The recent increase in monkeypox (MPX) cases has attracted attention of public health authorities due to its quick spread and transmission across non-endemic regions. This outbreak, unlike previous ones, displays different epidemiological features and transmission dynamics, which appear to be largely influenced by the newly divergent MPX lineages (B.1). Yet, the genomic characteristics driving the high dispersal and diversification of these lineages remain largely unknown. Herein, we sought to explore and characterize the genomic features and phylogenetic diversity of the B.1 lineages through a comparative genomic analysis inclusive of 1900 high quality complete MPXV genomes. Our analyses indicate that the current MPXV-2022 outbreak encompasses thirteen derived lineages with ten unique non-synonymous mutations in several genes linked to immune evasion, virulence factors and host recognition. Such mutations may translate in the rapid evolution and diversification of current MPXV lineages. Moreover, our analyses uncovered signals of genomic modifications suggestive of immune-modulatory enzymatic activity, such as APOBEC3 editing, which, as previously suggested could have favored evolutionary trends leading to the rapid spread of MPXV into non-endemic countries. Genomic surveillance continues to play a major role in unveiling the genomic signatures signaling potential adaptation of this emerging MPXV lineage and how it will continue to impact public health in the near future.
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