The monkeypox virus (particles shown in this coloured image from a transmission electron microscope) is a DNA virus that readily detects and repairs small mutations in its genome, so it evolves more slowly than other pathogens.Credit: National Institutes of Health/Science Photo Library
In some samples, large chunks of the virus’s genome have disappeared — but understanding whether the mutations affect its behaviour will be difficult
A few months ago, when analyzing samples of the monkeypox virus, scientists at the Minnesota Department of Health in St. Paul made an unexpected discovery. A significant portion of the virus’s genome was missing in one sample taken from an infected person, while another portion had migrated to a completely other location in the sequence.
A microbiologist from the US Centers for Disease Control and Prevention in Atlanta, Georgia, named Crystal Gigante was enlisted to assist in looking into the mutations. According to a study they published on the preprint server bioRxiv on September 17 that has not been subjected to peer review1, she and her colleagues discovered comparable deletions and rearrangements in a small number of other monkeypox genomes collected in the United States1.
Although they are not concerned, experts are keeping a close eye on the situation to learn why the changes have occurred and what they might indicate for the current outbreak of monkeypox worldwide. According to Elliot Lefkowitz, a computational virologist at the University of Alabama at Birmingham, these mutations serve as a stark reminder that even poxviruses, which are DNA viruses that have a tendency to evolve more slowly than RNA viruses like the SARS-CoV-2 coronavirus, will change over time. He continues by saying that the monkeypox virus will have more opportunity to mutate the more human contact it receives.
The mutations that Gigante examined were not the single-letter changes that are often found in the SARS-CoV-2 genome. In some instances, entire genes had disappeared: a sample from an infected person in Florida had missing DNA that covered nearly 7% of the genome. Lefkowitz notes that it is still too early to determine if the alterations are helpful, neutral, or harmful to the virus. Health experts may be able to tell that these alterations are aiding the virus’s transmission if they notice an increase in the number of virus samples with these mutations.
Eneida Hatcher, an evolutionary virologist at the National Center for Biotechnology Information in Bethesda, Maryland, was unsurprised by the significant deletions and rearrangements that were initially discovered in Minnesota. She and Lefkowitz co-authored a study2 in 2015 that demonstrated the prevalence of these mutations in most poxviruses and the location of the bulk of the disrupted genes in the terminal, or end, sections of the viral genome. It was wonderful to see some of the mutational tactics we have previously observed repeated, according to Hatcher.
Orthopoxviruses, a group of poxviruses that includes the smallpox-causing variola virus and the monkeypox virus, share a core set of 174 genes in common. Their terminal areas, however, are less consistent and include fewer crucial genes. According to Lefkowitz, some of the genes in these regions are considered to encode proteins that are specialized for infecting particular hosts and aid in disarming hosts’ immune systems. This supports one theory for how variola evolved to be proficient at infecting people: over thousands of years, an earlier strain of the virus may have lost genes from its termini that had allowed it to infect a variety of animal species, ultimately developing a specialty for infecting people. (Prior to its eradication, smallpox killed around three out of every ten afflicted individuals.)
Monkeypox, which can infect a wide variety of mammals, including humans and other rodent species, is currently more of a generalist. Some experts are concerned that a similar situation could develop with monkeypox.
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However, since many genes in the vast genome of the monkeypox virus have not yet had their functions fully described, it is challenging to predict how the behavior of the virus will alter as it mutates. For instance, despite the fact that two strains of the monkeypox virus have been found to be circulating in Africa for more than 17 years, researchers are still having difficulty pinpointing the exact genes that account for the two strains’ different death rates, according to Lefkowitz. One of them, clade I, which predominates in Central Africa, has a death rate of roughly 10%. The mortality rate of Clade II, which is present throughout West Africa, ranges from 1% to 3%.
Researchers are also learning more about how the virus may have caused the worldwide outbreak by analyzing the sequences of the monkeypox virus. Separate from the modifications discovered in Minnesota, researchers have found a pattern of single-letter mutations that appear to be the genetic legacy of the ongoing conflict between the human immune system and the virus. They predicted that the strain responsible for the global outbreak crossed the animal-to-human transition in the early months of 2016. They did this by utilizing data gathered thus far to roughly quantify the number of these mutations expected each year. That is more than a year and a half before Nigerian health officials declared an outbreak in their nation, which has never fully subsided, after discovering the strain in humans for the first time.
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The good news is that despite the monkeypox virus’s ongoing evolution, no mutations have been found in the region of its genome that codes for a protein that tecovirimat, an antiviral medication being evaluated for use against monkeypox in humans, targets. Diagnostic testing, however, can eventually run into issues. Technicians use a polymerase chain reaction (PCR) to find specific sequences in the virus’ genome and identify monkeypox virus in samples. In one of the samples they examined, Gigante and her coworkers discovered that one of two copies of a monkeypox target had been destroyed. Despite the fact that the PCR test produced a positive result, the authors caution that these particular mutations may eventually render it useless.
According to Hatcher, the increased awareness of monkeypox will aid research into poxviruses in general as well as the virus that causes monkeypox specifically. Only roughly 100 nearly full monkeypox genomes were known prior to this year, according to her. Currently, almost 2,000 of them have been added to reputable worldwide repositories. Beyond the COVID-19 pandemic, she says, “I’m quite glad to see the international cooperation attitude toward surveillance and genomic sequences.”
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By: Miss Cherry May Timbol – Independent Reporter
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