17th Century Variola Virus Reveals the Recent History of Smallpox

Abstract

SummarySmallpox holds a unique position in the history of medicine. It was the first disease for which a vaccine was developed and remains the only human disease eradicated by vaccination. Although there have been claims of smallpox in Egypt, India, and China dating back millennia [1, 2, 3, 4], the timescale of emergence of the causative agent, variola virus (VARV), and how it evolved in the context of increasingly widespread immunization, have proven controversial [4, 5, 6, 7, 8, 9]. In particular, some molecular-clock-based studies have suggested that key events in VARV evolution only occurred during the last two centuries [4, 5, 6] and hence in apparent conflict with anecdotal historical reports, although it is difficult to distinguish smallpox from other pustular rashes by description alone. To address these issues, we captured, sequenced, and reconstructed a draft genome of an ancient strain of VARV, sampled from a Lithuanian child mummy dating between 1643 and 1665 and close to the time of several documented European epidemics [1, 2, 10]. When compared to vaccinia virus, this archival strain contained the same pattern of gene degradation as 20th century VARVs, indicating that such loss of gene function had occurred before ca. 1650. Strikingly, the mummy sequence fell basal to all currently sequenced strains of VARV on phylogenetic trees. Molecular-clock analyses revealed a strong clock-like structure and that the timescale of smallpox evolution is more recent than often supposed, with the diversification of major viral lineages only occurring within the 18th and 19th centuries, concomitant with the development of modern vaccination.

A phylogenomic analysis of Marek's disease virus reveals independent paths to virulence in Eurasia and North America

“…Our use of MDV samples collected between 1968 and 2015 enables a first insight into the origin and tempo of MDV evolution, representing the first alphaherpesvirus affecting agricultural animals to have undergone such a detailed genome‐scale phylogenetic analysis. Our temporal phylogeny of MDV yielded an evolutionary rate of ~1.6 × 10 −5 , which is in line with a range of rates that have been recorded for similarly sized dsDNA viruses such as variola virus (~9 × 10 −6 ) (Duggan et al., ; Firth et al., ) and MYXV (~1 × 10 −5 ) (Kerr et al., , ). Overall, such rates are generally higher than typically expected for dsDNA viruses and imply higher rates of nucleotide substitution than those inferred by host–virus codivergence analysis (Firth et al., ).…”

Bayesian reconstruction of the evolutionary history and cross‐species transition of variola virus and orthopoxviruses

“…On the contrary a recent study based on viral sequences amplified from a Lithuanian mummy dated to middle of the XVII century estimated a more rapid rate of evolution of between 7.3 and 9.6 × 10 −6 nucleotide substitutions/site/year (mean: 8.5 × 10 −6 subs/site/year), and allowed the authors to place the origin of VARV between 1588 and 1645.…”

“…Studies of the evolution of VARV based on the phylogenesis of conserved core genes have dated the divergence between TATV, CMLPV, and VARV about 3000‐4000 years ago (YA) and that the VARV strains circulating in the XX century had a common ancestor between about 500 and 1000 YA, including two studies based on VARV sequences isolated from mummies of the XVII‐XVIII centuries . The results of these studies have left many unanswered questions.…”

Ancient pathogen genomics as an emerging tool for infectious disease research

“…Other types of specimen have also shown potential for aDNA retrieval. Examples are dental calculus as a source of oral pathogens, such as Tannerella forsythia 46 ; calcified nodules, which have yielded whole genomes from Brucella melitensis 47 , Staphylococcus saprophyticus and Gardnerella vaginalis 48 ; mummified tissues, which have yielded Helicobacter pylori 49 , Variola virus (VARV; also known as smallpox) 50,51 , M. tuberculosis 52 and HBV 53,54 ; alcohol preserved human tissue as a source for Vibrio cholerae DNA 55 ; historical blood stains preserv ing P. falciparum and Plasmodium vivax 56 Pandemics refers to increased, often sudden, disease occurrence within populations across more than one region or continent, whereas epidemics refers to increased disease occurrences within a confined region or country.…”