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 A group of graduate students in a spring-semester
Bioinformatics and Systems Biology class at Illinois tracked the
mutation rate in the virus’s proteome – the collection of proteins
encoded by genetic material – through time, starting with the first
SARS-CoV-2 genome published in January and ending more than 15,300
genomes later in May.
The team found some regions still actively spinning off new
mutations, indicating continuing adaptation to the host environment.
But the mutation rate in other regions showed signs of slowing,
coalescing around single versions of key proteins.
“That is bad news. The virus is changing and changing, but it is
keeping the things that are most useful or interesting for itself,”
says Gustavo Caetano-Anolles, professor of bioinformatics in the
Department of Crop Sciences at Illinois and senior author on the
study.
Importantly, however, the stabilization of certain proteins could be
good news for the treatment of COVID-19.
According to first author Tre Tomaszewski, a doctoral student in the
School of Information Sciences at Illinois, “In vaccine development,
for example, you need to know what the antibodies are attaching to.
New mutations could change everything, including the way proteins
are constructed, their shape. An antibody target could go from the
surface of a protein to being folded inside of it, and you can't get
to it anymore. Knowing which proteins and structures are sticking
around will provide important insights for vaccines and other
therapies.”
The research team documented a general slowdown in the virus’s
mutation rate starting in April, after an initial period of rapid
change. This included stabilization within the spike protein, those
pokey appendages that give coronaviruses their crowned appearance.
Within the spike, the researchers found that an amino acid at site
614 was replaced with another (aspartic acid to glycine), a mutation
that took over the entire virus population during March and April.
“The spike was a completely different protein at the very beginning
than it is now. You can barely find that initial version now,”
Tomaszewski says.
The spike protein, which is organized into two main domains, is
responsible for attaching to human cells and helping inject the
virus’s genetic material, RNA, inside to be replicated. The 614
mutation breaks an important bond between distinct domains and
protein subunits in the spike.
“For some reason, this must help the virus increase its spread and
infectivity in entering the host. Or else the mutation wouldn’t be
kept,” Caetano-Anolles says. The 614
mutation was associated with increased viral loads and higher
infectivity in a previous study, with no effect on disease severity.
Yet, in another study, the mutation was linked with higher case
fatality rates.
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Tomaszewski says although its role in virulence needs
confirmation, the mutation clearly mediates entry into host cells
and therefore is critical for understanding virus transmission and
spread.
Remarkably, sites within two other notable proteins also became more
stable starting in April, including the NSP12 polymerase protein,
which duplicates RNA, and the NSP13 helicase protein, which
proofreads the duplicated RNA strands.
“All three mutations seem to be coordinated with each other,”
Caetano-Anolles says. “They are in different molecules, but they are
following the same evolutionary process.”
The researchers also noted regions of the virus proteome becoming
more variable through time, which they say may give us an indication
of what to expect next with COVID-19. Specifically, they found
increasing mutations in the nucleocapsid protein, which packages the
virus’s RNA after entering a host cell, and the 3a viroporin
protein, which creates pores in host cells to facilitate viral
release, replication, and virulence.
The research team says these are regions to watch, because
increasing non-random variability in these proteins suggests the
virus is actively seeking ways to improve its spread. Caetano-Anolles
explains these two proteins interfere with how our bodies combat the
virus. They are the main blockers of the beta-interferon pathway
that make up our antiviral defenses. Their mutation could explain
the uncontrolled immune responses responsible for so many COVID-19
deaths.
“Considering this virus will be in our midst for some time, we hope
the exploration of mutational pathways can anticipate moving targets
for speedy therapeutics and vaccine development as we prepare for
the next wave,” Tomaszewski says. “We, along with thousands of other
researchers sequencing, uploading, and curating genome samples
through the GISAID Initiative, will continue to keep track of this
virus.”
The article, “New pathways of mutational change in SARS-CoV-2
proteomes involve regions of intrinsic disorder important for virus
replication and release,” is published on the preprint server
BioRxiv [DOI: 10.1101/2020.07.31.231472]. Authors include Tre
Tomaszewski, Ryan S. DeVries, Mengyi Dong, Gitanshu Bhatia, Miles D.
Norsworthy, Xuying Zheng, and Gustavo Caetano-Anolles.
The Department of Crop Sciences is in the College of Agricultural,
Consumer and Environmental Sciences at the University of Illinois.
[Sources: Gustavo Caetano-Anolles,
Tre Tomaszewski
News writer: Lauren Quinn] |
