Abstract
Like all biological populations, viral populations exist as networks of genotypes connected through mutation. Mapping the topology of these networks and quantifying population dynamics across them is crucial to understanding how populations adapt to changes in their selective environment. The influence of mutational networks is especially profound in viral populations that rapidly explore their mutational neighborhoods via high mutation rates. Using a single-cell sequencing method, scRNA-seq-enabled acquisition of mRNA and consensus haplotypes linking individual genotypes and host transcriptomes (SEARCHLIGHT), we captured and assembled viral haplotypes from hundreds of individual infected cells, revealing the complexity of viral population structures. We obtained these genotypes in parallel with host cell transcriptome information, enabling us to link host cell transcriptional phenotypes to the genetic structures underlying virus adaptation. Our examination of these structures reveals the common evolutionary dynamics of enterovirus populations and illustrates how viral populations reach through mutational "tunnels" to span evolutionary landscapes and maintain connection with multiple adaptive genotypes simultaneously.