Abstract
Variola virus, the agent of smallpox, has a severely restricted host range (humans) but a devastatingly high mortality rate. Although smallpox has been eradicated by a World Health Organization vaccination program, knowledge of the evolutionary processes by which human super-pathogens such as variola virus arise is important. By analyzing the evolution of variola and other closely related poxviruses at the level of single nucleotide polymorphisms we detected a hotspot of genome variation within the smallpox ortholog of the vaccinia virus O1L gene, which is known to be necessary for efficient replication of vaccinia virus in human cells. These mutations in the variola virus ortholog and the subsequent loss of the functional gene from camelpox virus and taterapox virus, the two closest relatives of variola virus, strongly suggest that changes within this region of the genome may have played a key role in the switch to humans as a host for the ancestral virus and the subsequent host-range restriction that must have occurred to create the phenotype exhibited by smallpox.
Highlights
The taxonomic family Poxviridae consists of a very diverse set of viruses that share the ability to replicate in the cytoplasm of host cells and a linear dsDNA genome structure
Individual VARV genomes have approximately 700 unique SNPs when compared to the common ancestor with camelpox virus (CMLV) and taterapox virus (TATV), and when compared to individual CPXVs, the pairs of genomes have approximately 2–3,000 SNPs representing changes in both CPXV and VARV genomes from the most recent common ancestor (MRCA; data not shown); this number is too large to identify potential smallpox-defining changes
Since CMLV and TATV, which form a unique clade with VARV, have very restricted host ranges, we decided to take a different approach and focus on the SNPs common to these three viruses and different in all other orthopoxvirus genomes within our test group
Summary
The taxonomic family Poxviridae consists of a very diverse set of viruses that share the ability to replicate in the cytoplasm of host cells and a linear dsDNA genome structure. This diversity manifests in a variety of ways: 1) genome size ranges from 134– 360 kbp; 2) G+C genome composition ranges from 35–78%; 3) host range for the family as a whole is extremely wide (mammals, birds, reptiles and insects); 4) host range for a particular virus maybe broad (e.g. cowpox virus (CPXV)) or narrow (e.g. smallpox, variola virus (VARV)); 5) infection may be acute (e.g. most poxviruses) or persistent (e.g. molluscum contagiosum virus (MCV)). The corollary that all of the lost genes are host-range determinants, themselves, is unlikely to be true; rather, they provide a selectable function in a particular host
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