Variola virus genome sequenced from an eighteenth-century museum specimen supports the recent origin of smallpox

Abstract

Smallpox, caused by the variola virus (VARV), was a highly virulent disease with high mortality rates causing a major threat for global human health until its successful eradication in 1980. Despite previously published historic and modern VARV genomes, its past dissemination and diversity remain debated. To understand the evolutionary history of VARV with respect to historic and modern VARV genetic variation in Europe, we sequenced a VARV genome from a well-described eighteenth-century case from England (specimen P328). In our phylogenetic analysis, the new genome falls between the modern strains and another historic strain from Lithuania, supporting previous claims of larger diversity in early modern Europe compared to the twentieth century. Our analyses also resolve a previous controversy regarding the common ancestor between modern and historic strains by confirming a later date around the seventeenth century. Overall, our results point to the benefit of historic genomes for better resolution of past VARV diversity and highlight the value of such historic genomes from around the world to further understand the evolutionary history of smallpox as well as related diseases. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.

Keywords: ancient DNA; metagenomics; museum specimens; smallpox; virus evolution.

Figure 1.

(a) Specimen RCSHC/P 328 showing smallpox lesions. Copyright © Museums at the Royal College of Surgeons. (b) Damage profile of reads mapping to the human mitochondrial genome (thick line) and the VARV reference genome (thin line). (c) Coverage diagram of the variola virus genome from sample P328. Blue indicates the coverage at a particular position (outer ring), coding areas of the genome are in grey (inner ring). The dotted circles indicate the coverage. (d) Conservation of genomic sequence between P328 and the variola virus reference genome NC_001611.1. The plot was generated with Dotter [45]. (Online version in colour.)

Figure 2.

(a) Maximum-likelihood tree based on 57 Orthopoxvirus genomes. The historic genomes are bolded, the newly sequenced genome is in red and underlined. The bootstrap values are given as node labels in grey (100 BS). (b) Dated Bayesian maximum clade credibility tree reconstructed with BEAST 2.5.2 [81] (using a strict clock and constant population size). The nodes are labelled with the 95% HPD interval. Historic genomes are in bold, the newly added genome in red and underlined. Posterior values are given as node labels in grey. (Online version in colour.)