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

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 ≈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
    jbloom@fhcrc.org
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 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.

Metrics

  • 6,256
    views
  • 760
    downloads
  • 173
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Bargavi Thyagarajan
  2. Jesse D Bloom
(2014)
The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin
eLife 3:e03300.
https://doi.org/10.7554/eLife.03300

Share this article

https://doi.org/10.7554/eLife.03300

Further reading

    1. Evolutionary Biology
    Mauna R Dasari, Kimberly E Roche ... Elizabeth A Archie
    Research Article

    Mammalian gut microbiomes are highly dynamic communities that shape and are shaped by host aging, including age-related changes to host immunity, metabolism, and behavior. As such, gut microbial composition may provide valuable information on host biological age. Here, we test this idea by creating a microbiome-based age predictor using 13,563 gut microbial profiles from 479 wild baboons collected over 14 years. The resulting ‘microbiome clock’ predicts host chronological age. Deviations from the clock’s predictions are linked to some demographic and socio-environmental factors that predict baboon health and survival: animals who appear old-for-age tend to be male, sampled in the dry season (for females), and have high social status (both sexes). However, an individual’s ‘microbiome age’ does not predict the attainment of developmental milestones or lifespan. Hence, in our host population, gut microbiome age largely reflects current, as opposed to past, social and environmental conditions, and does not predict the pace of host development or host mortality risk. We add to a growing understanding of how age is reflected in different host phenotypes and what forces modify biological age in primates.

    1. Evolutionary Biology
    2. Genetics and Genomics
    Christopher S McAllester, John E Pool
    Research Article

    Chromosomal inversion polymorphisms can be common, but the causes of their persistence are often unclear. We propose a model for the maintenance of inversion polymorphism, which requires that some variants contribute antagonistically to two phenotypes, one of which has negative frequency-dependent fitness. These conditions yield a form of frequency-dependent disruptive selection, favoring two predominant haplotypes segregating alleles that favor opposing antagonistic phenotypes. An inversion associated with one haplotype can reduce the fitness load incurred by generating recombinant offspring, reinforcing its linkage to the haplotype and enabling both haplotypes to accumulate more antagonistic variants than expected otherwise. We develop and apply a forward simulator to examine these dynamics under a tradeoff between survival and male display. These simulations indeed generate inversion-associated haplotypes with opposing sex-specific fitness effects. Antagonism strengthens with time, and can ultimately yield karyotypes at surprisingly predictable frequencies, with striking genotype frequency differences between sexes and between developmental stages. To test whether this model may contribute to well-studied yet enigmatic inversion polymorphisms in Drosophila melanogaster, we track inversion frequencies in laboratory crosses to test whether they influence male reproductive success or survival. We find that two of the four tested inversions show significant evidence for the tradeoff examined, with In(3 R)K favoring survival and In(3 L)Ok favoring male reproduction. In line with the apparent sex-specific fitness effects implied for both of those inversions, In(3 L)Ok was also found to be less costly to the viability and/or longevity of males than females, whereas In(3 R)K was more beneficial to female survival. Based on this work, we expect that balancing selection on antagonistically pleiotropic traits may provide a significant and underappreciated contribution to the maintenance of natural inversion polymorphism.