Ongoing Positive Selection Drives the Evolution of SARS-CoV-2 Genomes

SARS-CoV-2 is a new RNA virus affecting humans and spreads extensively throughout the world since its first outbreak in December, 2019. Whether the transmissibility and pathogenicity of SARS-CoV-2 in humans after zoonotic transfer are actively evolving, and driven by adaptation to the new host and environments is still under debate. Understanding the evolutionary mechanism underlying epidemiological and pathological characteristics of COVID-19 is essential for predicting the epidemic trend, and providing guidance for disease control and treatments. Interrogating novel strategies for identifying natural selection using within-species polymorphisms and 3,674,076 SARS-CoV-2 genome sequences of 169 countries as of December 30, 2021, we demonstrate with popula-tion genetic evidence that during the course of SARS-CoV-2 pandemic in humans, 1) SARS-CoV-2 genomes are overall conserved under purifying selection, especially for the 14 genes related to viral RNA replication, transcription, and assembly; 2) ongoing positive selection is actively driving the evolution of 6 genes (e.g., S, ORF3a, and N) that play critical roles in molecular processes involving pathogen-host interactions, including viral invasion into and egress from host cells, and viral inhi-bition and evasion of host immune response, possibly leading to high transmissibility and mild symptom in SARS-CoV-2 evolution. According to an established haplotype phylogenetic relation-ship of 138 viral clusters, a spatial and temporal landscape of 556 critical mutations is constructed based on their divergence among viral haplotype clusters or repeatedly increase in frequency within at least 2 clusters, of which multiple mutations potentially conferring alterations in viral transmis-sibility, pathogenicity, and virulence of SARS-CoV-2 are highlighted, warranting attention.

Automated summary

SARS-CoV-2 is a new RNA virus that has been spreading extensively since its first outbreak in December, 2019. The evolution of the virus and its impact on transmission and pathogenicity in humans are still under debate. Understanding the evolutionary mechanism is essential for predicting the epidemic trend and guiding disease control and treatments.