A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses

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Abstract

Influenza virus' low replicative fidelity contributes to its capacity for rapid evolution. Clonal sequencing and fluctuation tests have suggested that the influenza virus mutation rate is 2.7x10^-6 - 3.0x10^-5 substitutions per nucleotide per strand copied (s/n/r). However, sequencing assays are biased toward mutations with minimal fitness impacts and fluctuation tests typically investigate only a subset of all possible single nucleotide mutations. We developed a fluctuation test based on reversion to fluorescence in a set of virally encoded mutant green fluorescent proteins, which allowed us to measure the rates of selectively neutral mutations representative of the twelve different mutation types. We measured an overall mutation rate of 1.8x10^-4 s/n/r for PR8 (H1N1) and 2.5x10^-4 s/n/r for Hong Kong 2014 (H3N2) and a transitional bias of 2.7-3.6. Our data suggest that each replicated genome will have an average of 2-3 mutations and highlight the importance of mutational load in influenza virus evolution.

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Matthew D Pauly

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Megan C Procario

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Adam S Lauring

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States

For correspondence
alauring@med.umich.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2906-8335

Funding

National Institute of Allergy and Infectious Diseases (R01 AI118886)

Adam S Lauring

Doris Duke Charitable Foundation (CSDA 2013105)

Adam S Lauring

National Institute of General Medical Sciences (T32 GM007544)

Matthew D Pauly

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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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.