Despite concerns to the contrary, none of the mutations currently documented in the SARS-CoV-2 virus appear to increase its transmissibility in humans, according to a new analysis of viral genomes from 46,723 people in 99 countries who contracted COVID-19.

The study, published in the Nov. 25, 2020, online issue of Nature Communications, modeled the evolutionary tree of SARS-CoV-2 to see if particular mutations were becoming increasingly common within a given branch of the tree. That is a means of assessing whether, after a mutation first occurs, descendants of that virus outperform closely related SARS-CoV-2 viruses without that particular mutation.

The research found no evidence that any of the common mutations are increasing the virus’s transmissibility; rather, most common mutations are neutral. That includes D614G, a mutation in the spike protein, which is widely reported as being a common mutation that may make SARS-CoV-2 more infectious.

“The number of SARS-CoV-2 genomes being generated for scientific research is staggering. We realized early on in the pandemic that we needed new approaches to analyze enormous amounts of data in close to real time, to flag new mutations in the virus that could affect its transmissibility or symptom severity,” said Lucy van Dorp, senior research fellow at University College London (UCL)’s Genetics Institute, who specializes in reconstructing the evolutionary history of significant infectious diseases.

“Fortunately, we found none of these mutations are making COVID-19 spread more rapidly,” said van Dorp. However, it will be important to continue monitoring new mutations, particularly as COVID-19 vaccines are rolled out, she noted.

The researchers from UCL, Oxford University and Université de La Réunion, France, have so far identified 12,706 mutations in SARS-CoV-2. For 398 of those, there is strong evidence they have occurred repeatedly and independently. Of those, the researchers homed in on 185 mutations that have occurred at least three times independently, since the start of the pandemic.

“We particularly focus on mutations which have appeared multiple times in the evolutionary tree of the virus and statistically test their impact. This allows us to distinguish mutations which are observed in a large fraction of viruses today only because they happened to be present in viruses introduced to a region of the world conducive to high transmission (so called founder effects), compared to those which have risen in frequency because they confer a significant advantage,” van Dorp told BioWorld.

Coronaviruses like SARS-CoV-2 can develop mutations through three different routes: by copy errors during replication; through recombination or reassortment when viruses interact with each other in the same host cell; or by host RNA modification as part of the immune response.

Different reasons for mutations

The analysis shows that most of the common mutations appear to have been induced by the human immune system, rather than being the result of the virus adapting to its novel human host.

“We noticed that there was a highly biased representation of the mutations present in the SARS-CoV-2 genome with many more cytosine to uracil changes than we would expect by chance,” said van Dorp. “Looking at particular sequence motifs surrounding these changes we identify known targets of human APOBEC3A proteins, which are known to play a role in inducing mutations as an antiviral defense mechanism. Our work suggests these may be a particularly important contributor to mutations observed in SARS-CoV-2,” she said.

The finding that the human host is driving mutations is in contrast to earlier research by the same team, into what happened when SARS-CoV-2 jumped from humans into farmed minks. Here, the same mutations appeared over and over again on different mink farms, despite those mutations having been rarely seen in humans.

“It is to be expected that on jumping into a new host the virus may go on to adapt, and we do indeed identify mutations pointing to rapid host adaptation of the virus to minks,” van Dorp said.

There are now many documented cases of transmission from minks into humans. “As a result, viruses carrying mutations acquired in mink can enter human circulation,” said van Dorp. However, to date the frequency of those mink adaptive mutations in human viruses is low and some of the documented cases are already extinct.

The lead author of the study, Francois Balloux, director of the UCL Genetics Institute, who is a professor of computational biology, said it is possible that the available genome sequences may not reflect early mutations that occurred when SARS-CoV-2 first jumped species.

That is estimated to have occurred in October or November 2019, but the first sequences date to the end of December. “We may well have missed this period of early adaptation of the virus in humans,” said Balloux. “By [the end of December] viral mutations crucial for transmissibility in humans may have emerged and become fixed, precluding us from studying them.”

Van Dorp added, “The virus seems well-adapted to transmission among humans, and it may have already reached its fitness optimum in the human host by the time it was identified as a novel virus.”

The imminent introduction of COVID-19 vaccines will exert new selective pressures on the virus to escape recognition by the immune system, possibly leading to the emergence of vaccine-escape mutants.

“We might soon expect mutations in regions relevant to immune evasion to go up in frequency depending on the advantage they may confer,” van Dorp said. But she added, “The method we developed in this study is exactly designed to pick up cases such as this.” Large-scale viral sequence repositories and mutation profiling initiatives will greatly aid work to flag such mutations early, to inform vaccine design.

“The news on the vaccine front looks great,” Balloux said. “The virus may well acquire vaccine-escape mutations in the future, but we’re confident we’ll be able to flag them up promptly, which would allow updating of vaccines in time, if required.”