TyCHE enables time-resolved lineage tracing of heterogeneously-evolving populations.

Phylogenetic methods for cell lineage tracing have driven significant insights into organismal development, immune responses, and tumor evolution. While most methods estimate mutation trees, time-resolved lineage trees are more interpretable and could relate cellular migration and differentiation to perturbations like vaccines and drug treatments. However, somatic mutation rates can vary dramatically by cell type, significantly biasing existing methods. We introduce TyCHE (Type-linked Clocks for Heterogeneous Evolution), a Bayesian phylogenetics package that infers time-resolved phylogenies of populations with distinct evolutionary rates. We demonstrate that TyCHE improves tree accuracy using a new simulation package SimBLE (Simulator of B cell Lineage Evolution). We use TyCHE to infer patterns of memory B cell formation during HIV infection, dynamics of recall germinal centers following influenza vaccination, temporal evolution of a glioma tumor lineage, and progression of a bacterial lung infection. TyCHE and SimBLE are available as open-source software compatible with the BEAST2 and Immcantation ecosystems.