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The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin.

Thyagarajan B, Bloom JD - Elife (2014)

Bottom Line: We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability.These data enable us to infer the preference for each amino acid at each site in hemagglutinin.These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.

ABSTRACT
Influenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the ≈10(4) amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenza's antigenic evolution.

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Inherent mutational tolerance of HA’s receptor-binding residues and antigenic sites.(A) Surface of HA with one monomer colored by site entropy as determined by the deep mutational scanning; blue indicates low mutational tolerance and red indicates high mutational tolerance. (B) The structure shows residues classified as antigenic sites by Caton et al. (1982) in colored spheres; the plot shows site entropy vs relative solvent accessibility (RSA) of these residues (red triangles) and all other HA1 residues in the crystal structure (blue circles). (C) Antigenic sites of Caton et al. (1982) plus all other surface-exposed residues that contact these sites. (D) Conserved receptor-binding residues. (E) All receptor-binding residues. Table 4 shows that residues in (B) and (C) have unusually high mutational tolerance, residues in (D) have unusually low mutational tolerance, and residues in (E) do not have unusual mutational tolerance. The data and code to create all panels of this figure is provided via http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html. The structure is PDB 1RVX (Gamblin et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.03300.021
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fig10: Inherent mutational tolerance of HA’s receptor-binding residues and antigenic sites.(A) Surface of HA with one monomer colored by site entropy as determined by the deep mutational scanning; blue indicates low mutational tolerance and red indicates high mutational tolerance. (B) The structure shows residues classified as antigenic sites by Caton et al. (1982) in colored spheres; the plot shows site entropy vs relative solvent accessibility (RSA) of these residues (red triangles) and all other HA1 residues in the crystal structure (blue circles). (C) Antigenic sites of Caton et al. (1982) plus all other surface-exposed residues that contact these sites. (D) Conserved receptor-binding residues. (E) All receptor-binding residues. Table 4 shows that residues in (B) and (C) have unusually high mutational tolerance, residues in (D) have unusually low mutational tolerance, and residues in (E) do not have unusual mutational tolerance. The data and code to create all panels of this figure is provided via http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html. The structure is PDB 1RVX (Gamblin et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.03300.021

Mentions: For a more quantitative analysis, we computed a site entropy from the inferred amino-acid preferences—larger site entropies indicate a higher inherent tolerance for mutations. The site entropies of all residues are displayed on the HA protein structure in Figure 10. Visual inspection suggests that both classifications of antigenic sites have unusually high mutational tolerance, whereas the conserved receptor-binding residues have unusually low mutational tolerance.10.7554/eLife.03300.021Figure 10.Inherent mutational tolerance of HA’s receptor-binding residues and antigenic sites.


The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin.

Thyagarajan B, Bloom JD - Elife (2014)

Inherent mutational tolerance of HA’s receptor-binding residues and antigenic sites.(A) Surface of HA with one monomer colored by site entropy as determined by the deep mutational scanning; blue indicates low mutational tolerance and red indicates high mutational tolerance. (B) The structure shows residues classified as antigenic sites by Caton et al. (1982) in colored spheres; the plot shows site entropy vs relative solvent accessibility (RSA) of these residues (red triangles) and all other HA1 residues in the crystal structure (blue circles). (C) Antigenic sites of Caton et al. (1982) plus all other surface-exposed residues that contact these sites. (D) Conserved receptor-binding residues. (E) All receptor-binding residues. Table 4 shows that residues in (B) and (C) have unusually high mutational tolerance, residues in (D) have unusually low mutational tolerance, and residues in (E) do not have unusual mutational tolerance. The data and code to create all panels of this figure is provided via http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html. The structure is PDB 1RVX (Gamblin et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.03300.021
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109307&req=5

fig10: Inherent mutational tolerance of HA’s receptor-binding residues and antigenic sites.(A) Surface of HA with one monomer colored by site entropy as determined by the deep mutational scanning; blue indicates low mutational tolerance and red indicates high mutational tolerance. (B) The structure shows residues classified as antigenic sites by Caton et al. (1982) in colored spheres; the plot shows site entropy vs relative solvent accessibility (RSA) of these residues (red triangles) and all other HA1 residues in the crystal structure (blue circles). (C) Antigenic sites of Caton et al. (1982) plus all other surface-exposed residues that contact these sites. (D) Conserved receptor-binding residues. (E) All receptor-binding residues. Table 4 shows that residues in (B) and (C) have unusually high mutational tolerance, residues in (D) have unusually low mutational tolerance, and residues in (E) do not have unusual mutational tolerance. The data and code to create all panels of this figure is provided via http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html. The structure is PDB 1RVX (Gamblin et al., 2004).DOI:http://dx.doi.org/10.7554/eLife.03300.021
Mentions: For a more quantitative analysis, we computed a site entropy from the inferred amino-acid preferences—larger site entropies indicate a higher inherent tolerance for mutations. The site entropies of all residues are displayed on the HA protein structure in Figure 10. Visual inspection suggests that both classifications of antigenic sites have unusually high mutational tolerance, whereas the conserved receptor-binding residues have unusually low mutational tolerance.10.7554/eLife.03300.021Figure 10.Inherent mutational tolerance of HA’s receptor-binding residues and antigenic sites.

Bottom Line: We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability.These data enable us to infer the preference for each amino acid at each site in hemagglutinin.These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.

ABSTRACT
Influenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the ≈10(4) amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenza's antigenic evolution.

Show MeSH
Related in: MedlinePlus