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.

Preparedness for a monkeypox outbreak

“…MPXV belongs to the genus Orthopoxvirus , which also includes the smallpox virus (causing smallpox), vaccinia virus (used for the smallpox vaccine), and cowpox virus [36] . Monkeypox was first discovered in a Danish laboratory in 1958 [37] .…”

Detection of Ancient Viruses and Long-Term Viral Evolution

“…Ferrari et al estimated the evolutionary ratio as 8.5 × 10 −6 substitutions/site/year using Lithuanian samples, and Ferrari et al estimated it as 1.067 × 10 −5 substitutions/site/year using Lithuanian, Czech, and British samples [155,159]. However, ancient VARV was sequenced using older samples of Northern European specimens approximately 970 to 1400 years old, indicating that the MRCA of VARV was ~1700 years ago, and the accumulation rate of nucleotide substitutions was 3.7 × 10 −6 to 6.5 × 10 −6 substitutions/site/year [66,160]. These estimation results differed from the ratio estimated from time-structured samples, 1 × 10 −5 substitutions/site/year, isolated in the 20th century [170].…”

“…It was suggested that the orthopoxvirus species originated from a common ancestor containing all genes present in current orthopoxviruses and that the long-term adaptation within host species caused the reduction in active genes. Babkin also revealed the differences in terms of gene contents between ancient VARV and its modern equivalent and suggested that the ancestral species contained all of the genes present in orthopoxviruses today and that long-term adaptation to within-host species occurred through a reduction of active genes [160].…”

“…The evolutionary ratio estimate ranged from 8.7 × 10 −6 to 1.45 × 10 −5 substitutions/site/year, and the root of the HBV tree was estimated to be between 8600 and 20,900 years ago [14]. Different estimation results were also obtained for VARV, as described in the previous section; the evolutionary ratio was estimated to be 1 × 10 −5 substitutions/site/year using time-structured samples isolated in the 20th century and 3.7 × 10 −6 to 6.5 × 10 −6 substitutions/site/year when about 970-to 1400-year-old Eurasian samples were used [66,160,170].…”

Quantitative temporal analysis of modified vaccinia Ankara, the monkeypox and smallpox vaccine

“…Monkeypox virus (MPXV) is a zoonotic orthopoxvirus endemic in Central and West Africa 5,6 . Since May 2022, thousands of cases of MPXV have been reported in 50 non-endemic countries worldwide, with sustained human-to-human transmission 7 .…”