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PLoS Comput Biol. 2020 Jan 17;16(1):e1007046. doi: 10.1371/journal.pcbi.1007046. eCollection 2020 Jan.

A new method for inferring timetrees from temporally sampled molecular sequences.

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Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania, United States of America.
Department of Biology, Temple University, Philadelphia, Pennsylvania, United States of America.
Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan.
Research Center for Genomics and Bioinformatics, Tokyo Metropolitan University, Tokyo, Japan.
Center for Excellence in Genome Medicine and Research, King Abdulaziz University, Jeddah, Saudi Arabia.


Pathogen timetrees are phylogenies scaled to time. They reveal the temporal history of a pathogen spread through the populations as captured in the evolutionary history of strains. These timetrees are inferred by using molecular sequences of pathogenic strains sampled at different times. That is, temporally sampled sequences enable the inference of sequence divergence times. Here, we present a new approach (RelTime with Dated Tips [RTDT]) to estimating pathogen timetrees based on a relative rate framework underlying the RelTime approach that is algebraic in nature and distinct from all other current methods. RTDT does not require many of the priors demanded by Bayesian approaches, and it has light computing requirements. In analyses of an extensive collection of computer-simulated datasets, we found the accuracy of RTDT time estimates and the coverage probabilities of their confidence intervals (CIs) to be excellent. In analyses of empirical datasets, RTDT produced dates that were similar to those reported in the literature. In comparative benchmarking with Bayesian and non-Bayesian methods (LSD, TreeTime, and treedater), we found that no method performed the best in every scenario. So, we provide a brief guideline for users to select the most appropriate method in empirical data analysis. RTDT is implemented for use via a graphical user interface and in high-throughput settings in the newest release of cross-platform MEGA X software, freely available from

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