Multiple lineages of monkeypox virus detected in the United States, 2021-2022

Abstract

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of monkeypox virus (MPXV) among two 2021 and seven 2022 US monkeypox cases: the major 2022 outbreak variant called B.1 and a minor contemporaneously sampled variant called A.2. Analyses of mutations among these two variants revealed an extreme preference for GA-to-AA mutations indicative of human APOBEC3 cytosine deaminase activity among Clade IIb MPXV (previously West African, Nigeria) sampled since 2017. Such mutations were not enriched within other MPXV clades. These findings suggest that APOBEC3 editing may be a recurrent and a dominant driver of MPXV evolution within the current outbreak.

Fig. 1.. Phylogenetic analysis of Clade IIb MPXV genome sequences.

Variant B.1 sequences are shown in blue text; variant A.2 is shown in orange; green branches indicate Clade IIb. Phylogenetic analysis was performed in BEAST v1.8.3 using HKY+G model and constant coalescent prior on complete genome alignments after removing all sites containing gaps. Scale bar is in substitutions per site; posterior support values are shown at branch points.

Fig. 2.. Analysis of APOBEC3 motif mutations in MPXV.

A. Maximum Likelihood phylogenetic tree using IQ-TREE. Enrichment for G-to-A APOBEC context mutations (shown by blue line) was found in Lineage A, within Clade IIb (green branches). A detailed version of this tree with taxa names is included in Fig. S2. The scale bar indicates the number of substitutions per sequence site. B. Mutational patterns found among Clade I, Clade IIa, and Lineage A in the phylogeny above. All unique mutations in a clade relative to the most recent common ancestor of that clade are shown in a single panel, and the class of each mutation is shown on either the forward or reverse complement strand. The increased number of APOBEC3 context mutations, indicated by blue ticks, in Lineage A, versus red and grey captures the dominance of GA-to-AA APOBEC3 context mutations in this lineage and contrasts with Clades I and IIa. The exact numbers and statistics are provided in Table 2. The A.2 and B.1 variants within Lineage A in the tree, and an updated analysis of 397 variant B.1 sequences from GISAID, demonstrate the continuing dominance of GA-to-AA APOBEC3 context mutations among currently sampled outbreak sequences. C. Bar charts showing the total number of each class of unique mutations within each clade in Fig. 2B, Clade I, Clade IIa, Lineage A, as well as for 397 sequences from lineage B.1 from Fig. S3A.