Trait-driven molecular clocks (TraM): dating the long-term evolution of re-emerging bacterial pathogens – TraM

The evolution of microbial pathogens is inextricably linked to that of their hosts. Key expamples are Leprosy and the Plage, human diseases caused by the bacteria Mycobacterium leprae and Yersinia pestis. The discovery of ancient DNA in these bacteria has revealed complex evolutionary histories, with repeated emergence in distant human populations over centuries.

Molecular clock models are statistical approaches to measure evolutionary change and can be used to set a timescale on evolutionary events, such as when a migration event occurred on when an outbreak started. However, both M. leprae and Y. pestis seem to undergo extended periods of very slow evolutionary change and sometimes display lineages with hypermutator traits. These patterns effectively violate the assumptions of many molecular clock models, and therefore their long-term evolutionary timescales remain unresolved.

The overarching aim of this project is to develop a molecular clock approach that explicitly evaluates whether traits, such as particular mutations, are responsible for changes in evolutionary rates. Such trait-driven molecular clock model is configured by information in the data, which can account for periods of slow or increased evolution. The model will be developed as a package for the popular BEAST phylogenetics platform, and therefore widely available to other researchers.

The traits-riven molecular clock will be applied to carefully curated ancient DNA data sets of M. leprae and Y. pestis in order to answer key fundamental questions:
- What is the timescale over which these pathogens have repeatedly emerged in humans?
- Is there evidence for periods of ‘dormancy’ or of hypermutator lineages in these bacteria and what is the role of these characteristics in their evolution?

This project will benefit from expertise in Bayesian phylogenetic approaches, access to ancient DNA collections and high performance computing, all of which will be available through the project lead.