Open Access Highly Accessed Research article

Evolutionary interactions between haemagglutinin and neuraminidase in avian influenza

Melissa J Ward1*, Samantha J Lycett1, Dorita Avila1, Jonathan P Bollback12 and Andrew J Leigh Brown1

Author Affiliations

1 Institute for Evolutionary Biology, University of Edinburgh, Ashworth Building, West Mains Road, Edinburgh EH9 3JT, Scotland, UK

2 IST Austria, Am Campus 1, Klosterneuburg 3400, Austria

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BMC Evolutionary Biology 2013, 13:222  doi:10.1186/1471-2148-13-222

Published: 9 October 2013



Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. It has been suggested that productive viral infection requires a balance in the level of functional activity of HA and NA, arising from their closely interacting roles in the viral life cycle, and that this functional balance could be mediated by genetic changes in the HA and NA. Here, we investigate how the selective pressure varies for H7 avian influenza HA on different NA subtype backgrounds.


By extending Bayesian stochastic mutational mapping methods to calculate the ratio of the rate of non-synonymous change to the rate of synonymous change (dN/dS), we found the average dN/dS across the avian influenza H7 HA1 region to be significantly greater on an N2 NA subtype background than on an N1, N3 or N7 background. Observed differences in evolutionary rates of H7 HA on different NA subtype backgrounds could not be attributed to underlying differences between avian host species or virus pathogenicity. Examination of dN/dS values for each subtype on a site-by-site basis indicated that the elevated dN/dS on the N2 NA background was a result of increased selection, rather than a relaxation of selective constraint.


Our results are consistent with the hypothesis that reassortment exposes influenza HA to significant changes in selective pressure through genetic interactions with NA. Such epistatic effects might be explicitly accounted for in future models of influenza evolution.

Influenza; Evolution; Reassortment; Selection; Subtype