Based on the information provided, it appears that there have been outbreaks of human monkeypox (MPX) in both endemic and non-endemic countries since early May 2022. The researchers have analyzed 27 genes or sequences from 643 full-length human monkeypox virus (MPXV) genomes collected after January 1 and submitted by August 7, 2022.The phylogenetic trees of the analyzed genes or sequences can be categorized into four types:
- Two-branch type: This type includes genes such as C10L, Ckbp, CrmB, K1L, O1L_trctd, Rep2, and V-slfn. It is further divided into sub-clade I and sub-clade II. Both sub-clades originated in Nigeria in 2017, with sub-clade I potentially emerging earlier. The epidemic areas of sub-clade I in 2022 seem to be relatively limited, mainly in the United States, India, and Thailand, while sub-clade II strains are circulating globally.
- Two-branch-plus type: This type includes the A46R and B5R genes. It represents variations of the two-branch type, where the clusters from sub-clade I still converge, and an additional branch emerges from sub-clade II.
- One-branch type: This type groups all the 2022 endemic clusters together compared to the reference sequences, such as the E3L gene. However, there are still one or two clusters belonging to sub-clade I that clearly show distance from other clusters, and there are also clusters belonging to sub-clade II that show significant distance from others.
- Irregular type: This type includes nine genes: B14R, C1L, C6R, D7L, F1L, Hemagglutinin, N2L, O1L, and P1L. In this phylogenetic tree type, most clusters display properties of either one-branch or two-branch types. However, the prominent branches no longer belong to the clusters within sub-clade I but rather to those within sub-clade II, with hMpxV/Hungary/NBL-001/2022 being the most common.
The analysis shows that the monkeypox virus exhibits gene heterogeneity and protein polymorphism, with different clusters and sub-clades showing variations in their genetic makeup. The outbreaks in both endemic and non-endemic countries suggest the potential for increased transmission and spread of the virus beyond its traditional geographic boundaries. Further research and monitoring are likely required to better understand and respond to the monkeypox outbreaks.
Gene Heterogeneity and Protein Polymorphism in 2022 Monkeypox Virusesa) Phylogenetic Analysis of B14R Genes in MPXVs: The phylogenetic tree displays B14R genes of MPXVs, with strains in red belonging to the Congo Basin clade, those in black from the West African clade before 2022, and those in blue representing current strains from 2022. Brace (2) includes strains from the ancient West African clade, while (1) comprises strains from after 2017, primarily responsible for the current epidemic. Within the Congo Basin clade, strains in brace (3) belong to sub-CBC II, while those outside brace (3) belong to sub-CBC I. The hMpxV/Luxembourg/LNS-0899423/2022 strain from the West African clade shows similarity to the Congo Basin clade.b) Polymorphism in Protein Length Encoded by B14R Genes of MPXVs: Proteins encoded by B14R genes of MPXVs exhibit polymorphism in length. Blue bars indicate a consistency of more than 90%, while cyan bars represent consistency of less than 90%. In the Congo Basin clade, MPXVs express two product lengths; one is 326 AA (sub-CBC I or Congo Basin clade I), and the other is 206-210 AA (sub-CBC II or Congo Basin clade II). The rest belong to the West African clade.c) Proteins Encoded by D7L, O1L, B5R, and T4 Genes of MPXVs: The proteins encoded by D7L, O1L, B5R, and T4 genes of MPXVs are shown, with the first representing the standard protein length, and the others being variants. The proteins are displayed as α-helix domains according to the Gamier-Robson method.d) The crmB Gene and Its Encoded Protein in hMpxV/Luxembourg/LNS-0899423/2022: This strain is from the West African clade but exhibits a hallmark similar to the Congo Basin clade. The crmB gene (below) and its encoding protein (upper) of hMpxV/Luxembourg/LNS-0899423/2022 are depicted.e, f) Complexities of B14R Proteins and Their Ligands: In most Congo Basin clade isolates, three hydrogen bonds are formed via 261G, 262M, and 316S to the ligand IL-1β’s 113N, 108K, and 20Q, with bond lengths of 3.4 Å, 3.4 Å, and 2.7 Å, respectively (e). In most current MPXVs in 2022, four hydrogen bonds are formed via the 108D, 131Q, and 113N (twice) to the ligand IL-1β’s 146Q, 27G, and 79K and 84T, with bond lengths of 2.0 Å, 2.0 Å, 3.0 Å, and 3.4 Å, respectively (f). The cyan ribbon and blue amino acid residues, as well as the green ribbon and red amino acid residues, represent the B14R proteins and the IL-1β ligands, respectively. The numbers denote the length values of hydrogen bonds.
Complex Gene Heterogeneity and Protein Polymorphism in 2022 Monkeypox VirusesThe complexity of the phylogenetic tree for 2022 Monkeypox Viruses (MPXVs) indicates a diverse gene composition, suggesting that the current human MPX outbreak may be more intricate than initially anticipated. Studies reveal that MPXVs in 2022 originated in Nigeria in 2017, implying the possibility of earlier circulation in humans before May 2022. The virus may have been spreading at a low intensity, accumulating genetic variations in genes susceptible to selective pressures. Some genes, due to their encoded protein properties, may be more vulnerable to host or environmental pressure and require special attention when developing vaccines or antibodies to combat human MPX.The presence of stop codons in B14R, D7L, O1L, B5R, and T4 genes of MPXVs 2022 results in truncated proteins of varying lengths, showing length polymorphism. An intriguing finding is that hMpxV/Luxembourg/LNS-0899423/2022, despite being from the West African clade, displays similarity to the virulent Congo Basin clade. Transitional strains with varying virulence may exist between these two clades.The study examined five virulence genes, including B14R, B19R, C7L, D14L, and T4. These genes play essential roles in determining MPXV virulence. Notably, B14R genes of current MPXVs 2022 exhibit distinct features from those of the virulent Congo Basin clade due to “AT” repeats with varying lengths in their ORFs. Polymorphism in protein length is observed in the Congo Basin clade, with the expression of two product lengths: 326 AA (sub-CBC I) and 206-210 AA (sub-CBC II). In contrast, ancient West African strains had shorter proteins, halted by consecutive stop codons. However, MPXVs 2022 display longer proteins, with some even resembling sub-CBC II strains. The truncated proteins demonstrate more efficient binding to IL-1β ligands, suggesting increased efficiency in the current MPXVs’ interactions with the ligand.Similarly, the T4 gene encodes proteins of varying lengths, with ancient West African strains having shorter ones. However, most West African clade strains of current MPXVs 2022 express the standard length of 221 AA, akin to the virulent Congo Basin clade.These gene variations in MPXVs 2022, especially in B14R and T4 genes, may influence virulence and human-to-human transmission capacity, potentially contributing to the extensive spread of infected populations and the widespread epidemic. To predict virus virulence trends and human-to-human transmission capacity and assess vaccine effectiveness, close monitoring of potential hosts or vectors and the evolution of MPXVs is crucial.