Age-dependent Phylodynamics with Application to Single-cell Lineage Trees.

As novel technologies for single-cell lineage tracing emerge, phylogenetic and phylodynamic tools are increasingly being used to study developmental processes. However, traditional phylodynamic methods rely on assumptions that are difficult to justify in developmental contexts. We present a generalization of the birth-death phylodynamic model to an age-dependent phylodynamic model. This method captures a key feature of development: due to cells dividing after characteristic generation times rather than after exponential waiting times, empirical cell lineage trees deviate from phylogenies generated under a birth-death model. By applying our method to a public dataset of stem cell colonies, we show how previous estimates of the underlying population-dynamic parameters were biased by the choice of a birth-death tree prior. We additionally showcase our method on embryonic lineage trees of an arthropod limb, demonstrating that age-dependence appears to be a common feature of development. Beyond developmental biology, our framework provides an approach for analyzing systems where classical birth-death assumptions may be violated or where empirical tree shapes are poorly captured by those expected under standard phylodynamic models. Our method is available as a BEAST2 package.