Abstract:Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare in the global viral population. Here, we compare viral variation within and between hosts to link influenza's evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites res… Show more
“…Purifying selection against deleterious mutations is especially apparent for mutations that are observed multiple times in circulating variants, with a substantial number of singletons being mildly or moderately deleterious, whereas mutations observed multiple times are largely neutral. This general pattern of increased purifying selection on more common mutations is consistent with theoretical expectation and empirical patterns observed for other viruses ( Pybus et al., 2007 ; Xue and Bloom, 2020 ). Figure 7 Phenotypic Impacts of Genetic Variation in the SARS-CoV-2 RBD (A) Distribution of effects on ACE2 binding of mutations observed among circulating SARS-CoV-2 isolates.…”
The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor and is a major determinant of host range and a dominant target of neutralizing antibodies. Here, we experimentally measure how all amino acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity-enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.
“…Purifying selection against deleterious mutations is especially apparent for mutations that are observed multiple times in circulating variants, with a substantial number of singletons being mildly or moderately deleterious, whereas mutations observed multiple times are largely neutral. This general pattern of increased purifying selection on more common mutations is consistent with theoretical expectation and empirical patterns observed for other viruses ( Pybus et al., 2007 ; Xue and Bloom, 2020 ). Figure 7 Phenotypic Impacts of Genetic Variation in the SARS-CoV-2 RBD (A) Distribution of effects on ACE2 binding of mutations observed among circulating SARS-CoV-2 isolates.…”
The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor and is a major determinant of host range and a dominant target of neutralizing antibodies. Here, we experimentally measure how all amino acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity-enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.
“…Purifying selection against deleterious mutations is especially apparent for mutations that are observed multiple times in circulating variants, with a substantial number of singletons being mildly or moderately deleterious whereas most mutations observed multiple times are largely neutral ( Figures 8A, S8A,B). This general pattern of increased purifying selection on more common mutations is consistent with theoretical expectation and empirical patterns observed for other viruses (Pybus et al, 2007;Xue and Bloom, 2020).…”
Section: Using Sequence-phenotype Maps To Interpret Genetic Variationsupporting
The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD's surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.
“…The IAV transmission bottleneck is stringent (19), which generally means that few variants that arise within hosts are able to transmit. Together, these studies suggest that positive selection of novel variants is an inefficient process in IAV-infected hosts, contrasting with its patterns of significant positive selection at the global level (23). Despite the importance of intrahost processes to influenza virus evolution, these dynamics have not been systematically investigated in IBV.…”
Influenza B virus (IBV) undergoes seasonal antigenic drift more slowly than influenza A virus, but the reasons for this difference are unclear. While the evolutionary dynamics of influenza viruses play out globally, they are fundamentally driven by mutation, reassortment, drift, and selection at the level of individual hosts. These processes have recently been described for influenza A virus, but little is known about the evolutionary dynamics of IBV during individual infections and transmission events. Here, we define the within-host evolutionary dynamics of IBV by sequencing virus populations from naturally infected individuals enrolled in a prospective, community-based cohort over 8,176 person-seasons of observation. Through analysis of high depth-of-coverage sequencing data from samples from 91 individuals with influenza B, we find that IBV accumulates lower genetic diversity than previously observed for influenza A virus during acute infections. Consistent with studies of influenza A viruses, the within-host evolution of IBVs is characterized by purifying selection and the general absence of widespread positive selection of within-host variants. Analysis of shared genetic diversity across 15 sequence-validated transmission pairs suggests that IBV experiences a tight transmission bottleneck similar to that of influenza A virus. These patterns of local-scale evolution are consistent with the lower global evolutionary rate of IBV.
IMPORTANCE The evolution of influenza virus is a significant public health problem and necessitates the annual evaluation of influenza vaccine formulation to keep pace with viral escape from herd immunity. Influenza B virus is a serious health concern for children, in particular, yet remains understudied compared to influenza A virus. Influenza B virus evolves more slowly than influenza A virus, but the factors underlying this are not completely understood. We studied how the within-host diversity of influenza B virus relates to its global evolution by sequencing viruses from a community-based cohort. We found that influenza B virus populations have lower within-host genetic diversity than influenza A virus and experience a tight genetic bottleneck during transmission. Our work provides insights into the varying dynamics of influenza viruses in human infection.
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