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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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Related in: MedlinePlus

Plots like those in Figure 4 for the individual biological replicates.(A) replicate 1, (B) replicate 2, and (C) replicate 3. These plots are the files replicate_1/countparsedmuts_multi-nt-codonmutcounts.pdf, replicate_2/countparsedmuts_multi-nt-codonmutcounts.pdf, and replicate_3/countparsedmuts_multi-nt-codonmutcounts.pdf described at http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html.DOI:http://dx.doi.org/10.7554/eLife.03300.010
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fig4s1: Plots like those in Figure 4 for the individual biological replicates.(A) replicate 1, (B) replicate 2, and (C) replicate 3. These plots are the files replicate_1/countparsedmuts_multi-nt-codonmutcounts.pdf, replicate_2/countparsedmuts_multi-nt-codonmutcounts.pdf, and replicate_3/countparsedmuts_multi-nt-codonmutcounts.pdf described at http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html.DOI:http://dx.doi.org/10.7554/eLife.03300.010

Mentions: Figure 4 shows the number of times that each mutation was observed in the combined sequencing data for the three biological replicates; Figure 4—figure supplement 1 shows the same data for the replicates individually. More than 99.5% of multi-nucleotide codon mutations are observed at least five times in the combined sequencing data from the plasmid mutant libraries (mutDNA samples), and ≈ 97.5% of all such mutations are observed at least five times in sequencing of the mutDNA for each individual replicate. These results indicate that the vast majority of codon mutations are represented in the plasmid mutant libraries.10.7554/eLife.03300.009Figure 4.The number of times that each possible multi-nucleotide codon mutation was observed in each sample after combining the data for the three biological replicates.


The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin.

Thyagarajan B, Bloom JD - Elife (2014)

Plots like those in Figure 4 for the individual biological replicates.(A) replicate 1, (B) replicate 2, and (C) replicate 3. These plots are the files replicate_1/countparsedmuts_multi-nt-codonmutcounts.pdf, replicate_2/countparsedmuts_multi-nt-codonmutcounts.pdf, and replicate_3/countparsedmuts_multi-nt-codonmutcounts.pdf described at http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html.DOI:http://dx.doi.org/10.7554/eLife.03300.010
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4s1: Plots like those in Figure 4 for the individual biological replicates.(A) replicate 1, (B) replicate 2, and (C) replicate 3. These plots are the files replicate_1/countparsedmuts_multi-nt-codonmutcounts.pdf, replicate_2/countparsedmuts_multi-nt-codonmutcounts.pdf, and replicate_3/countparsedmuts_multi-nt-codonmutcounts.pdf described at http://jbloom.github.io/mapmuts/example_WSN_HA_2014Analysis.html.DOI:http://dx.doi.org/10.7554/eLife.03300.010
Mentions: Figure 4 shows the number of times that each mutation was observed in the combined sequencing data for the three biological replicates; Figure 4—figure supplement 1 shows the same data for the replicates individually. More than 99.5% of multi-nucleotide codon mutations are observed at least five times in the combined sequencing data from the plasmid mutant libraries (mutDNA samples), and ≈ 97.5% of all such mutations are observed at least five times in sequencing of the mutDNA for each individual replicate. These results indicate that the vast majority of codon mutations are represented in the plasmid mutant libraries.10.7554/eLife.03300.009Figure 4.The number of times that each possible multi-nucleotide codon mutation was observed in each sample after combining the data for the three biological replicates.

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