Intra- vs. inter-host evolution of SARS-CoV-2 driven by uncorrelated selection - The evolution thwarted

Abstract In viral evolution, a new mutation has to proliferate within the host (Stage I) in order to be transmitted and then compete in the host population (Stage II). We now analyze the intra-host single nucleotide variants (iSNVs) in a set of 79 SARS-CoV-2 infected patients with most transmissions tracked. Here, every mutation has two measures: i) iSNV frequency within each individual host in Stage I; ii) occurrence among individuals ranging from 1 (private), 2-78 (public) to 79 (global) occurrences in Stage II. In Stage I, a small fraction of non-synonymous iSNVs are sufficiently advantageous to rise to a high frequency, often 100%. However, such iSNVs usually fail to become public mutations. Thus, the selective forces in the two stages of evolution are uncorrelated and, possibly, antagonistic. For that reason, successful mutants, including many VOCs (variants of concern), have to avoid being eliminated in Stage I when they first emerge. As a result, they may not have the transmission advantage to outcompete the dominant strains and, hence, are rare in the host population. Few of them could manage to slowly accumulate advantageous mutations to compete in Stage II. When they do, they would appear suddenly as in each of the 6 successive waves of SARS-CoV-2 strains. In conclusion, Stage I evolution, the gate-keeper, may contravene the long-term viral evolution and should be heeded in viral studies.