Evolution, epidemiology, geographical distribution, and mutational landscape of newly emerging monkeypox virus

Evolution of hMPXV1 through molecular phylogenetics

We have analyzed molecular evolution depicted from October 2017 and August 2022, and two types of the phylogenetic tree have been described using 692 genome samples. The first type is rectangular, representing a phylogram (Fig. 2a). Here, we have found reference lineages or sub-lineages which are A, A.1, A.1.1, A.2, B.1, B.1.1, B.1.2, B.1.3, B.1.4, B.1.5, B.1.6, B.1.7, and B.1.8, which are situated in the terminal node of the phylogenetic tree.

Fig. 2figure 2

The phylogenetic tree of hMPXV1 shows the origin of different recent lineages. a The phylogenetic tree of hMPXV1 shows the origin and evolution of different lineages of A, A.1, A.1.1, A.2, B.1, B.1.1, B.1.2, B.1.3, B.1.4, B.1.5, B.1.6, B.1.7, and B.1.8. The phylogenetic tree illustrates the evolution of hMPXV1 with a time scale from October 2017 to August 2022. b The phylogenetic tree of the B.1 lineage shows the microevolution of B.1. It depicts the evolution of the B.1 lineage with a time scale from May to August 2022. c The circular phylogenetic tree of hMPXV1 shows the origin and evolution of different lineages of A, A.1, A.1.1, A.2, B.1, B.1.1, B.1.2, B.1.3, B.1.4, B.1.5, B.1.6, B.1.7, and B.1.8. d The circular phylogenetic tree of the B.1 lineage shows the microevolution of B.1

In the present 2022 hMPXV1 outbreaks, we have noted the involvement of one major lineage, B.1. In this phylogenetic tree, several genomes of the B.1 lineage have aggregated in the tree. The recent B.1 lineage has shown some association with the other four lineages (A, A.1.1, A.2, and B.1) and participated in forming the phylogenetic tree. However, it is apparent that the recent B.1. lineage is associated with the current MPX outbreaks.

Again, we have illustrated the B.1 lineages through an extended phylogenetic tree using 671 genome samples, showing the microevolution of the B.1 lineage (Fig. 2b). The microevolution of the B.1 lineage shows several sub-lineages such as B.1.1, B.1.2, B.1.3, B.1.4, B.1.5, B.1.6, B.1.7, and B.1.8. The microevolution of the B.1 lineage indicates its further evolution and creation of several sub-lineages. The comprehensive phylogenetic tree of the B.1 lineage has demonstrated that the genome sequence is situated between the timeline of May to August 2022. At the same time, we have also developed a circular phylogenetic tree (Fig. 2c). In the circular phylogenetic tree, the two lineages, A and A.1 are situated in different parts of the tree. Lineage A is located in the center, and lineage B.1 is situated in the radius (Fig. 2c). To highlight the B.1 lineage, we developed an extended circular phylogenetic tree (Fig. 2d). However, the circular phylogenetic tree (Fig. 1c and Fig. 1d) did not show the timeline of the evolution of the hMPXV1.

Divergence and the scatter plot of genome cluster of hMPXV1

We have tried to assess the divergence of the hMPXV1 evolution and depicted the scatter plot of the genome cluster of hMPXV1 from 2017/2018 to 2022. The cluster analysis was performed, and scattered plot was developed to indicate the clustering of the MPXV genome samples. To show the divergence, we have depicted the regression line (Fig. 3). It intimates the divergence of the 692 hMPXV1 genomes along the regression line. The pattern of the scatter plot with the linear regression model illustrates that the model shows the light and spread distribution pattern of line samples. The model also informed us that 671 genome samples of the B.1 lineage had formed a cluster on the upper side of the regression line. Divergence analysis has shown the result of about 5.70 e-5 or 5.70 × 10–5 substitutions per site per year.

Fig. 3figure 3

Scatter plot depicting the genome diversity cluster of all recent lineages of hMPXV1

Epidemiology of MPXV and hMPXV1

We have tried to illustrate the infected cases in previous and present outbreaks of MPXV and hMPXV1 infection. From the several literature databases, we described the MPXV and hMPXV1 infection cases reported in different countries during 1970–2021 (Table 1). We found the highest number of cases of DRC, Africa. Here, it has been noted that there were 386 infected cases during 1970–1990 and 511 numbers of infected patients during 1991–1999. Besides DRC, we found Nigeria and the Republic of Congo’s documenting the highest number of cases. In the Republic of Congo, we noted 110 patients (11 confirmed) during 2000–2018 and 39 cases (suspected) during 2019–2021. Again, in Nigeria, we observed 244 (101 confirmed) cases during 2000–2018 and 113 (45 confirmed) from 2019 to 2021.

