Intra- vs. Interhost Evolution of SARS-CoV-2 Driven by Uncorrelated Selection-The Evolution Thwarted

Area of Science:

• Virology
• Evolutionary Biology
• Genetics

Background:

• Viral evolution requires mutations to first proliferate within a host (Stage I) before spreading and competing within the broader population (Stage II).
• Understanding the dynamics of intrahost single nucleotide variants (iSNVs) is crucial for tracking viral adaptation and the emergence of new strains.

Purpose of the Study:

• To analyze the relationship between iSNV frequency within individual hosts and their subsequent occurrence in the wider host population for SARS-CoV-2.
• To investigate the selective forces acting on viral mutations during intrahost replication versus interhost transmission and competition.

Main Methods:

• Analysis of iSNVs from 79 SARS-CoV-2 infected patients with tracked transmissions.
• Quantification of iSNV frequency within hosts (Stage I) and mutation occurrence across hosts (Stage II).

Main Results:

• A small fraction of nonsynonymous iSNVs reach high frequencies within hosts but rarely become common in the population.
• Selective pressures in Stage I (intrahost) and Stage II (interhost) are often uncorrelated and potentially opposing.
• Mutations that are successful in Stage I may lack the transmission advantage needed for Stage II, leading to their rarity.

Conclusions:

• Intrahost evolution (Stage I) acts as a bottleneck that can hinder or oppose long-term viral evolution.
• Successful viral variants, including variants of concern, must overcome intrahost selection to emerge and dominate.
• The findings highlight the importance of considering intrahost dynamics in understanding viral adaptation and the emergence of new SARS-CoV-2 strains.