Evolution of viral genomes and their clouds of sequence
PNAS December 22, 2025
When a novel virus such as Sudden Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects a new host species, it faces an inhospitable environment. However, a few mutations can be all the virus needs to get a bit of replication accomplished. As we know from the SARS-CoV-2 pandemic, the results of adaptation in even a few hosts can be catastrophic for the entire new host population. The remarkable paper by Martínez-González et al. (1) has documented both the rate of viral population change and the sizes of the quasispecies clouds that accompanied the waves of SARS-CoV-2 infection as they reached one metropolitan area, Madrid, during the first years of the pandemic (1).
What Is a Quasispecies Cloud?
Following its introduction into the human population in 2019, the approximately 30,000-nucleotide SARS-CoV-2 genome has evolved at a relatively constant rate of 10−3 to 10−4 substitutions per nucleotide each year (1; figure 2). These mutations remained in the population via genetic drift or via selective pressure from the millions of variants produced. Within each infected cell, the viral RNA replication machinery makes errors at a frequency such that each templating event gives rise to approximately one mutation per genome. Mutations accumulate because multiple positive-to-negative and negative-to-positive templating events are needed to create the thousands of viral RNAs in each infected cell. The iterative and cumulative nature of mutation acquisition results in the structure of the “quasispecies cloud” in each infected cell and ultimately in each infected person.
The size of this cloud in an infected individual will depend on the viral RNA load, the intrinsic mutation frequency of the viral polymerase complex, and the number of templating steps required to create infectious virions in the infected cell types. Unless these parameters change, the polymerase mutation frequency and quasispecies cloud size should remain proportionate.
The surprising finding that viral quasispecies complexity can alter during and after adaptation to a new host alters our understanding of viral emergence. Whether the larger magnitude of the quasispecies cloud was due to stress responses that altered protein synthesis, to changes in iterative viral RNA templating or as-yet-unimagined mechanisms, understanding this new twist in viral evolution may inform antiviral design and pandemic management. It will certainly inspire increased precision in our discussions of the roles of polymerase misincorporation frequencies, quasispecies complexity and virus-host relationships as they, too, continue to evolve.
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