title: Bayesian codon substitution modelling to identify sources of pathogen evolutionary rate variation.
abstract: Phylodynamic reconstructions rely on a measurable molecular footprint of epidemic processes in pathogen genomes. Identifying the factors that govern the tempo and mode by which these processes leave a footprint in pathogen genomes represents an important goal towards understanding infectious disease evolution. Discriminating between synonymous and non-synonymous substitution rates is crucial for testing hypotheses about the sources of evolutionary rate variation. Here, we implement a codon substitution model in a Bayesian statistical framework to estimate absolute rates of synonymous and non-synonymous substitution in unknown evolutionary histories. To demonstrate how this model can provide critical insights into pathogen evolutionary dynamics, we adopt hierarchical phylogenetic modelling with fixed effects and apply it to two viral examples. Using within-host HIV-1 data from patients with different host genetic background and different disease progression rates, we show that viral populations undergo faster absolute synonymous substitution rates in patients with faster disease progression, probably reflecting faster replication rates. We also re-analyse rabies data from different bat species in the Americas to demonstrate that climate predicts absolute synonymous substitution rates, which can be attributed to climate-associated bat activity and viral transmission dynamics. In conclusion, our model to estimate absolute rates of synonymous and non-synonymous substitution can provide a powerful approach to investigate how host ecology can shape the tempo of pathogen evolution.
authors.affiliation: 1​Department of Microbiology and Immunology, Rega Institute, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Baele
authors.affiliation: 2​Departments of Biomathematics, Human Genetics and Biostatistics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Suchard
authors.affiliation: 1​Department of Microbiology and Immunology, Rega Institute, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Bielejec
authors.affiliation: 1​Department of Microbiology and Immunology, Rega Institute, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001499:Bayes Theorem; D002685:Chiroptera / Q000821:virology; D003062:Codon / Q000235:genetics; D019143:Evolution, Molecular; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010802:Phylogeny; D011818:Rabies / Q000821:virology*; D011820:Rabies virus / Q000235:genetics
chemical_list: D003062:Codon
keywords: Bat Rabies; Bayesian inference; Codon substitution model; Evolutionary rate variation; Hierarchical phylogenetic modeling; Intrahost HIV