Molluscum contagiosum virus (MCV), a member of the diverse taxonomical family Poxviridae and the subfamily Chordipoxvirinae, is one of the two constituent members of the genus Molluscipoxvirus. Since the successful eradication of smallpox, MCV is the last known, still circulating, uniquely homotropic poxvirus. MCV infection is clinically manifested by firm skin lesions, papules of varied sizes – mollusca, which are normally limited in number and often spontaneously regress over time. In immune-compromised patients mollusca can manifest in greater numbers and may persist during longer time spans. Early studies of the diversity of MCV, based on mapping of MCV DNA restriction patterns, indicated the existence of at least four MCV subtypes (MCV1, 2, 3 and 4). Due to a lack of information, it is currently unknown whether the four subtypes represent specific genomic variants of MCV, which have evolved along divergent evolutionary paths from a common ancestor. In modern molecular-epidemiological studies the characterization of MCV subtypes is often based on amplification and sequencing of specific parts of the viral DNA. On one hand, modern molecular methods, have, in practice, simplified the process of MCV subtype assignment, however, due to the lack of data on other MCV subtypes, by doing so they have also narrowed the range of MCV subtypes that can be determined to MCV1 and MCV2.
The aim of our study was to, for the first time, characterize the genomic diversity of MCV1, MCV2 and other potentially detected MCV subtypes, and to develop a modern platform for the classification MCV subtypes, including MCV3 and MCV4. Based on characterization of complete MCV genome sequences we aimed to determine the evolutionary relationships between specific MCV subtypes, to clarify whether the evolutionary history of MCV had been to some degree shaped by recombination and to clarify whether different MCV genes evolve co-linearly at similar rates. In addition, we aspired to illuminate the genomic diversity of MCV populations originating from a single molluscum, multiple mollusca of the same host and from mollusca of multiple hosts.
A total of 62 complete MCV genome sequences were interrogated during this study, including 43 novel complete genome sequences of MCV1 and 12 novel sequences of MCV2. Phylogenetic analysis determined that the two subtypes MCV1 and MCV2, do in fact represent distinct genomic entities of MCV, genotypes MCV1 and MCV2. Syntenic relationships between genomes of MCV1 and MCV2, genome- and individual gene-scale similarity analyses indicated a generally co-linear, but divergent evolutionary paths with common ancestry. Greater genomic diversity was found among genomes of different MCV genotypes than among genomes of the same MCV genotype. Genomic diversity among MCV genomes originating from multiple hosts was found greater than among those that originated from the same host. The genomic diversities of the two genotypes assumed similar intervals of values, and both were found to contain similar numbers of homologous genes. On the other hand, we identified a significant difference between the guanosine and cytosine contents of MCV1 and MCV2. We identified evidence of recombination in the genomic regions of some of the MCV genes related to host immune-evasion. On the other hand, non-recombinant genes indicated that they have evolved co-linearly but not necessarily at the same local rates, which is reflected in a mosaic genetic structure of MCV. The presence/absence of recombination in specific genomes coincided with the assignment to sub-genotype groups determined phylogenetically, as well as with the BamHI, ClaI and HindIII restriction maps determined in silico. By knowing one of the three contexts: the recombination pattern, the phylogenetic sub-genotype group or the restriction patterns, the other two contexts could be predicted effectively. By interrogating the in silico BamHI, ClaI in HindIII restriction profiles each MCV genome could be assigned an MCV subtype, coinciding with the genotype, determined phylogenetically.
In conclusion, the current study greatly expands the knowledge of MCV genomic diversity and its genotypes and provides a valuable resource for future epidemiological, evolutionary, functional pathogenicity and molecular assay development studies.
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