Study discovers the hidden mechanism behind the rapid mutation of the new coronavirus

The SARS-CoV-2 virus that causes COVID-19 has the troubling ability to frequently mutate itself. Other viruses mutate, but as SARS-CoV-2 spread rapidly throughout humanity during the pandemic, killing millions, the dynamic evolution of the virus raised serious questions: It repeatedly challenged our bodies The immune response against the virus hinders our immune response.

Understanding the genetic mechanisms underlying SARS-CoV-2’s ability to mutate could be helpful in stopping the new coronavirus.Posted in this natural microbiologyResearchers at Baylor College of Medicine and collaborating institutions have developed a new technology called tARC-seq that reveals the genetic mechanisms that influence SARS-CoV-2 differentiation and allows the team to calculate the mutation rate of SARS-CoV-2. The researchers also used tARC-seq in the lab to capture novel mutations in SARS-CoV-2 in infected cells that recapitulated observations revealed by sequencing data on the global pandemic virus. These findings could be used to monitor viral evolution in human populations.

The SARS-CoV-2 virus uses RNA rather than DNA to store its genetic information. Our lab has long been interested in studying RNA biology, and when SARS-CoV-2 emerged, we decided to study its RNA replication process, which is often error-prone in RNA viruses.

Christophe Herman, Ph.D., study corresponding author and professor of molecular and human genetics at Baylor College of Medicine

Researchers want to track RNA replication errors because they are critical to understanding how the virus evolves, changes and adapts as it spreads through people, but current methods lack the precision to detect rare new SARS-CoV-2 mutations, specifically In samples with low amounts of virus, such as those from patients.

“Because there are so few copies of SARS-CoV-2 RNA in patient samples, it is difficult to distinguish errors made by SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), the enzyme that copies the virus’s RNA, and sequences errors in other enzymes used in the analysis,” said Herman, a member of the Dan L. Duncan Comprehensive Cancer Center. “We developed a technology called Targeted Accurate RNA Consensus Sequencing (tARC-seq) that allows us to measure true errors when copying very small amounts of a specific RNA.”

A new perspective on the drivers of SARS-CoV-2 mutation diversity

The initial thinking was that because SARS-CoV-2 has internal mechanisms to repair errors made by the RdRp, the virus should not evolve or mutate quickly.

“This idea stands in stark contrast to the fact that new COVID-19 variants are frequently emerging around the world during the pandemic,” Herman said. “Since the beginning of the pandemic, we have seen a number of prominent variants, including Alpha, Beta , Delta and Omicron, and variants within these groups.”

With improved analytical tools at their disposal, Herman and his colleagues accurately determined the frequency and type of mutations in SARS-CoV-2 in laboratory cell cultures and clinical samples. “We found a higher mutation rate than initially expected, which helps explain the frequent emergence of new coronavirus variants,” Herman said.

They also found hotspots in the SARS-CoV-2 RNA, locations that are more susceptible to mutations than others. “For example, we found a hotspot on a region of RNA that corresponds to the spike protein, which allows the virus to invade cells. Additionally, the spike protein’s RNA makes up many vaccines,” Herman said.

The tARC-seq approach also revealed that the generation of new variants involves template switching. “We determined that when the RdRp copies an RNA template or sequence, it jumps to another template in a nearby virus and then proceeds to copy that RNA, so the new RNA copy produced is a mixture of the two RNA templates,” Herman said. This template switching will lead to sequence insertion or deletion, thereby bringing about complex mutations. We also observed that SARS-CoV-2 utilizes two powerful biological mechanisms, template switching and complex mutation, to enable rapid evolution. , producing variants that adapt and persist in humans.

“What’s interesting and exciting is that tARC-seq allows us to capture the emergence of new mutations in laboratory cell cultures that recapitulate those observed through global pandemic sequencing data,” Herman said. “We “The new technology captures snapshots of new mutations in clinical samples from individual patients and can be used to monitor viral evolution in populations.”

First author Catherine C. Bradley, Chen Wang, Alasdair JE Gordon, Alice X. Wen, Pamela N. Luna, Matthew B. Cooke, Brendan F. Kohrn, Scott R. Kennedy, Vasanthi Avadhanula, Pedro A. Piedra, Olivier Lichtarge , Chad A. Shaw, and Shannon E. Ronca were contributors to this work. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Washington, and Texas Children’s Hospital.

This research was supported by National Institutes of Health Grants R01GM088653, 3R01AG061105-03S1, 1R21CA259780, and 1R21HG011229, and National Science Foundation Grant DBI-2032904.