SARS CoV-2 Mutations Provide Clues on Origins, Spread

Viruses adapt to their environments by mutating, and SARS CoV-2 is no exception. After decades of studying epidemics and virology we know that mutations tend to make viruses more transmissible but less deadly, which, from a public health perspective, is somewhat of a mixed blessing: More people contract the virus but fewer get very sick or die. Normally this would signal the beginning of the end of a pandemic—the early stages of a process through which COVID-19 becomes not a superbug but just another of the 380 trillion viruses that inhabit all of us.

End-of-days clickbait aside, coronavirus mutations provide a molecular natural history to help us uncover the virus's origins, spread, and perhaps potential ways to mitigate its effects.

Which mutations matter?

Viruses like SARS-CoV-2 evolve through genetic mutations—biochemical mistakes occurring during replication. "Mutations toward higher virulence cause more hosts to die, so these virulent mutations are less likely to be carried forward," says Prof. Changchuan Yin, a mathematician at the University of Illinois, Chicago.

From the molecular perspective, mutations arise from either random genome replication errors or through interactions with the host's immune system.

Through the first mechanism, the SARS-CoV-2 genome experiences random errors during replication, most of which are corrected or "proof-read" successfully, so these mutations are normally of little or no consequence. "The mutation rate of SARS-CoV-2 RNA viruses, naturally, can be very low," Yin notes, on the range of between one in one million to one in ten thousand mismatches per nucleotide per year. Yin has calculated the SARS-CoV-2 mutation rate at closer to one in a thousand, which is 10 times higher than the mutation rate of other RNA virus.

What accounts for the tenfold increase is the second factor. "Aside from random replication errors, the major driving force for mutation is the human immune system, which may actively modify the viral genome to induce even more mutations," Yin explains. Immune system RNA editing of the SARS-CoV-2 genome, in fact, helps the virus to adapt to the host's immune system. "I think this is the major event behind SARS-CoV-2 mutations as they relate to human infection. We have found more editing and more possible mutations in SARS-CoV-2 isolates from people with weak immune systems, for example the aged or those with underlying conditions. These people shed viruses harboring more mutations, which likely have less virulence and possibly higher transmission capability."

Natural selection

"Natural selection determines whether a mutation persists," says Anjali Shah, Senior Director of Product Management at Thermo Fisher Scientific. "Mutations that confer an increase to transmission rate, replication rate, or that evade the immune response are likely to increase in frequency in the population."

While these genetic changes are unpredictable in their origins or public health implications, making the connection between genetics and population health is possible.

"There are ways to correlate mutations with changes in virulence or infectivity. As one example, population genetic studies can determine if a particular strain has increased transmissibility due to its apparent dominance in a population. In addition, genetic and phylodynamic analysis of SARS-CoV-2 virus in a particular region over time can be used to determine increased virulence or infectivity," Shah adds.

Investigators use next-generation sequencing (NGS) to view all mutations in a particular viral strain, as well as to detect heteroplasmy—the presence of more than one viral strain in a sample. "NGS can also be used as a surveillance method to detect and track new and emerging mutations, while quantitative PCR or microarrays can be used to detect specific known strains cost-effectively," Shah tells Biocompare.

Matching viral variants to treatments

A huge positive from the perspective of rapid response to the pandemic has been consortia and government-industry collaboration. Virtually all coronavirus treatments approved under emergency use authorizations have emerged from such efforts, for example the Coronavirus Immunotherapy Consortium (CoVIC), which is spearheaded by the La Jolla Institute for Immunology (LJI) and associated with various public health foundations.

CoVIC uses high-throughput surface plasmon resonance (HT-SPR) and epitope binning to match diverse panels of potentially therapeutic monoclonal antibodies with viral variants. "Rapid assessment of binding kinetics to various coronavirus spike constructs and mutants helps us to understand the effects of coronavirus mutations against a broad spectrum of neutralizing antibodies," says Dan Bedinger, Application Science Team Lead at Carterra.

HT-SPR embodied in the Carterra LSA platform has enabled the clustering of the mAbs into epitope bins, which have been validated by structure analysis using cryogenic electron microscopy at La Jolla.

"The ability to assign antibodies to established epitope classes allows rapid determination of the uniqueness among newly identified mAbs, and helps us predict which clones will show neutralization behaviors and sensitivities to mutations or deletions within the spike protein," Bedinger adds. HT-SPR-enabled epitope binning also helps discovery teams identify which antibodies have the potential to be combined as potent, mutation-resistant combination mAb therapies.

Actionable or not?

Thanks to the intersection of academic, government, and industry, we are at a point in the coronavirus pandemic that would have been considered unachievable just one year ago. We have moved beyond the virus to recognize that multiple strains exist that must be dealt with.

But the question remains of what constitutes a noteworthy mutation? Does a change in one base or amino acid qualify? According to Prof. Yin, if the substitution is minor the end result may be as well. But in some instances, even mutations that do not result in amino acid substitutions may involve structurally critical changes in translation initialization or frameshift position, which could result in a highly pathogenic phenotype.

"I think each mutation in SARS-CoV-2 is significant if it arises from the human immune response," Yin says. Our group continues to investigate the effects of structure and functional changes brought about from each mutation. But due to the natural complexity of viral mutations, it is very difficult to predict their effects because current predictive models are unsatisfactory."