PubMed2026
MOTIVATION: Recent dynamic lineage tracing technologies use genome editing to induce heritable mutations, or edits, that accumulate across successive cell divisions. These edits are measured using single-cell sequencing or imaging, providing data to reconstruct cell lineages at single-cell resolution. Current computational approaches to infer cell lineage trees, or phylogenies, from these data perform two separate steps: (i) Identify each cell's edits (genotype) from the raw sequencing or imaging data; (ii) Infer a cell lineage tree from the cell genotypes. However, genotyping cells is an inexact process and genotype errors can yield an inaccurate lineage tree. For example, using fluorescence based-imaging to measure edits results in a high fraction (≈25%-50%) of uncertain or erroneous genotypes. RESULTS: We introduce Lineage Analysis via Maximum Likelihood with PRobabilistic Observations (LAML-Pro), an algorithm that jointly infers cell genotypes and a cell lineage tree. LAML-Pro is based on the Probabilistic Mixed-type Missing Observation (PMMO) model, which we derive to describe both the genome editing and genotype observation processes. LAML-Pro constructs lineage trees from thousands of cells in under an hour by leveraging the sparsity of transitions under the PMMO model. On simulated data, we demonstrate that LAML-Pro corrects genotype errors and infers substantially more accurate trees than existing methods which are vulnerable to genotype errors. Applied to data from two recent imaging-based lineage tracing systems, LAML-Pro reduces genotype errors by 5-fold and produces more spatially coherent lineage trees compared to existing methods. AVAILABILITY AND IMPLEMENTATION: LAML-Pro is implemented in C++ and is available as both a command-line interface and as a Python library at: github.com/raphael-group/LAML-Pro.