Study discovers hidden mechanism behind rapid COVID variants

Study discovers hidden mechanism behind rapid COVID variants

The SARS-CoV-2 virus that causes COVID has the disturbing ability to frequently create variants of itself. Other viruses also mutate, but as SARS-CoV-2 spread rapidly throughout the human population during the pandemic and killed millions of people, the dynamic evolution of the virus posed a serious problem: it repeatedly challenged our body's immune response in the fight against the virus and hindered the process of delivering updated vaccines.

Understanding the genetic mechanism that drives SARS-CoV-2's ability to generate variants can go a long way toward keeping COVID at bay. In this study published inNatural microbiologyResearchers from Baylor College of Medicine and collaborating institutions developed a new technology called tARC-seq, which uncovered a genetic mechanism influencing SARS-CoV-2 divergence and allowed the team to calculate the mutation rate of SARS-CoV-2. Using tARC-seq, researchers in the lab also detected new mutations in SARS-CoV-2 in infected cells, summarizing observations from global pandemic virus sequencing data. The results may be useful for monitoring virus evolution in the human population.

The SARS-CoV-2 virus uses RNA instead of 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 process of RNA replication, which is typically error-prone in RNA viruses.”

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

The researchers wanted to track RNA replication errors because they are critical to understanding how the virus evolves, changes and adapts as it spreads through the human population. However, current methods lacked the precision to detect rare new SARS-CoV-2 mutations, particularly in samples with small numbers of viruses, for example from patients.

"Because samples from patients contain very few SARS-CoV-2 RNA copies, it is difficult to distinguish between the errors of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), the enzyme that makes copies of this virus's RNA, and the errors of the other enzymes used in the sequence analysis," said Herman, a member of the Dan L Duncan Comprehensive Cancer Center. “We have developed a technique we call Targeted Accurate RNA Consensus Sequencing (tARC-seq) that allows us to measure real errors in copying specific RNA that is present in very small quantities.”

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

The original thought was that because SARS-CoV-2 has an internal mechanism to repair the mistakes that RdRp makes, the virus should not evolve or mutate very quickly.

“This idea was in contrast to the fact that new COVID variants were frequently emerging around the world during the pandemic,” Herman said. “Since the start of the pandemic, we have seen a number of prominent variants, including Alpha, Beta, Delta and Omicron, as well as variants within these groups.”

Using their improved analysis tool, Herman and his colleagues precisely determined the mutation frequency of SARS-CoV-2 and the types of mutations, both in cell cultures in the laboratory and in clinical samples. “We found that the mutation rate was higher than originally expected, and this explains the frequent emergence of COVID variants,” Herman said.

They also discovered that there are hotspots in the SARS-CoV-2 RNA, places that are more susceptible to mutations than others. "For example, we identified a hotspot in the RNA region that corresponds to the spike protein, the protein that allows the virus to enter cells. Additionally, the RNA of the spike protein is made up of many vaccines," Herman said.

The tARC-seq method also revealed that the generation of new variants involved template switching. “We found that when one RNA template or sequence is copied, RdRp jumps to another template on a nearby virus and then continues copying the RNA, so that the resulting new RNA copy is a mixture of both RNA templates,” Herman said. "This template switch leads to sequence insertions or deletions that lead to viral variability. We also observed complex mutations. SARS-CoV-2 exploits these two powerful biological mechanisms, template switches and complex mutations, which enable rapid evolution." Generation of variants to adapt to and persist in human populations.”

“It was interesting and exciting to see that tARC-seq allowed us to capture the emergence of new mutations in laboratory cell cultures that recapitulate the mutations observed with global pandemic sequencing data,” Herman said. “Our new technology captures a snapshot of new mutations in clinical samples from individual patients and may be useful for monitoring virus evolution in the human population.”

Lead 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 are 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.

The study was supported by National Institutes of Health grants R01GM088653, 3R01AG061105-03S1, 1R21CA259780, and 1R21HG011229 and National Science Foundation grant DBI-2032904.

Sources: