The Limits of the Constant-rate Birth-Death Prior for Phylogenetic Tree Topology Inference.

Birth-death models are stochastic processes describing speciation and extinction through time and across taxa and are widely used in biology for inference of evolutionary timescales. Previous research has highlighted how the expected trees under the constant-rate birth-death (crBD) model tend to differ from empirical trees, for example, with respect to the amount of phylogenetic imbalance. However, our understanding of how trees differ between the crBD model and the signal in empirical data remains incomplete. In this Point of View, we aim to expose the degree to which the crBD model differs from empirically inferred phylogenies and test the limits of the model in practice. Using a wide range of topology indices to compare crBD expectations against a comprehensive dataset of 1189 empirically estimated trees, we confirm that crBD model trees frequently differ topologically compared with empirical trees. To place this in the context of standard practice in the field, we conducted a meta-analysis for a subset of the empirical studies. When comparing studies that used Bayesian methods and crBD priors with those that used other non-crBD priors and non-Bayesian methods (i.e., maximum likelihood methods), we do not find any significant differences in tree topology inferences. To scrutinize this finding for the case of highly imbalanced trees, we selected the 100 trees with the greatest imbalance from our dataset, simulated sequence data for these tree topologies under various evolutionary rates, and re-inferred the trees under maximum likelihood and using the crBD model in a Bayesian setting. We find that when the substitution rate is low, the crBD prior results in overly balanced trees, but the tendency is negligible when substitution rates are sufficiently high. Overall, our findings demonstrate the general robustness of crBD priors across a broad range of phylogenetic inference scenarios but also highlight that empirically observed phylogenetic imbalance is highly improbable under the crBD model, leading to systematic bias in data sets with limited information content.