An Update of Orthopoxvirus Molecular Evolution

Abstract

Although variola virus (VARV) has been eradicated through widespread vaccination, other orthopoxviruses pathogenic for humans circulate in nature. Recently, new orthopoxviruses, including some able to infect humans, have been found and their complete genomes have been sequenced. Questions about the orthopoxvirus mutation rate and the emergence of new threats to humankind as a result of the evolution of circulating orthopoxviruses remain open. Based on contemporary data on ancient VARV DNA and DNA of new orthopoxvirus species, an analysis of the molecular evolution of orthopoxviruses was carried out and the timescale of their emergence was estimated. It was calculated that the orthopoxviruses of the Old and New Worlds separated approximately 40,000 years ago; the recently discovered Akhmeta virus and Alaskapox virus separated from other orthopoxviruses approximately 10,000-20,000 years ago; the rest of modern orthopoxvirus species originated from 1700 to 6000 years ago, with the exception of VARV, which emerged in approximately 300 AD. Later, there was a separation of genetic variants of some orthopoxvirus species, so the monkeypox virus West African subtype originated approximately 600 years ago, and the VARV minor alastrim subtype emerged approximately 300 years ago.

Keywords: evolution; origin; orthopoxvirus; variola virus.

Figure 1

Phylogenetic tree for the highly conserved central genome region of the orthopoxviruses was generated using the maximum-likelihood method. Numbers above branches are SH-aLRT support (%)/bootstrap support (%). Divergence (substitutions per site) scales are given at the bottom. The strains are designated as in Table 1.

Figure 2

Maximum clade credibility tree for the highly conserved central genome region of VARV, CMLV, and TATV. The chronogram was generated using BEAST 2 software. A log-normal relaxed clock and coalescent Bayesian skyline population prior were used, as well as a HKY substitution model with unequal base frequencies, invariant sites, and gamma-distributed rate heterogeneity among sites. The taxon name fields indicate: the GenBank accession number, the virus, the strain name, the region of sequence origin, and the collection date. The numbers on the nodes indicate the time to the most recent common ancestor (tMRCA) of the clades (years ago) with the 95% highest posterior density (HPD) interval given in square brackets. The rates of mutation accumulation are shown near the branches (substitutions/site/year). The strains are designated as in Table 1.

Figure 3

Maximum clade credibility tree for the highly conserved central genome region of the orthopoxviruses. The chronogram was generated using BEAST 2 software. A log-normal relaxed clock and coalescent Bayesian skyline population prior were used, as well as a HKY substitution model with unequal base frequencies, invariant sites, and gamma distributed rate heterogeneity among sites. The taxon name fields indicate: the GenBank accession number, the virus, the strain name, the region of sequence origin, and the collection date. The numbers on the nodes indicate the time to the most recent common ancestor (tMRCA) of the clades (years ago) with the 95% highest posterior density (HPD) interval given in square brackets. The strains are designated as in Table 1.

Figure 4

Bayesian skyline plot showing the demographic history of the orthopoxviruses. The x axis is in units of years, while the y axis represents effective population size. The black line represents the median value of the population size, and the 95% HPD (highest posterior density) is shown by gray area.