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May 30 2022
ARTIC Network
This document is an initial report on the observation of an abundance of specific mutations in the 2022 MPXV outbreak and related virus genomes that can be ascribed to the action of APOBEC3 host enzymes. It should be considered work in progress and we plan to add additional analysis and interpretation. We also welcome discussion in the thread below. The analyses here are made possible by the groups and researchers who have shared MPXV genome sequence data (Table 1).
The first MPXV genome sequences from monkeypox cases in 2022 (Isidro et al. 2022; Selhorst et al. 2022) showed, phylogenetically, that these viruses had descended from a clade sampled in 2017-2019 from cases diagnosed in Singapore, Israel, Nigeria and the UK. Comparing 2022 genomes from Portugal, Belgium, USA, Australia, and Germany (see Table 1) with the closest earlier genomes (denoted UK_P2 and UK_P3), the authors identified 47 shared single nucleotide differences (Figure 1).
The long term evolutionary rate of the related variola virus (VARV; the smallpox virus) has previously been estimated to be about 9x10-6 (with 95% credible intervals of 7.8x10-6 – 10.2x10-6) substitutions per site per year (Firth et al. 2010) translating into about 1-2 nucleotide changes per year for a nearly 200,000 nucleotide genome. This makes 47 substitutions in the space of 3-4 years an unexpectedly large number. As MPXV is considered a zoonotic virus with limited human to human transmission, this long branch may be evidence of adaptation to humans allowing for the sustained transmission that is now observed.
However, 42 out of 47 of these nucleotide changes are of a particular type, a dinucleotide change from TC→TT or its reverse complement GA→AA. This specific mutation is characteristic of the action of the APOBEC3 family of deaminases. These act on single stranded DNA to deaminate cytosine to uracil causing a G→A mutation in the other strand when it is synthesised. Most human APOBEC3 molecules have a strong bias towards deaminating 5’TC dinucleotides , with the exception being APOBEC3G which prefers 5’CC dinucleotides (Yu et al. 2004).
Of the remaining 5 nucleotide changes between 2018 and 2022, 3 are GG→AG compatible with negative strand deamination and in the context preferred by APOBEC3G. A previous study showed that the related vaccinia virus was not significantly restricted by APOBEC3G (Kremer et al. 2006) and the low number of mutations at dimers preferred by this enzyme would seem to confirm this. The final 2 mutations are not the result of deamination of cytosine. Given the estimated rate of evolution for variola viruses between 2 and 5 substitutions would be within the expectation for 4 years of evolution. This could indicate that the 42 G→A and C→T changes were the result of bouts of deamination during virus replication due to host antiviral defences. ...
ARTIC Network
This document is an initial report on the observation of an abundance of specific mutations in the 2022 MPXV outbreak and related virus genomes that can be ascribed to the action of APOBEC3 host enzymes. It should be considered work in progress and we plan to add additional analysis and interpretation. We also welcome discussion in the thread below. The analyses here are made possible by the groups and researchers who have shared MPXV genome sequence data (Table 1).
Áine O’Toole & Andrew Rambaut
Institute of Evolutionary Biology
University of Edinburgh
Edinburgh, UK
Institute of Evolutionary Biology
University of Edinburgh
Edinburgh, UK
The first MPXV genome sequences from monkeypox cases in 2022 (Isidro et al. 2022; Selhorst et al. 2022) showed, phylogenetically, that these viruses had descended from a clade sampled in 2017-2019 from cases diagnosed in Singapore, Israel, Nigeria and the UK. Comparing 2022 genomes from Portugal, Belgium, USA, Australia, and Germany (see Table 1) with the closest earlier genomes (denoted UK_P2 and UK_P3), the authors identified 47 shared single nucleotide differences (Figure 1).
The long term evolutionary rate of the related variola virus (VARV; the smallpox virus) has previously been estimated to be about 9x10-6 (with 95% credible intervals of 7.8x10-6 – 10.2x10-6) substitutions per site per year (Firth et al. 2010) translating into about 1-2 nucleotide changes per year for a nearly 200,000 nucleotide genome. This makes 47 substitutions in the space of 3-4 years an unexpectedly large number. As MPXV is considered a zoonotic virus with limited human to human transmission, this long branch may be evidence of adaptation to humans allowing for the sustained transmission that is now observed.
However, 42 out of 47 of these nucleotide changes are of a particular type, a dinucleotide change from TC→TT or its reverse complement GA→AA. This specific mutation is characteristic of the action of the APOBEC3 family of deaminases. These act on single stranded DNA to deaminate cytosine to uracil causing a G→A mutation in the other strand when it is synthesised. Most human APOBEC3 molecules have a strong bias towards deaminating 5’TC dinucleotides , with the exception being APOBEC3G which prefers 5’CC dinucleotides (Yu et al. 2004).
Of the remaining 5 nucleotide changes between 2018 and 2022, 3 are GG→AG compatible with negative strand deamination and in the context preferred by APOBEC3G. A previous study showed that the related vaccinia virus was not significantly restricted by APOBEC3G (Kremer et al. 2006) and the low number of mutations at dimers preferred by this enzyme would seem to confirm this. The final 2 mutations are not the result of deamination of cytosine. Given the estimated rate of evolution for variola viruses between 2 and 5 substitutions would be within the expectation for 4 years of evolution. This could indicate that the 42 G→A and C→T changes were the result of bouts of deamination during virus replication due to host antiviral defences. ...
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