Theoretical Guarantees for Phylogeny Inference from Single-Cell Lineage Tracing

Abstract

CRISPR-Cas9 lineage tracing technologies have emerged as a powerful tool for investigating development in single-cell contexts, but exact reconstruction of the underlying clonal relationships in experiment is plagued by data-related complications. These complications are functions of the experimental parameters in these systems, such as the Cas9 cutting rate, the diversity of indel outcomes, and the rate of missing data. In this paper, we develop two theoretically grounded algorithms for reconstruction of the underlying phylogenetic tree, as well as asymptotic bounds for the number of recording sites necessary for exact recapitulation of the ground truth phylogeny at high probability. In doing so, we explore the relationship between the problem difficulty and the experimental parameters, with implications for experimental design. Lastly, we provide simulations validating these bounds and showing the empirical performance of these algorithms. Overall, this work provides a first theoretical analysis of phylogenetic reconstruction in the CRISPR-Cas9 lineage tracing technology.