A study of "Two-step fitness selection for intra-host variations in SARS-CoV-2" Li et al
Spontaneous mutations introduce uncertainty into COVID-19 control procedures and vaccine development. As additional mutants emerge worldwide, it is important to study dynamic changes in mutations within hosts to explore the epidemiology, transmission, and pathogenesis of SARS-CoV-2. Here, we performed spatio-temporal analysis on intra-host single-nucleotide variations (iSNVs) in 402 clinical samples from 170 patients, which revealed an increase in genetic diversity over time post-symptom onset within individual patients. Nonsynonymous mutations were over-represented in the pool of iSNVs, but underrepresented at the single nucleotide polymorphism (SNP) level. This finding suggests a two-step fitness selection process for iSNVs: even as large numbers of nonsynonymous substitutions are generated within the host (positive selection), these substitutions tend not to be fixed as SNPs at the population level (negative selection). Dynamic changes in iSNVs in subpopulations differed with gender, age, illness severity and viral shedding time, indicating positive selection at the intra-host level. Further investigation of the effects of iSNVs in the spike protein suggests that these mutations result in lower binding affinity with target receptors. This study of the within- and between-host dynamics of an emerging virus highlights the characteristics of SARS-CoV-2 that are related to viral infection and global transmission.