Human monkeypox and smallpox viruses: genomic comparison

Abstract

Monkeypox virus (MPV) causes a human disease which resembles smallpox but with a lower person-to-person transmission rate. To determine the genetic relationship between the orthopoxviruses causing these two diseases, we sequenced the 197-kb genome of MPV isolated from a patient during a large human monkeypox outbreak in Zaire in 1996. The nucleotide sequence within the central region of the MPV genome, which encodes essential enzymes and structural proteins, was 96.3% identical with that of variola (smallpox) virus (VAR). In contrast, there were considerable differences between MPV and VAR in the regions encoding virulence and host-range factors near the ends of the genome. Our data indicate that MPV is not the direct ancestor of VAR and is unlikely to naturally acquire all properties of VAR.

Fig. 1

Schematic representation of the terminal species-specific variable genomic regions of MPV-ZAI and VAR-IND. TIRs are designated with arrows, and regions of short tandem terminal repeats are designated with rectangles. Coinciding sequences are shown by wide black blocks; deletions in one genome relative to others are shown as lines. Borders of the variable genomic regions are marked by nucleotide numbers corresponding to their positions in the genomes.

Fig. 2

A: Alignment of amino acid sequences of orthopoxviral E3L IFN resistance factor encoded by the corresponding genes of VAR-IND, VAR-GAR, and MPV-ZAI. Blocks containing the N-terminal adenosine deaminase Z-α domain (marked gray) and C-terminal double-stranded RNA binding motif are indicated. Amino acid residues that are identical to those in VAR-IND are marked with dots; amino acid deletions are marked with dashes. The first and second methionine residues from which begins a long or short form of the protein are marked by asterisks above the sequence. B: Alignment of amino acid sequences of the orthopoxviral complement-binding proteins. ORFs of VAR-IND and MPV-ZAI are shown. The conserved cysteine residues are marked with black vertical blocks, other conserved residues are marked with gray vertical blocks. The numbers above the blocks indicate four repeating domains typical of the complement-control proteins .

Fig. 3

Unrooted phylogenetic tree derived from alignments of the nucleotide sequences in the terminal variable genomic regions of MPV-ZAI, VAR-GAR , VAR-IND , VAC-COP (VAC strain Copenhagen) , and CPV-GRI (CPV strain GRI-90) . The total alignment length was 117 600 bp. NJ analysis of aligned sequences provided bootstrap confidence intervals (values in bold) after 1000 heuristic search replicates. ClustralX software version 1.81 was used.