Detecting branching rate heterogeneity in multifurcating trees with applications in lineage tracing data

Abstract

AbstractUnderstanding cellular birth rate differences is crucial for predicting cancer progression and interpreting tumor-derived genetic data. Lineage tracing experiments enable detailed reconstruction of cellular genealogies, offering new opportunities to measure branching rate heterogeneity. However, the lineage tracing process can introduce complex tree features that complicate this effort. Here, we examine tree characteristics in lineage tracing-derived genealogies and find that editing window placement leads to multifurcations at a tree’s root or tips. We propose several ways in which existing tree topology-based metrics can be extended to test for rate heterogeneity on trees even in the presence of lineage-tracing associated distortions. Although these methods vary in power and robustness, a test based on theJ1statistic effectively detects branching rate heterogeneity in simulated lineage tracing data. Tests based on other common statistics (ŝand the Sackin index) show interior performance toJ1. We apply our validated methods to xenograft experimental data and find widespread rate heterogeneity across multiple study systems. Our results demonstrate the potential of tree topology statistics in analyzing lineage tracing data, and highlight the challenges associated with adapting phylogenetic methods to these systems.