Dr. Gai and Dr. Dien Bard in the Laboratory
Dr. Gai and Dr. Dien Bard in the Laboratory
Research and Breakthroughs

A Pediatric Research Institution is Setting the Pace for Monitoring SARS-CoV-2 Mutations and COVID-19 Variants

As the coronavirus evolves, health authorities across the globe rely on the work of scientists at Children’s Hospital Los Angeles, who use genomic sequencing to track mutations.

The COVID-19 pandemic has introduced many new words into our everyday lives. Beyond N-95 and quarantine, new terms like Delta variant are now commonplace. But what is a variant? How are variants identified? And why is it important to track them?

Scientists at Children’s Hospital Los Angeles have been paying close attention to the behavior of SARS-CoV-2, since the beginning of the pandemic. This means reading out the genetic sequence of the virus from every COVID-19-positive sample to identify mutations. But this also means alerting authorities to notable changes in the virus. Recently, in fact, their research has uncovered mutations recognized by the global scientific community, mutations that may explain why certain versions of the virus—like the Delta variant—are so much more contagious.

“Genomic surveillance is critical,” says Xiaowu Gai, PhD, Director of Bioinformatics in the Center for Personalized Medicine at Children’s Hospital Los Angeles. “This is the only tool we have to identify mutations. We can track these mutations to help guide public health measures.” This tracking has been critical throughout the pandemic.

“Sequencing the genome of SARS-CoV-2 allowed for development of the vaccine,” adds Dr. Gai. “Now it remains just as important given the evolving virus and all its variants.”

What is a variant?

When a virus infects someone, it replicates, making many copies of itself. Inevitably, mistakes called mutations are made in that process. Sometimes, these mutations make it easier for the virus to be spread or infect cells. When this happens, the new version of the virus—or variant—will become more common in the population.  The more a virus spreads from person to person, the more chances it has to mutate and for new variants to develop. 

SARS-CoV-2 has infected more than 200 million individuals worldwide, giving it ample chance to mutate. According to experts, SARS-CoV-2, the virus that causes COVID-19, mutates every couple of weeks. At Children’s Hospital Los Angeles, scientists in the Department of Pathology & Laboratory Medicine and the Center for Personalized Medicine have been tracking these mutations since the beginning of the pandemic in order to identify variants and anticipate the emergence of “variants of concern,” which can potentially be more contagious or cause more severe disease.

A virus family tree

Over time, a variant will develop new mutations of its own, leading to multiple sub-lineages, much like a family tree. But not all mutations are cause for concern. In fact, many of them are inconsequential, much like how dropping one letter from a word still leaves a sentence that can be read. In some cases, mutations may even cause the virus to become weaker and die off. But in others—such as the current Delta variant—these changes can help a virus spread.

The Centers for Disease Control and Prevention (CDC) reports that the Delta variant is twice as contagious as previous strains. This means that people exposed to the Delta variant are more likely to be infected, and that over time the Delta variant out-competes other variants to become dominant.  Today more than 90% of new COVID-19 cases are caused by the Delta variant.

Our understanding and awareness of variants depends on scientists tracking the mutations using a technology called sequencing. With specialized high-throughput machines, scientists can read the entire genetic sequence, sometimes called the genome, of SARS-CoV-2. Then, samples can be compared to determine where mutations have arisen. This allows public health officials to be aware of the presence of different variants and the emergence of new more contagious strains of SARS-CoV-2.

Tracking the virus

At Children’s Hospital Los Angeles, geneticist Dr. Gai and his colleagues have sequenced every COVID-19-positive sample they have received since the beginning of the pandemic, over 3,000 samples to date. In addition to sequencing, Dr. Gai’s bioinformatics team analyzes the results for viral mutations. This allows them to identify existing and emerging variants to support CHLA’s contact tracing and genomic epidemiology efforts to track transmission patterns. The team then shares findings with databases used to by investigators studying COVID-19 around the world.

Sharing information across the globe

Working with Jennifer Dien Bard, PhD, and colleagues in the Department of Pathology & Laboratory Medicine, Dr. Gai and his team have helped CHLA publish the result of multiple SARS-CoV-2 studies, including the largest pediatric COVID-19 study of its time last year, which identified a potential link between certain mutations and severity of disease in children. Another publication demonstrated the effectiveness of public safety measures in limiting the spread of specific strains of the virus.

As the pandemic reaches the year and a half mark, Dr. Gai’s team is not slowing down. In fact, their recent work has been recognized internationally.

Recently, investigators in the Center for Personalized Medicine analyzed more than 1.3 million SARS-CoV-2 genome sequences from global databases to trace the lineage of the Alpha variant, which emerged in the U.K. in September 2020. The Alpha variant rapidly became dominant, accounting for over 90% of cases in Europe and nearly 60% of COVID-19 cases in the United States, until the emergence of the Delta variant.

The team’s most recent work reveals mutations in genes that affect the virus’s ability to bind to and infect human cells. One study identified a sub-lineage of the Alpha variant that became officially recognized and named “Q.3.” in the internationally recognized SARS-CoV-2 classification system Pangolin. The study was also included in the CDC’s COVID-19 Genomics and Precision Public Health Weekly Update and cited by the Global Virus Network, an international resource portal for tracking SARS-CoV-2 mutations.

One of the mutations they reported in the paper (called “M:I82T”) is now a recognized feature in the well-known Delta variant. “This mutation affects a protein that sits on the surface of the virus,” says Lishuang Shen, PhD, Senior Bioinformatics Scientist at Children’s Hospital Los Angeles and the first author of the publication. “This mutation may indeed be the reason the Delta variant is so much more infectious and—in some cases—more deadly.”

 A second study identified the emergence of a mutation that increased in frequency by more than a factor of 10 in the United States in just two months (February through April of 2021). The team is carefully tracking the mutation for any signs that it may contribute to an emerging variant of concern.

“We need to know what is happening with this virus in as much detail as possible,” says Dr. Gai. “Sequencing COVID-19 positive samples allows us to do this.” Keeping tabs on the behavior of the virus will alert public health officials to things like how well the vaccine works against new variants.

At the beginning of the pandemic, Dr. Gai and his colleagues in the Department of Pathology & Laboratory Medicine and Center for Personalized Medicine began working around the clock to keep up with testing and sequencing. Almost a year and a half into the pandemic, the team continues to remain vigilant. “The pandemic is not going away,” says Dr. Gai, “so neither are we.”

The team conducting this work in the Department of Pathology & Laboratory Medicine and the Center for Personalized Medicine includes: Lishuang Shen, first author on both new publications; Jennifer Dien Bard, PhD, the Director of the Clinical Microbiology and Virology Laboratories; Maurice O’Gorman, PhD, Chief of Laboratory Medicine, Jaclyn Biegel, PhD, Chief of Genomic Medicine and Director of the Center for Personalized Medicine, Timothy Triche, MD, PhD, Co-Director of the Center for Personalized Medicine; Alexander Judkins, MD, Pathologist in Chief and Executive Director of the Center for Personalized Medicine.

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