Table 1 Monkeypox infection cases were reported in different countries from 1970 to 2021

For the present MPX outbreaks, we have plotted the number of confirmed cases in different countries till August 22, 2022, and developed a statistical model (Fig. 4a). In this model, it has been noted that the UK is having highest infection cases (14,049), and the second-highest cases are indicated in Spain (6119 cases). Other significant cases are pointed out in Germany (3295 cases), Portugal (588 cases), and Canada (1168 cases). Again, to understand the continent-wide epidemiology, we have analyzed continent-wise confirmed cases till August 22, 2022 (Fig. 4b). We found Europe to show the highest number of confirmed cases (20,625), and the Western Pacific showed the lowest number of confirmed cases (121). North and South America also revealed several infected cases (20,436 cases), and the cases are more compared to Africa (404 cases).. The result informed us that this hMPXV1 outbreak has spread in high economic countries, especially in Europe and North and South America. At the same time, it has also been noted that the virus has spread in the Eastern Mediterranean like UAE and Morocco. Therefore, this outbreak is a global outbreak. Several scientists have also reported that the cases of this MPX virus infection in Africa were relatively low compared to previous episodes [10].

Fig. 4figure 4

Developed two statistical models and a schematic diagram from our study to illustrate the epidemiology of MPX. a A statistical model shows the number of confirmed cases of MPX in different countries till August 22, 2022. b A statistical model shows continent-wise confirmed cases till August 22, 2022. c A schematic diagram illustrates the current and previous outbreaks' age-related pattern of infection cases of MPX

Again, we have analyzed the current and previous outbreaks' age-related pattern of hMPXV1 infection cases (Fig. 4c). The earlier episodes show the infected individuals' median age of about 4 to 15.5 years. Until 2010 in African countries, the outbreak led to the lower age group of infected individuals' median age (4 to 15.5 years). However, Nigeria’s 2017 and 2018 outbreak showed a higher age group of infected individuals (median age 30 years). Similarly, the outbreak of 2017 in the Central African Republic also showed a higher age group of infected individuals (median age 35 years).

The current MPX outbreaks show the infection among individuals in a higher age group compared to previous episodes. However, the recent outbreak offers the infected individuals a median age range of about 31 to 61 years. In the UK, the age range is 31 to 43 years, and in the USA, the age range is 28 to 61 years. Zumla et al. have also reported that most infection cases in the current outbreak are noted in the age of 20 to 50 years of men [10]. At the same time, WHO has also reported that, in 99% of cases, the observed age group is about 0 to 65 years (median age about 37 years, interquartile range about 32 to 43 years) [6]. Kupferschmidt reported that the MPX spreads among MSM individuals (men who have sex with men) [74]. At the same time, Mahase reported that the virus might be spreading in gay and bisexual men in England and concluded these population at high risk. However, these population might be vaccinated soon [75]. The sexual activity among MSM, gay, and bisexual men might be one reason for higher infection. However, it has been noted that severe cases of the virus occur more usually among children, which is associated with the level of virus exposure [6].

Geographical distribution of hMPXV1 infection

We have analyzed the geographical distribution of hMPXV1 infection for the recent outbreaks, and depicted the distribution of hMPXV1 lineages and their distribution throughout the world (Fig. 5a). We found infection case clusters in different regions of the world. Several disease case clusters have been noted in Europe (Fig. 5b). The countries in the cluster include the UK, France, Germany, Portugal, Spain, Italy, and Finland. However, in the figure, the generated circles for the cases of Germany, Portugal, and the UK are more significant than others. It might be due to the higher number of cases in those countries. At the same time, it has been observed that 433 genome sequences have been submitted from Europe between September 2018 and August 2022.

Fig. 5figure 5

Geographical distribution of recent outbreak of MPX. a The geographical distribution of hMPXV1 lineages and their geographical distribution throughout the world. b Geographical distribution of MPX case clusters observed in Europe. c Geographical distribution of MPX case clusters observed in North America

Again, the country-wise plot was generated for North America (Fig. 5c). The geographical plot shows the infection region of America and Canada. From the figure, it has been noted that the generated circles for the cases of Canada are bigger than the USA. It might be a higher number of cases in Canada than in the USA. However, it has been observed that 237 genome sequences were submitted from North America between September 2018 and August 2022.

Entropy diversity of hMPXV1 genome

We have analyzed the entropy diversity of the hMPXV1 genome. We illustrated the entropy in different positions of the hMPXV1 genome in the nucleotide (nt) context (Fig. 6a). The hMPXV1 genome is about 198 kbp long. The entropy changes were noted in different positions in the positive strand in the genome. The first positional entropy change was noted in the hMPXV1 genome at 1262 position (entropy: 0.131) and the last positional entropy change was noted at the 190,660 position (entropy: 0.204). Some other significant entropy changes are noted in the different nucleotide positions such as 3818 position (entropy: 0.131), 14,000 position (entropy: 0.131), 38,360 position (entropy: 0.131), 64,426 position (entropy: 0.174), 65,571 position (entropy: 0.131), 74,360 position (entropy: 0.346), 124,130 position (entropy: 0.131), 124,674 position (entropy: 0.131), 150,469 position (entropy: 0.136), 162,331 position (entropy: 0.131), 165,782 position (entropy: 0.036), and 181,980 position (entropy: 0.131).

