These ‘Silent’ Mutations May Give Covid-19 Coronavirus An Evolutionary Advantage

It’s evident that SARS-CoV-2, the virus responsible for Covid-19, existed in a benign way in bats and other wildlife populations before it jumped to humans.

But the stability of the virus in bats and other wildlife populations—the result of so-called “silent mutations”—may also potentially help to explain its virulence, setting the stage for the current global pandemic.  

Duke researchers have now discovered a set of these silent mutations among the 30,000 base pairs of the virus’s genetic code that allowed it to replicate so efficiently as it jumped into humans. These mutations ultimately involve how the virus has managed to “fold” its RNA molecules inside human cells.

“RNA folding” is the intricate process of how RNA goes from an unfolded disordered state to its ideal working or functional form—i.e. the folded state. RNA folding is important because in order to exert its specific functions in cells, it must fold into specific 3-D structures. Because a single strand of RNA can fold back on itself by forming base pairs, it results in a greater functional capacity compared to DNA. Yet, at the same time, it also becomes more challenging to “engineer” due to greater complexity.

For the study, the researchers relied on a statistical algorithm they developed to pinpoint such adaptive mutations that developed in the SARS-CoV-2 genome in humans, but not seen in closely related coronaviruses found in bats and pangolins.

“We’re trying to figure out what made this virus so unique,” said lead author Alejandro Berrio, in a press release.

Past research has detected so-called “fingerprints” of positive (Darwinian) selection within a gene that encodes the “spike” proteins covering the coronavirus’s surface, which is now known to play a key role in SARS-CoV-2’s ability to infect new cells. The spike protein allows the virus to attach and infect the host cell by attaching to the angiotensin-converting enzyme 2 receptor (ACE2).

The new study also identified mutations that altered the spike proteins, implying that viral strains carrying these mutations were also more likely to thrive. But the researchers also highlighted two novel candidates for mutations that have yet to be identified, since the genetic sequence of SARS-CoV-2 was first publicly shared. (January 12, 2020)

The researchers found that silent mutations in two other regions of the SARS-CoV-2 genome—Nsp4 and Nsp16—seem to have provided the virus a biological advantage over previous strains, but without changing the structure of the proteins they encode.

Rather than influencing the proteins themselves, these mutations most likely affected how SARS-CoV-2’s genetic material, composed of RNA, folds up into different 3-D shapes and functions inside human cells.

The researchers believe that mutations in RNA folding may have potentially enabled the virus to rapidly and asymptomatically spread before detection, in contrast to the SARS outbreak during 2002-2003. The authors also suggest that the results of their research may also lead to new molecular targets for treating or preventing COVID-19.

“Nsp4 and Nsp16 are among the first RNA molecules that are produced when the virus infects a new person,” said Berrio. “The spike protein doesn’t get expressed until later. So they could make a better therapeutic target because they appear earlier in the viral life cycle.” 

The implication is also that by identifying specific genetic changes that allowed SARS-CoV-2 to survive and reproduce in human hosts, we will be better equipped to predict and respond to future outbreaks when such viruses jump to humans—potentially before they occur.

“Viruses are constantly mutating and evolving,” Berrio said. “So it’s possible that a new strain of coronavirus capable of infecting other animals may come along that also has the potential to spread to people, like SARS-CoV-2 did. We’ll need to be able to recognize it and make efforts to contain it early.”

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