Abstract
The surface proteins hemagglutinin (HA) and neuraminidase (NA) of human influenza A virus evolve under selection pressures to escape adaptive immune responses and antiviral drug treatments. In addition to these external selection pressures, some mutations in HA are known to affect the adaptive landscape of NA, and vice versa, because these two proteins are physiologically interlinked. However, the extent to which evolution of one protein affects the evolution of the other one is unknown. Here we develop a novel phylogenetic method for detecting the signatures of such genetic interactions between mutations in different genes – that is, inter-gene epistasis. Using this method, we show that influenza surface proteins evolve in a coordinated way, with mutations in HA affecting subsequent spread of mutations in NA and vice versa, at many sites. Of particular interest is our finding that the oseltamivir-resistance mutations in NA in subtype H1N1 were likely facilitated by prior mutations in HA. Our results illustrate that the adaptive landscape of a viral protein is remarkably sensitive to its genomic context and, more generally, that the evolution of any single protein must be understood within the context of the entire evolving genome.
Highlights
One of the central obstacles in controlling many pathogen-borne diseases is their exceptional ability to adapt through evolutionary changes [1]
We find that origination of mutant alleles at many sites in NA facilitated the spread of subsequent mutations in HA and vice versa, implying that inter-gene epistasis has shaped the molecular evolution of influenza viruses
We reconstructed individual phylogenetic trees for each of the two surface proteins HA and NA for the two major influenza subtypes circulating in humans, H3N2 and H1N1
Summary
One of the central obstacles in controlling many pathogen-borne diseases is their exceptional ability to adapt through evolutionary changes [1]. Our ability to prevent or even predict such escape mutations is hampered by limited knowledge of the effects of new mutations on pathogen fitness. This problem is made especially difficult because the effect of any particular mutation is often dependent on the genetic background in which it occurs, a phenomenon called epistasis [7,8,9,10,11,12,13,14,15,16]. The surface proteins hemagglutinin (HA) and neuraminidase (NA) of the human influenza A virus evolve under strong selection pressures imposed by the human immune system and, possibly, antiviral drugs [4,19]. Several previous studies have found that epistasis within each of these proteins is widespread, so that mutations in a given protein are often beneficial only in the presence of mutations at other sites in the same protein [19,20,21]
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