Fig. 6figure 6

A diagram that illustrates the entropy diversity of the hMPXV1 genome. a The figure illustrates the entropy diversity in several positions of the hMPXV1 genome in the nucleic acid context. b The figure illustrates the entropy diversity in several positions of the hMPXV1 genome in the codon context

Again, we illustrated the entropy in different positions of the hMPXV1 genome in the codon context (Fig. 6b). The first positional entropy change was noted in the MPXV genome at the codon position 9 in OPG015 protein (entropy: 0.069). The last positional entropy change was noted at the codon position 84 NBT03_gp174 protein (entropy: 0.215). Some other significant entropy changes are noted in the different codon positions such as codon position 62 in OPG019 protein (entropy: 0.046), codon position 48 in OPG047 protein (entropy: 0.131), codon position 194 in OPG094 protein (entropy: 0.346), codon position 740 in OPG109 protein (entropy: 0.082), codon position 4 in OPG118 protein (entropy: 0.073), codon position 92 in OPG165 protein (entropy: 0.110), and codon position 1741 in OPG210 protein (entropy: 0.137).

However, we have observed high entropy diversity in the hMPXV1 genome in both the nucleic acid and codon context.

Mutational landscape of hMPXV1 genome

We have analyzed the mutational landscape of the hMPXV1 genome. We have tried to demonstrate the different positions of mutations in the hMPXV1 genome in nucleotide (nt) context (Fig. 7a). The first position of the mutation was observed in the hMPXV1 genome at the 814 nt position with one mutation, and the last mutation was noted at the 190,668 nt position with one mutation. The highest number of mutations was observed as four at the 168,120 nt positions. In most of the genome positions, we found one mutation. However, we have noted two numbers of mutation in some positions, which are nucleotide positions at 39,139, 44,220, 61,844, 63,147, 77,807, 132,625, 148,427, 164,832, 165,782, 170,698, 182,189. We have noted three mutations in some positions, which are nucleotide positions at 14,611, 63,811, 70,190, 70,780, 94,798, and 100,182.

Fig. 7figure 7

A diagram that illustrates the mutational landscape of the hMPXV1 genome. a The figure illustrates the mutations in several positions of the hMPXV1 genome in the nucleic acid context. b The figure illustrates the mutations in several positions of the hMPXV1 genome in the codon context. c A figure demonstrates the NGA /TNC context of G- > A/C- > T mutation from the perspective of different regions. d A figure demonstrates the NGA /TNC context of G- > A/C- > T mutation in the angle of the human host

At the same time, we have tried to demonstrate the different positions of mutations in the hMPXV1 genome in the codon context (Fig. 7b). The first position of the mutation was observed in the hMPXV1 genome codon position 17 in OPG015 protein with four mutations. With two mutations, the last mutation was noted at the codon position 87 in the NBT03_gp174 protein. The most mutations were observed at seven at the codon position 261 in OPG015. The second-highest number of mutations was observed at six at the codon position 740 in OPG023. For most of the parts of the genome at the protein level, we found one mutation. However, we have noted two or more mutations in some positions, which are codon position 343 in OPG015 protein with five mutations, codon position 408 in OPG015 protein with five mutations, codon position 470 in OPG023 protein with five mutations, codon position 525 in OPG023 protein with five mutations, codon position 353 in OPG057 protein with two mutations, codon position 148 in OPG178 protein with two mutations, codon position 689 in OPG205 protein with two mutations, codon position 1622 in OPG210 protein with two mutations.

We have also studied of NGA /TNC context of G- > A/C- > T mutation from the perspective of different regions (Fig. 7c). Here, we found the recent hMPXV1 lineage B.1 has formed two clusters in North America and Europe. In Europe, we found several NGA /TNC contexts of G- > A/C- > T mutations encompass value 1. At the same time, the hMPXV-1 lineage has been noted African region.

We have also studied of NGA /TNC context of G- > A/C- > T mutation in the angle of the host (Fig. 7d). Here, we found the result of the NGA /TNC context of G- > A/C- > T mutation has developed for human (Homo sapiens) host. The recent hMPXV1 lineage B.1 and its sub-lineages have formed several clusters, especially B.1, B.1.1, B.1.2, B.1.3, B.1.4, B.1.7, and B.1.8. At the same time, the A lineage has also developed one cluster. However, the recent lineage B.1 and its sub-lineages clusters are more danced than lineage A and A.1.

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