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Monkeypox Genome Analysis Points to Single Origin of Recent Outbreak

Monkeypox virus particles

NEW YORK — An analysis of monkeypox virus (MPXV) genomes from the ongoing global outbreak has found that the samples cluster together, indicating a single origin for them.

Between the beginning of the year and the middle of June, there have been more than 2,100 laboratory-confirmed cases of monkeypox, most of which have been reported since the start of May, according to the World Health Organization. More than 80 percent of these cases have been reported in Europe and 12 percent in the Americas, where the virus is not endemic and the cases have no known links to endemic regions.

Researchers in Portugal — where there have been about 300 cases, according to the European Centre for Disease Prevention and Control — have now conducted a phylogenetic analysis of 2022 MPXV and found that the outbreak likely has a single source related to a 2017/2018 outbreak in Nigeria. They additionally reported in Nature Medicine on Friday that the virus samples appeared to be undergoing accelerated evolution, likely influenced by host APOBEC3, a class of mRNA-editing enzymes that help defend against viruses.

"The accelerated evolution is an observation, but we do not know yet how that happened. It was quite unexpected to find so many mutations in the 2022 MPXV," senior author João Paulo Gomes from the National Institute of Health Doutor Ricardo Jorge in Lisbon said in an email.

He and his colleagues analyzed the first 2022 MPXV genome from the outbreak, which they released publicly on May 19, in conjunction with 14 other MPXV genome sequences, most of which were also from Portugal.

A phylogenetic analysis placed the 2022 outbreak samples among clade 3, within what was formerly known as the "West African" clade. All the outbreak samples clustered tightly together, indicating a single origin for the ongoing outbreak.

At the same time, the outbreak samples formed a branch that diverges from viruses linked to cases in the UK, Israel, and Singapore in 2018 and 2019, which themselves stemmed from an outbreak in Nigeria from 2017/2018. This suggested to the researchers that the 2022 outbreak could be due to the continuous circulation and evolution of the virus from the Nigeria outbreak.

However, 2022 MPXV differs from the 2018/2019 virus by an average 50 SNPs, which Gomes noted is many more than expected. For this type of virus, he said, one or two mutations would be expected to arise each year. As 2022 MPXV is likely a descendant of the 2017/2018 Nigeria outbreak — which led to the UK, Israel, and Singapore cases in 2018/2019 — about 5 to 10 additional mutations would be expected, not 50.

"So, unquestionably, we are facing a scenario of accelerated evolution," Gomes said.

The changes also tended to follow a certain pattern of incorporating more adenines and thymines into an already A/T-rich viral genome, which suggested that the human APOBEC3 system could be involved in this accelerated evolution.

APOBEC3 is a host antiviral mechanism that induces mutations into viruses, but that could lead to hypermutation if the enzymes do not fully restrict the viruses. Gomes noted that this mechanism has already been described in HIV and HPV.

"We do not know about the consequences but we know, for instance, that [a number] of these mutations are affecting viral proteins that are associated with the interaction with the human immune system, so, hypothetically, a mechanism of immune evasion cannot be completely discarded," he added.

In all, the researchers said that viral genome sequencing of outbreak samples may enable scientists to better understand how 2022 MPXV is spreading and provide insight into ways to control that spread. "We will focus on identifying and monitoring the mutations that will arise in real time during the ongoing transmission in order to better understand the host adaptation," Gomes said.