understanding of development.