New research published on the pre-print server bioRxiv* carried out genomic simulations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to understand the evolutionary transition from a SARS-CoV-2 adapted to bats to a virus adapted to humans. The results show that adaptive mutations in viral lines over time contributed to genomic diversity, including mutations capable of evading the immune response.
The researchers write:
“Both [microbial long-term evolution experiments] and our analysis suggests that the temporal link between mutations is a sensitive way to identify emerging human adaptive mutations and vaccine-escape mutations, particularly when mutation frequencies are tracked at local and regional levels.
Increasing genomic surveillance and profiling of high-frequency clusters of missense mutations would help develop therapies and vaccines targeting viral variants.
Data collection to train the CovSimulator software
Researchers used the first known SARS-CoV-2 genome collected in Wuhan, China in December 2019 to serve as the CovSimulator – a model simulating the evolution of the genome.
While examining approximately 1 million SARS-CoV-2 genomes through March 31, 2021, a custom database was created and profiled 815,402 genomes. About 70% of genome mutations were single nucleotide substitutions, including C> T or G> T substitutions.
Increase in hyper-mutated viral variants
The researchers took around 100 genome samples from six continents – excluding Antarctica – to examine mutational differences. They found that the rate of mutations varied in viral samples circulating in Asia, Europe, Oceania and South America since October 2020.
The emergence of variants after October 2020 appears to be attributed to multiple missense mutations with little viral genome divergence. However, the researchers note that the missense divergence occurred before the emergence of new viral lines in North America.
Synonymous and non-synonymous divergence rate of SARS-CoV-2 genomes
Driving forces behind SARS-CoV-2 mutations
Variants with beneficial mutations that allowed it to survive and spread have overtaken the original strain of SARS-CoV-2 as the dominant viral lineage.
As mutations were expected to occur with the virus, researchers wondered if SARS-CoV-2 was accelerating its rate of mutation due to other outside forces.
Simulation of the SARS-CoV-2 genome showed great genomic diversity across six continents in 2020. “Obviously, global viral populations are far from reaching a balanced level of genomic diversity as the virus has grown. has spread within and across continents, reflecting the failures. in tackling local and global outbreaks. In addition, the increasing genomic diversity may reflect a growing mix of viral subpopulations spread across continents, ”the team wrote.
Another potential factor towards viral genomic diversity was the relaxation of selective constraints and adaptive mutations.
Mixed course of SARS-CoV-2
Although most missense mutations are deleterious, adaptive mutations and a strong genome-wide binding imbalance appear to be the main contributors to genomic variability, suggesting that SARS-CoV-2 has undergone an evolutionary pathway. mixed genome.
When sampling 20 SARS-CoV-2 genomes, there was a shortened time since the most recent common ancestor. There were also 11 out of 19 adaptive mutations that dominated the viral population.
“Critically, it is clear from Muller’s diagrams that within each ‘genotype’ (eg, G1, G2, G3, G8, and G9) at least one genetic change was the adaptive driver mutation.”
Characterize adaptive mutations
The SARS-CoV-2 mixed genomic evolution model showed that adaptive mutations were common among single-nucleotide variations. About 10.9% of missense mutations were adaptive mutations in a sample population of genomes. In 31 missense mutations, 45% of adaptive mutations reached a frequency of 0.5% or more.
The rate of adaptive mutations among missense mutations increased over time.
Twenty genomes from the previous viral generation showed that fixed missense mutations included 70% adaptive mutations, 20% deleterious mutations and 10% neutral mutations. At least one – G1, G2, G3, G8, and G9 – were adaptive drivers of mutation in groups of mutations.
The researchers then looked at the rate of mutation over time for each continent. There were about 52 missense mutations on the SARS-CoV-2 spike protein with a frequency of over 5% in at least one month.
These mutations, including the D614G substitution, appeared to form in clusters distributed around the world. Other advanced protein mutations that constitute several variants of concern, such as B.1.351, have also been identified.
But not all variants and their associated mutations have experienced global transmission. When the researchers examined missense mutations in the genomes of SARS-CoV-2 circulating in the United States, they found that most mutations only reached the 5% threshold at the state level – at the exception of the mutations associated with B.1.1.7, B. Lines 1.427 and B.1.429.
bioRxiv publishes preliminary scientific reports that are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or be treated as established information.