The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin

  1. Bargavi Thyagarajan
  2. Jesse D Bloom  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States


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 ≈104 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.

Article and author information

Author details

  1. Bargavi Thyagarajan

    Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jesse D Bloom

    Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Mercedes Pascual, University of Michigan, United States

Publication history

  1. Received: May 7, 2014
  2. Accepted: July 3, 2014
  3. Accepted Manuscript published: July 8, 2014 (version 1)
  4. Accepted Manuscript updated: July 9, 2014 (version 2)
  5. Accepted Manuscript updated: July 11, 2014 (version 3)
  6. Version of Record published: July 29, 2014 (version 4)


© 2014, Thyagarajan & Bloom

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Bargavi Thyagarajan
  2. Jesse D Bloom
The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin
eLife 3:e03300.

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