Abstract
Viral variants that arise in the global influenza population begin as de novo mutations in single infected hosts, but the evolutionary dynamics that transform within-host variation to global genetic diversity are poorly understood. Here, we demonstrate that influenza evolution within infected humans recapitulates many evolutionary dynamics observed at the global scale. We deep-sequence longitudinal samples from four immunocompromised patients with long-term H3N2 influenza infections. We find parallel evolution across three scales: within individual patients, in different patients in our study, and in the global influenza population. In hemagglutinin, a small set of mutations arises independently in multiple patients. These same mutations emerge repeatedly within single patients and compete with one another, providing a vivid clinical example of clonal interference. Many of these recurrent within-host mutations also reach a high global frequency in the decade following the patient infections. Our results demonstrate surprising concordance in evolutionary dynamics across multiple spatiotemporal scales.
Highlights
Viruses rapidly acquire de novo mutations as they replicate within infected hosts (Andino and Domingo, 2015), but only a small fraction of these variants transmit between hosts and eventually fix on a global scale
We identify a small set of mutations that arise repeatedly within individual patients, across multiple patients in our study, and at the global scale, revealing surprising similarities in evolutionary dynamics across multiple spatiotemporal scales
It is remarkable that influenza evolution shows such extensive parallelism at these disparate spatiotemporal scales despite heterogeneity in host immunity, viral genetic background, and the severity and duration of infection
Summary
Viruses rapidly acquire de novo mutations as they replicate within infected hosts (Andino and Domingo, 2015), but only a small fraction of these variants transmit between hosts and eventually fix on a global scale. At larger scales of space and time, transmission bottlenecks (Varble et al, 2014; Poon et al, 2016) and host heterogeneity shape viral genetic diversity. Influenza’s rapid global evolution has been the subject of intense study (Ghedin et al, 2005; Rambaut et al, 2008), but the origins of this variation within single infected hosts are still poorly understood. Recent deep-sequencing studies of human clinical samples suggest that influenza accumulates relatively limited genetic diversity within hosts during most acute infections (Dinis et al, 2016; Poon et al, 2016; Sobel Leonard et al, 2016; Debbink et al, 2017), in line with earlier studies in dogs and horses (Murcia et al, 2010; Hoelzer et al, 2010). Some within-host mutations may confer novel antigenic properties (Dinis et al, 2016), but most lack clear functional
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