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Duplicated gene helps bats survive ‘arms race’ with viruses

Bats are very unusual creatures. They are the only mammals to have the gift of motorized flight; different species have adapted to feast on a wide variety of foods ranging from mosquitoes to fruit to blood; and, as probes into the origin of the COVID-19 pandemic point out, they can harbor myriad viruses that are dangerous or deadly to other mammals without getting sick themselves.

According to a study published today (23 November) in Scientists progress, the ability of bats to survive as so-called viral reservoirs may stem in part from unique mutations, including the duplication of the gene encoding an antiviral protein called protein kinase R (PKR). This second copy stems from an ongoing evolutionary “arms race,” according to the study, resulting in adaptation and apparent immunity in bats to a wide range of viruses over their evolutionary history.

“The biggest surprise to me are the extra copies of PKR in the genomes of some bat species,” said study co-author Nels Elde, a geneticist at the University of Utah and at the Howard Hughes Medical Institute. The scientist by email. “Even cooler is the new evidence that these copies diverge and may become less vulnerable to virus-encoded PKR inhibitors. It seems that two PKRs can be better than one.

See “Are climate-related changes in bat diversity to blame for COVID-19?” »

The researchers set out to identify how genetic similarities between bats, as well as differences between bats and other vertebrates, influenced their viral immunity. More specifically, they searched the genomes for sequences encoding PKR; Study co-author Stephanie Jacquet, an evolutionary biologist at Claude Bernard Lyon 1 University in France, explains in an email that the team chose it for comparison because it is conserved among invertebrates. and important for immunity.

Focusing on 33 of over 130 different species of mouse-eared bats (genus Myotis), the researchers first had to sequence and assemble the genomes of 15 bat species, with bat genomes being particularly rare in the literature.

For me, these results are another “aha” as to possible mechanisms explaining how and why bats are so cool!

—Riley Bernard, University of Wyoming

“We are still in the early days of sampling the genetic diversity of bats for comparative studies of modern species,” says Elde. “In the meantime, we need to go off-road and collect nucleic acids from bat species to get datasets that give us insight into evolutionary signals like those found in this study for PKR.”

With this genomic data in hand, the researchers discovered that the gene EIF2AK2, which encodes PKR, evolved rapidly and underwent at least one duplication event early enough in the evolutionary history of bats for the extra copy to be present in all sampled species. Some species had more than two copies of EIF2AK2; or closely related sequences, they found, many of which encode paralogs of PKR and share its primary function as a first-line defense against viral invaders that block translation of viral DNA and RNA. By comparing these sequences to those of humans, mice (mouse muscle), cows (bos bull) and dogs (Canis lupus familiaris), the team found that the PKR duplication is indeed unique to bats.

See “Bat coronaviruses can infect tens of thousands of people each year”

The unique trajectory of PKR in animals “suggests that while bats evolved to tolerate certain viruses, they also evolved to effectively control viral infections – in response to past pathogenic viruses,” says Jacquet.

The arms race against the bat virus

To test the function of multiplicity of PKRs in bats, researchers modified gene yeast to produce various bat PKRs or their orthologs, then exposed the cells to known kinase antagonists derived from viruses infecting bats. bats, including poxviruses, herpesviruses and orthomyxoviruses. They found that PKR deploys an array of mechanisms to combat various viruses, suggesting that over time viruses have evolved to counter bats’ existing defense mechanisms, and that bats have developed new and improved PKRs in response. Alexa Sadier of the University of California, Los Angeles, an evolutionary developmental biologist who did not work on the study, says the finding is a clear example of the Red Queen hypothesis, named after a character of Alice in Wonderland, which posits that a kind of evolutionary arms race is taking place between predators and prey, or in this case viruses and their host, in which the selective pressure imposed by an adaptation in one imposes new pressures – and adaptations – to another. “The host will adapt and the virus will adapt,” she says. “It really fits with what we know.”

Functionally, having multiple copies of the gene allowed the extras to diverge and produce proteins that were more resistant to viral inhibitors, Elde says. “Almost like an evolutionary hot potato game where if the virus blocks one copy of PKR, the other might be more active during infections. If the virus blocks the other, the original copy of PKR might be more effective.

This mechanism makes sense for why bats are apparently immune to so many viruses, experts say The scientist.

“To me, these findings are another ‘aha’ as to possible mechanisms explaining how and why bats are so cool!” University of Wyoming zoologist and physiologist Riley Bernard, who did not work on the study, says The scientist by email. “There are over 1,400 species of bats, the second most diverse group of mammals, so naturally there will be a lot of diseases that have co-evolved with these different species over time. Not only that, but bats are so diverse in their type of foraging (ranging from insects and nectar to blood and fish!), body size, reproductive output, migratory abilities The fact that they have developed these mechanisms to fight infection or minimize morbidity and mortality caused by infection is not surprising.

Amy Wray, a bat biologist who recently completed her doctorate at the University of Wisconsin-Madison and who also did not work on the study, shares a similar sentiment: “Since bats are a diverse group and have so many unique traits, ranging from their genomes to their morphology and even their behaviors – it’s not too surprising (but it’s still very exciting) to discover another unusual adaptation in bats” , she says.

What makes bats unique?

The origins of PKR duplication—and why it didn’t occur in other mammals—remain unknown. One of the main hypotheses is that the unusual immune abilities of bats could be linked to the other trait that sets them apart from the rest of their mammalian cousins: their ability for powered flight.

“We think because of the flight they have different physiological needs, like high energy, that sort of thing,” Sadier suggests. “They [may] have evolved things differently for this reason.

“Also, some bats might be more prone to genetic duplications [than other mammals]for example because of their higher levels of transposable elements which are known to facilitate duplications”, explains Jacquet.

See “Adaptation with a little help from jumping genes”

Understanding the mechanisms of host-virus interactions, especially in such a large viral reservoir as bats, may lead to new strategies to prevent viral spread from bats to other species, suggests Jacquet.

“We’ve changed the environment so much that it’s up to us to think holistically, not just ‘conserving animals’ but in a one health approach,” says Bernard. “A healthy ecosystem leads to healthy wildlife and humans.”

See “Climate change and deforestation are driving the spillover of bat virus to humans”

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