Identifying featured indels associated with SARS-CoV-2 fitness

As an RNA virus, severe acute respiratory coronavirus 2 (SARS-CoV-2) is known for frequent substitution mutations, and substitutions in important genome regions are often associated with viral fitness. However, whether indel mutations are related to viral fitness is generally ignored. Here we developed a computational methodology to investigate indels linked to fitness occurring in over 9 million SARS-CoV-2 genomes. Remarkably, by analyzing 31,642,404 deletion records and 1,981,308 insertion records, our pipeline identified 26,765 deletion types and 21,054 insertion types and discovered 65 indel types with a significant association with Pango lineages. We proposed the concept of featured indels representing the population of specific Pango lineages and variants as substitution mutations and termed these 65 indels as featured indels. The selective pressure of all indel types is assessed using the Bayesian model to explore the importance of indels. Our results exhibited higher selective pressure of indels like substitution mutations, which are important for assessing viral fitness and consistent with previous studies in vitro. Evaluation of the growth rate of each viral lineage indicated that indels play key roles in SARS-CoV-2 evolution and deserve more attention as substitution mutations. IMPORTANCE: The fitness of indels in pathogen genome evolution has rarely been studied. We developed a computational methodology to investigate the severe acute respiratory coronavirus 2 genomes and analyze over 33 million records of indels systematically, ultimately proposing the concept of featured indels that can represent specific Pango lineages and identifying 65 featured indels. Machine learning model based on Bayesian inference and viral lineage growth rate evaluation suggests that these featured indels exhibit selection pressure comparable to replacement mutations. In conclusion, indels are not negligible for evaluating viral fitness.