The evolutionary dynamics of influenza A virus adaptation to mammalian hosts

Abstract

Few questions on infectious disease are more important than understanding how and why avian influenza A viruses successfully emerge in mammalian populations, yet little is known about the rate and nature of the virus' genetic adaptation in new hosts. Here, we measure, for the first time, the genomic rate of adaptive evolution of swine influenza viruses (SwIV) that originated in birds. By using a curated dataset of more than 24 000 human and swine influenza gene sequences, including 41 newly characterized genomes, we reconstructed the adaptive dynamics of three major SwIV lineages (Eurasian, EA; classical swine, CS; triple reassortant, TR). We found that, following the transfer of the EA lineage from birds to swine in the late 1970s, EA virus genes have undergone substantially faster adaptive evolution than those of the CS lineage, which had circulated among swine for decades. Further, the adaptation rates of the EA lineage antigenic haemagglutinin and neuraminidase genes were unexpectedly high and similar to those observed in human influenza A. We show that the successful establishment of avian influenza viruses in swine is associated with raised adaptive evolution across the entire genome for many years after zoonosis, reflecting the contribution of multiple mutations to the coordinated optimization of viral fitness in a new environment. This dynamics is replicated independently in the polymerase genes of the TR lineage, which established in swine following separate transmission from non-swine hosts.

Figure 1.

Maximum-likelihood phylogenies illustrating the evolutionary history of the EA SwIV lineage (green) and the phylogenetic distribution of the EA genomes reported in this study (purple circles). The AIV out-group is represented by a black triangle. Scale bar is in units of estimated nucleotide substitutions per site. (a) Phylogeny estimated from HA sequences. (b) Phylogeny estimated from NA sequences. The phylogenetic position of the pH1N1/09 lineage is represented by a red triangle. Note that the AIV and pH1N1/09 isolates shown here were not included in the subsequent adaptation rate analyses.

Figure 2.

The estimated mean rate of adaptive substitution (per codon per year) for all genes and lineages of influenza A studied. The rate represents the gradient of a linear regression fitted to the time series shown in figures 3 and 4. Circles indicate the point estimate and the error bars show the 95% percentiles of estimate, obtained from 1000 bootstrap replicates. Lineages are colour-coded: EA, green; CS, blue; H1N1 human influenza, orange; H3N2 human influenza, black; TR swine, magenta.

Figure 3.

The accumulation of adaptive substitutions through time in the HA and NA genes of avian-origin H1N1 SwIV. Each point represents the estimated number of adaptive substitutions between that time point and the ancestral sequence for that lineage. The error bars show the 95% percentiles of this estimate, obtained from 1000 bootstrap replicates. The black line shows the best-fit regression model for the time series; the grey lines show the equivalent regression lines for the 1000 bootstrap replicates. All bootstrap replicates pass through the same origin, because the number of adaptive substitutions at the time of the ancestral sequence is, by definition, zero (EA lineage, green and CS lineage, blue). (a) The results for the whole HA and NA genes. (b,c) The results for the surface and internal partitions of these genes. Note that the number of adaptations here are per gene values, whereas the results in figure 2 are per codon values.

Figure 4.

The accumulation of adaptive substitutions through time in the PB2, PB1, PA, NP, M1, M2 and NS1 genes of avian-origin H1N1 SwIV (EA lineage, green; CS lineage, blue; TR lineage, magenta). See figure 3 legend for further details.