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arambaut
ARTIC Network
9 9d
...
Initial observations about putative APOBEC3 deaminase editing driving short-term evolution of MPXV since 2017.
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Áine O’Toole & Andrew Rambaut
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), 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).
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This observation prompts a number of questions: Is this putative APOBEC3 editing occurring in a non-human animal reservoir host prior to emergence into humans in limited chains of human transmission? Or does this tree represent a multi-year history of sustained human transmission? Is the action of APOBEC3 acting as a driver of adaptation to humans as a host?
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If APOBEC3 deamination is characteristic of replication in humans then we would expect to see very little evidence of it prior to the 2017 outbreak as this would primarily represent replication in the non-human reservoir. To examine this, we selected a further outgroup from Liberia, 1970 (accession number DQ011156.1; Likos et al. 2005) and identified 28 mutations that occur on the branch leading to the common ancestor of the 2017 MPXV genomes (Figure 3A). The mutations on this branch do not show such a strong signal, with only 10 of 28 SNPs matching the signature for APOBEC3 editing (Figure 3B). We therefore suggest that the pattern we see in these MPXV genomes since 2017 is indicative of replication in humans and the inheritance of the specific changes that occurred between 2017 and 2018 and then in the viruses from 2022 means that there has been sustained human to human transmission since at least 2017. The 10 mutations that do fit the APOBEC3 profile may represent an additional period of human to human transmission prior to the 2017 cases. Given that this is fewer APOBEC3 type mutations than seen in the branch between 2017 and 2018 (branch C in Figure 1), it is not likely that this represents a long period.
...
arambaut
ARTIC Network
9 9d
...
Initial observations about putative APOBEC3 deaminase editing driving short-term evolution of MPXV since 2017.
...
Áine O’Toole & Andrew Rambaut
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), 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).
...
This observation prompts a number of questions: Is this putative APOBEC3 editing occurring in a non-human animal reservoir host prior to emergence into humans in limited chains of human transmission? Or does this tree represent a multi-year history of sustained human transmission? Is the action of APOBEC3 acting as a driver of adaptation to humans as a host?
...
If APOBEC3 deamination is characteristic of replication in humans then we would expect to see very little evidence of it prior to the 2017 outbreak as this would primarily represent replication in the non-human reservoir. To examine this, we selected a further outgroup from Liberia, 1970 (accession number DQ011156.1; Likos et al. 2005) and identified 28 mutations that occur on the branch leading to the common ancestor of the 2017 MPXV genomes (Figure 3A). The mutations on this branch do not show such a strong signal, with only 10 of 28 SNPs matching the signature for APOBEC3 editing (Figure 3B). We therefore suggest that the pattern we see in these MPXV genomes since 2017 is indicative of replication in humans and the inheritance of the specific changes that occurred between 2017 and 2018 and then in the viruses from 2022 means that there has been sustained human to human transmission since at least 2017. The 10 mutations that do fit the APOBEC3 profile may represent an additional period of human to human transmission prior to the 2017 cases. Given that this is fewer APOBEC3 type mutations than seen in the branch between 2017 and 2018 (branch C in Figure 1), it is not likely that this represents a long period.
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