Independent evolution of monkeypox and variola viruses

Smallpox was eradicated more than 10 years ago, but infection with another Orthopoxvirus, monkeypox virus, can result in a clinical picture resembling smallpox. Human infection with monkeypox virus is extremely rare, not easily transmitted, and confined to the rain forest belt of Africa (Z. Jezek and F. Fenner, p. 81-102, in Human Monkeypox, 1988). Evidence that variola virus, the causative agent of smallpox, might be readily derived from monkeypox virus was presented [S. S. Marennikova and E. M. Shelukhina, Nature (London) 276:291-292, 1978; S. S. Marennikova, E. M. Shelukhina, N. N. Maltseva, and G. R. Matsevich Intervirology 11:333-340, 1979], but this was not confirmed [K. R. Dumbell and L. C. Archard, Nature (London) 286:29-32, 1980] and was subsequently discounted (J. J. Esposito, J. H. Nakano, and J. F. Obijeski, Bull. W.H.O. 63:695-703, 1985). Although enough difference between the genomes of monkeypox and variola viruses to rule out a simple interconversion has been demonstrated [K. R. Dumbell and L. C. Archard, Nature (London) 286:29-32, 1980; J. J. Esposito and J. C. Knight, Virology 143:230-251, 1985; J. J. Esposito, J. H. Nakano, and J. F. Obijeski, Bull. W.H.O. 63:695-703, 1985; M. Mackett and L. C. Archard, J. Gen. Virol. 45:683-701, 1979], the possibility that monkeypox virus was a more remote ancestor of variola virus remained. We have now identified a sequence in monkeypox virus DNA which is a homolog of a 1,065-bp open reading frame in the conserved region of the variola virus genome but which has multiple deletions. This is strong evidence that monkeypox virus is not ancestral to variola virus and strengthens confidence in the long-term success of smallpox eradication.