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The finding that stasis is the prevailing modality of H3N2 evolution suggests that antigenic changes that lead to an increase in fitness typically result from epistatic interactions between several amino acid substitutions in the HA and, perhaps, other viral proteins.

The strains that become dominant due to increased fitness emerge from low frequency strains thanks to the last amino acid replacement that completes the set of replacements required to produce a significant antigenic change; no subset of substitutions results in a biologically significant antigenic change and corresponding fitness increase.

The observations of extremely rapid evolution of influenza A, especially in the HA gene, has led to the suggestion that the evolution of the surface regions of the HA is driven by continual positive selection.

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These observations have implications for influenza surveillance and vaccine formulation; in particular, the possibility exists that parallel amino acid replacements could serve as a predictor of new dominant strains. Unlike most pathogens where exposure leads to lasting immunity in the host, influenza A virus presents a moving antigenic target, evading specific immunity triggered by previous infections. Antigenic shift occurs when the virus acquires an HA of a different influenza subtype via reassortment of one or more gene segments and is thought to be the basis for the more devastating influenza pandemics that occurred several times in the last century[].

There have been three pandemics in the last hundred years: in 1918 (H1N1 subtype), 1957 (H2N2 subtype), and in 1968 (H3N2 subtype).

We analyzed this data set along with other currently available H3N2 and H1N1 sequences to further refine our understanding of the interpandemic evolution of influenza A virus, the relative role of positive selection versus random genetic drift in HA, and the implications for epidemic surveillance.

shows juxtaposed evolutionary trees of human H3N2 HA and PA (polymerase) genes, with colored shading connecting HA and PA tree partitions comprised of gene segments from the same clinical isolate.

During each of these pandemics, the new virus drove the previous pandemic subtype out of circulation.

In 1977, the H1N1 subtype reappeared, albeit with a lower virulence than both the original H1N1 of the 1918–1956 period and the H3N2 subtype, and since then has been co-circulating with H3N2 [], demonstrating the epidemiological significance of this phenomenon.

In contrast to H3N2, no clear intervals of evolution under positive selection were detected for the H1N1 HA during the same time span.

Thus, the ascendancy of H1N1 in some seasons is, most likely, caused by the drop in the relative fitness of the previously prevailing H3N2 lineages as the fraction of susceptible hosts decreases during the stasis intervals.

The preponderance of positive selection during intervals of rapid evolution is supported by the dramatic excess of amino acid replacements in the epitope regions of HA compared to replacements in the rest of the HA molecule.

In contrast, the stasis intervals showed a much more uniform distribution of replacements over the HA molecule, with a statistically significant difference in the rate of synonymous over nonsynonymous substitution in the epitope regions between the two modes of evolution.

Unexpectedly, it was found that the evolution of H3N2 HA includes long intervals of generally neutral sequence evolution without apparent substantial antigenic change ("stasis" periods) that are characterized by an excess of synonymous over nonsynonymous substitutions per site, lack of association of amino acid replacements with epitope regions, and slow extinction of coexisting virus lineages.

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