Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes

Abstract

APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational “hotspots,” can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TC motifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TC hotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TC hotspots than expected by chance (over-representation) and fewer GC hotspots than expected (under-representation). These results suggest the MPXV genome: 1) may have evolved in a host with a particular APOBEC GC hotspot preference, 2) has inverted terminal repeat (ITR) regions –which may be exposed to APOBEC3 for longer during viral replication– and longer genes likely to evolve faster, and therefore 3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host.

Exploring the Transcriptomic Profile of Human Monkeypox Virus via CAGE and Native RNA Sequencing Approaches

“…Phylogenetic studies show a relatively high mutation rate within this lineage (107,108). This accelerated evolution is suggested to be driven by the action of the cellular APOBEC3 nucleic acid editing enzyme in the terminal genomic region (109)(110)(111). Genotyping hMPXV via gene or genome sequencing and identifying point mutations are frequently employed to track the pandemic's progression (8,112).…”

Evolution and diversity of nucleotide and dinucleotide composition in poxviruses

“…This conclusion does not exclude that host immune responses may contribute to the shaping of genome composition in poxviruses. For instance, recent evidence indicates that the evolutionary history of MPV during the global mpox outbreak, as well as the evolution of other human-infecting poxviruses, has been accompanied by APOBEC3-mediated editing (which introduces TC→TT changes and contributes thus directionally to the viral mutational spectrum) [102,105,139]. Also, even if interaction with the host immune system has not patterned the genomic composition in poxviruses, it has probably exerted a selective driving positive selection at individual sites [140,141].…”