COVID-19 virus evolved quickly but within strict genetic limits

A new paper in Genome Biology and Evolution, published by Oxford University Press, indicates that while the COVID-19 virus has developed rapidly since 2019, it has done so within limited genetic channels. These genetic limits have remained unchanged. Despite scientists' earlier fears about dramatic, rapid evolution of the COVID-19 virus, it appears recent changes in the virus were relatively constrained; the virus altered by combining pre-existing mutations. The virus has not expanded the number of genetic routes it can take to evolve.

SARS-CoV-2 underwent rapid evolution after first infecting humans in late 2019, resulting in new viral variants with properties that made them successful in human hosts. Previous work has shown how these variants were not closely related to the major circulating variants that preceded them, which led many scientists to believe that changes to the spike protein structure (the spikes or "crown" portion of the familiar COVID-19 microscopic image) drove SARS-CoV-2 variant evolution, enabling new mutations which had previously been impossible for the virus.

The SARS-CoV-2 pandemic was the worst pandemic of an infectious disease in recent decades, causing global mortality, economic damage, and social disruption. However, the response to the pandemic using contemporary technologies like affordable mass sequencing has resulted in a unique and significant scientific dataset.

Researchers here took advantage of the scale of global genome sequencing, protein structural determination, and targeted studies related to the virus. They used rich SARS-CoV-2 datasets to investigate the role of protein structural constraint in SARS-CoV-2 evolution and whether changes to spike protein structure made the virus stronger. They applied multiple computational predictors of structural constraint across different structural backgrounds and assessed how constraint has changed during SARS-CoV-2 variant evolution.

The investigation found that SARS-CoV-2 has undergone several distinct phases of evolution. An initial period of neutral diversification ended in late 2020 when multi-mutant variants began to arise. The World Health Organization classified variants with suspected phenotypic characteristics, such as increased transmissibility or immune escape properties, as variants of concern. But despite the unprecedentedly rich and granular dataset, the investigators find no evidence that structural constraints have changed substantially or played a role in SARS-CoV-2 S protein variant evolution. Despite high mutation rates and strong selective pressure, the SARS-CoV-2 S protein was under strong structural constraints after moving to human hosts.

It appears that while SARS-CoV-2 evolved rapidly during the pandemic, there were no substantial changes in the set of structurally viable mutations. The findings suggest that variant emergence came not from relaxation of structural constraints but by novel combinations of mutations with functional genetic interactions. But overall evolution remained tightly constrained by spike protein stability.

Our research explores the dynamics of evolutionary change in SARS-CoV-2 in the period following its spillover into the human population. We found that strong constraints acting on the virus' spike protein limited what mutations could occur. This helps us understand how other coronaviruses might behave when they jump between species and could have important implications for the design of future vaccines and antiviral drugs."

James Herzig, paper's lead author