While researchers at the Minnesota Department of Health in St. Paul were sequencing samples of the monkeypox virus a few months ago, they made a surprising discovery. In one sample collected from an infected person, a large part of the virus’s genome was missing, and another part had moved to a completely different place in the sequence.
Crystal Gigante, a microbiologist at the US Centers for Disease Control and Prevention in Atlanta, Georgia, was brought in to help examine the mutations. She and her colleagues found similar deletions and rearrangements in several other monkeypox genomes collected in the United States, according to a report they published Sept. 17 on the peer-reviewed print server bioRqiv1.
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Although scientists are not alarmed, they are closely monitoring the situation to understand why the changes occurred and what they could mean for the global epidemic of monkeypox. These mutations are a stark reminder that even poxviruses — which are DNA viruses that tend to evolve more slowly than RNA viruses, such as the SARS-CoV-2 coronavirus — will change over time, says Eliot Lefkowitz, a computational virologist at the University of Alabama in Birmingham. And the more the monkeypox virus is transmitted between humans, he adds, the more opportunity it will have to evolve.
The mutations Gigante assessed were not the single-letter changes scientists are used to seeing in the SARS-CoV-2 genome. In some cases, entire genes have disappeared: a portion of about 7% of the genome was missing from a sample of an infected person in Florida. But it’s too early to say whether the mutations are beneficial, neutral or harmful to the virus, Lefkowitz says. If health officials detect an increase in virus samples carrying these mutations, it could be a possible signal that they are helping the virus spread.
The large deletions and rearrangements first reported in Minnesota did not surprise Aeneid Hatcher, an evolutionary virologist at the National Center for Biotechnology Information in Bethesda, Maryland. In 2015, he co-authored the study2 with Lefkowitz showing that such mutations are common in most poxviruses and that most of the genes they disrupt are located toward the end, or terminal, regions of the viral genome. “It was really nice to see some of the mutational strategies that we’ve seen in the past replicated,” says Hatcher.
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Orthopoxviruses, a genus of poxviruses that includes monkeypox virus and variola virus, which causes smallpox, share a core set of about 174 genes at the center of their genomes. But their terminal regions are more variable and contain fewer essential genes. Some of the genes in these regions are thought to encode proteins that help disarm the host’s immune responses and are adapted to infect specific hosts, Lefkowitz says. This underlies one hypothesis as to why variola became adept at infecting humans: over a period of thousands of years, an earlier version of the virus may have lost genes from its ends that allowed it to infect a wide range of animal species, eventually becoming a specialist in infecting humans . (Before smallpox was eradicated, it killed about three out of ten people who were infected.)
Some scientists worry that a similar situation could arise with monkeypox, which is currently more general; can infect many mammals, including several species of rodents and humans.
However, it is difficult to predict how the behavior of the monkeypox virus will change as it mutates, because researchers have not yet characterized the function of many genes in its large genome. For example, although researchers first discovered that two strains of the monkeypox virus were spreading across Africa more than 17 years ago, they are still struggling to determine which genes are responsible for the difference in death rates between them, Lefkowitz says. The mortality rate for one of them — clade I, which predominates in Central Africa — is about 10%. Clade II, which circulates in West Africa, has a mortality rate of about 1% to 3%.
By analyzing the monkeypox sequences, the researchers are also learning more about how the virus could have caused the global epidemic. The scientists observed a pattern of single-letter mutations, separate from the changes first observed in Minnesota, that appear to be the genetic imprint of the ongoing battle between the human immune system and the virus. Using the data collected so far to roughly calculate the number of these mutations expected each year, they estimated that the strain responsible for the global outbreak crossed from animals to humans in early 2016. That’s more than a year and a half before the strain was first have been discovered in humans by Nigerian health officials, who have declared an epidemic in their country that has never fully stopped.
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The good news is that while the monkeypox virus continues to evolve, no mutations have affected the part of its genome that codes for the protein targeted by tecavirimat, an antiviral drug being tested for use against monkeypox in humans. But problems can eventually arise in diagnostic testing. To detect monkeypox virus in samples, technicians perform polymerase chain reaction (PCR) to detect target sequences in the virus genome. Gigante and her colleagues found that one of the two copies of the monkeypox target was deleted in one of the samples they analyzed. Although the PCR test gave a positive result, the authors caution that these types of mutations could render it ineffective.
Global attention to monkeypox will help researchers understand not only the virus that causes the disease, but poxviruses in general, Hatcher says. Before this year, there were only about 100 near-complete monkeypox genomes, she says. Now about 2,000 have been deposited in established international repositories. “I’m very happy to see that the international collaborative relationship towards surveillance and genomic sequencing” has continued after the COVID-19 pandemic, she says.