Speaker
Description
Mpox has evolved from a rare zoonotic disease to a significant human disease of international concern. Several studies have demonstrated the role of APOBEC3-driven hypermutation in enhancing the human adaptability of the virus. However, modelling this substitution process in BEAST has been challenging. We, therefore, develop a novel APOBEC3 substitution process in BEAST that correctly captures this hypermutation. This model takes aligned Mpox genomes that have been partitioned into two. The first partition comprises sites with potential APOBEC3 modifications (C>T and G>A substitutions in the dinucleotide context TC and GA), with every other site masked to feature the APOBEC3 mutations. The second partition is the inverse of the first, with the APOBEC3 target sites masked to represent non-APOBEC3 sites. We used the standard nucleotide GTR+G substitution model with four distinct rate categories for the non-APOBEC3 partition. For the APOBEC3 partition, we developed a substitution process to categorise the nucleotides into modified (T) and unmodified (C). We used a two-state continuous-time Markov chain with an asymmetric rate to permit C>T mutations but not the reverse. We used a two-epoch molecular clock model that allows the evolutionary rate to transition from the non-APOBEC3 rate to the APOBEC3 rate. To test if our model correctly captured the evolutionary dynamics in the mpox genome. We analysed mpox genomes not edited by the APOBEC3 activity (sequences from a non-human host). Our background rate estimate had an approximately twofold increase relative to what would be expected in a non-human host. These elevated rates in our model reflect evolutionary rates that tend to be higher during outbreaks due to the short duration of sequence sampling. Hence, our model correctly captures the APOBEC3 and non-APOBEC3 activities in the context of the recent mpox outbreak.
