The duplicated gene helps bats survive the “arms race” with viruses

bats are very unusual creatures. They are the only mammals with the gift of powered flight; different species have adapted to feast on a wide variety of foods ranging from mosquitoes to fruit to blood; and, as investigations into the origin of the COVID-19 pandemic point out, they can harbor a myriad of viruses that are dangerous or fatal to other mammals without becoming ill.

According to research published today (November 23) in The progress of science, bats’ ability to survive as so-called viral reservoirs may result in part from unique mutations, including duplication of the gene encoding an antiviral protein called protein kinase R (PKR). That second copy comes from an ongoing evolutionary “arms race,” according to the study, which has led to bats’ adaptation and apparent immunity to a wide range of viruses throughout their evolutionary history.

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

See “Are climate-driven 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, affected their viral immunity. Specifically, they searched the genomes for the sequences that encode PKR; Study co-author Stéphanie Jacquet, an evolutionary biologist at Claude Bernard University Lyon 1 in France, explains in an email that the team chose it for comparison because it is conserved in invertebrates and is important for immunity.

Focusing on 33 of the more than 130 different species of mouse-eared bats (genus Myotis), the researchers first had to sequence and assemble the genomes of 15 bat species, as bat genomes are particularly scarce in the literature.

To me these results are another ‘aha’ regarding possible mechanisms as to 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,” Elde says. “In the meantime, we need to go off-roading a bit and collect nucleic acids from bat species to get datasets that tell us about evolutionary signals like those found in this study for PKR.”

With that genomic data in hand, the researchers found that the gene EIF2AK2, which encodes PKR, rapidly evolved and underwent at least one duplication event early enough in bats’ evolutionary history that the extra copy was present in every species they sampled. Some species had more than two copies of EIF2AK2; or closely related sequences, they found, many of which encode paralogues of PKR and share its primary function as a frontline defense against viral invaders that block translation of viral DNA and RNA. By comparing these sequences with those of humans, mice (Mus muscle), cows (Forest bull), and dogs (Canis lupus familiaris), the team found that PKR duplication is very unique to bats.

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

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

The bat virus arms race

To test the function of bat PKR multiplicity, the researchers genetically modified yeast to produce various bat PKR or its orthologues, then exposed the cells to known kinase antagonists taken from viruses that infect bats, including poxviruses, herpesviruses and orthomyxoviruses. They found that PKR implements a number of mechanisms to fight various viruses, suggesting that over time, viruses evolved to counteract bats’ existing defense mechanisms, and bats evolved new and improved PKRs in response. Alexa Sadier, an evolutionary developmental biologist at the University of California, Los Angeles who did not work on the study, explains that this finding is a clear example of the Red Queen hypothesis, which is named after a character in Alice in Wonderland, which posits that there is a sort of evolutionary arms race between predators and prey, or in this case viruses and their host, in which selection pressure imposed by one adaptation in one imposes new pressures – and adaptations – in the other. “The host will adapt and the virus will adapt,” she says. “This is really in line with what we know.”

Functionally, having more 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 may be more effective.”

This mechanism makes sense as an explanation for why bats are seemingly immune to so many viruses, experts say The scientist.

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

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

What makes bats unique?

The origins of PKR duplication and why it has not occurred in other mammals remain unknown. One leading hypothesis is that bats’ unusual immune capabilities may be related to the other distinguishing trait that sets them apart from the rest of their mammalian cousins: their ability for powered flight.

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

“Also, some bats may be more prone to gene duplications [than other mammals]for example due to their higher rates of transposable elements which are known to facilitate duplications,” says Jacquet.

See “Fitting in with a little help from jumping genes”

Understanding the mechanisms of host-virus interactions, especially in an important viral reservoir like bats, may lead to new strategies for preventing viral spread from bats to other species, Jacquet suggests.

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

See “Climate change, deforestation lead to spread of bat virus in humans”

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