But that's not necessarily good news
University of Nebraska-Lincoln
New research from the University of Nebraska-Lincoln has shown that the mutations arising in the COVID-19-causing SARS-CoV-2 virus seem to run in the family -- or at least the genus of coronaviruses most dangerous to humans.
After
comparing the early evolution of SARS-CoV-2 against that of its closest
relatives, the betacoronaviruses, the Nebraska team found that SARS-CoV-2
mutations are occurring in essentially the same locations, both genetically and
structurally.
The
mutational similarities between SARS-CoV-2 and its predecessors, including the
human-infecting SARS-CoV-1 and MERS-CoV, could help inform predictions of how
the COVID-causing virus will continue to evolve, the researchers said.
"The
problem of looking at only one virus at a time is that you lose the forest for
the trees," said Katherine LaTourrette, a doctoral student in the Complex
Biosystems program at Nebraska. "By looking at this big picture, we were
able to predict the mutational nature of SARS-CoV-2.
"That
gets into these questions of: Are vaccines going to be effective long term?
Which variants are going to sneak by? Do we need that booster shot? Are
vaccinated people going to be infected a second time?"
'You're more likely to be hitting that bull's-eye'
The
genetic code of a virus determines its ability to infect cells and direct them
to churn out more copies of itself. That code consists of fundamental
compounds, or nucleotides, with mutations occurring wherever those nucleotides
get added, subtracted or swapped for one another. Many mutations have little or
no effect, in the same way that trying to hack an intricate password by
changing just one character will likely fail.
But
given enough chances, a virus will eventually happen upon a mutation or mutations
that change the assembly of its structural joints, or amino acids, enough to
help it better invade cells and replicate -- advantages that help it outcompete
other strains. In some cases, a new strain can also evade the immune responses
stirred by existing vaccines, necessitating the development of new vaccines to
protect against it.
LaTourrette and her adviser, Hernan Garcia-Ruiz, were busy comparing mutational patterns across viruses that invade a different biological kingdom -- plants -- when the SARS-CoV-2 pandemic struck. To do it, the researchers were analyzing segments of sequenced DNA from parallel locations on the genomes of all viruses in a genus.
They were hunting specifically for single-point mutations: segments in
which just one nucleotide had changed. By pinpointing them, the team was
sussing out whether certain mutations pop up across related plant viruses, then
tracing those mutations to functional amino acid changes in the viruses.
"A
lot of times, researchers have a specific plant virus they study,"
LaTourrette said. "They know it really well. But our question was: Big
picture, what is the genus doing? We know that variation isn't random. It
accumulates in specific areas of the genome, and those areas are (sometimes)
consistent across the genus. Those tend to be areas important for things like
host adaptation -- basically, areas that are going to need to keep changing in
order to keep co-evolving with their host.
"So
when COVID-19 happened, we thought, well, we can download the (betacoronavirus)
sequences and run them through the pipeline and see where the variation is
occurring."
When
they did, LaTourrette and her colleagues found that the so-called spike
protein, which protrudes from betacoronaviruses and keys their entry into host
cells by binding with receptors on the surface, mutates rapidly across all
known betacoronaviruses, including SARS-CoV-2.
Despite
accounting for just 17% of the SARS-CoV-2 genome, the
"hyper-variable" spike protein has so far accumulated roughly 50% of
the virus's total mutations, the researchers discovered. Those mutations are
emerging in the same regions of the genome, and even the same sub-units of the
spike protein, as they have in every other betacoronavirus to date.
"All
of our analyses showed that that's really where the variation is
happening," LaTourrette said. "It didn't matter when we looked at it,
what variant we looked at -- the spike protein was key."
The
team also concluded, as other virologists have, that the SARS-CoV-2 spike
protein is disordered -- that while its amino acids assemble into the same
general architecture, that architecture has what LaTourrette called "some
wiggle room" to shift into slightly different configurations. That's bad
news, she said, given that its structural flexibility likely gives it some
functional wiggle room, too.
"Humans
may have slightly different cell receptors, person to person," LaTourrette
said. "So then you have to have a (spike protein) receptor that can
accommodate those little shifts. If it were very ordered, and it couldn't
shift, then maybe it couldn't infect everyone. But by having that flexibility,
it's a much better virus.
"Basically,
this area is hyper-variable, and it's flexible. So it's the double
whammy."
Those
qualities will continue to make SARS-CoV-2 a formidable foe that requires
vigilance to stave off for the foreseeable future, LaTourrette said. But
knowing its strengths, and that the evolutionary history of other
betacoronaviruses might serve as a reasonable preview of that future, should
help virologists and vaccinologists strategize accordingly.
Vaccines
may have to continue targeting the distinctive spike protein as SARS-CoV-2
evolves, but consulting the mutational patterns of betacoronaviruses could help
researchers forecast which domains of the protein are most and least likely to
mutate. And that could make a moving target much easier to hit, LaTourrette
said.
"If
you close your eyes when you're throwing a dart at a dartboard, it could go
anywhere," she said. "But by looking at the other (betacoronavirus)
species, you have an idea of where it's likely to land. And you're more likely
to be hitting that bull's-eye."
Though
LaTourrette has already returned to the kingdom of plants, she said the
opportunity to adapt her work to such a pressing purpose proved gratifying at a
time when gratification was in short supply.
"For
us, getting to (transition) from plants to coronaviruses was a really positive
way of showing that you can take your science and your knowledge, and you can
apply it to the benefit of society," LaTourrette said. "We've seen
some really great examples in the past year-and-a-half of groups making that
shift.
"Even
though this is a very difficult time, and there's a lot of hardship, I think
it's really positive to see scientists come together and be able to contribute
to a cause together."
LaTourrette
and Garcia-Ruiz, an associate professor of plant pathology at the Nebraska
Center for Virology, conducted the research with recent master's graduate
Natalie Holste, doctoral student Rosalba Rodriguez-Peña and Raquel Arruda Leme,
a visiting researcher from Brazil.
The
team, which received support from the National Institutes of Health and the
U.S. Department of Agriculture's National Institute of Food and Agriculture,
recently reported its findings in the Journal of Virology.
