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The Influenza Genome Sequencing Project, funded and managed by the US National Institute of Allergy and Infectious Diseases, has recently generated over 1000 fully sequenced influenza genomes from clinical isolates obtained between 19 and publicly available in Genbank [].

One goal of this project was to provide researchers with a large set of sequenced isolates that represent a relatively unbiased, i.e., not enriched in antigenically novel isolates, view of influenza strains in the population [].

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

Notably, however, this reassortant strain is completely replaced by the non-reassorted Fujian strain ("late Fujian") from 2004 onwards.

This observation has not been made by Barr et al or Holmes et al. The results were further subdivided to consider mutations anywhere in the HA protein, or restricted to the HA1 domain, the HA2 domain, the epitope regions of the HA1, and the non-epitope regions of the HA1 (see Methods).

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).

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.

In particular, Ratner et al., in a phylogenetic analysis of human H3 subtype HA genes, found a significantly higher rate of amino acid replacements than silent changes in antigenic positions of the HA1 domain (which consists of the N-terminal 329 residues of HA and includes the epitopes recognized by the immune system) as compared to the same rates (or rate ratios) for the C-terminal HA2 domain [].

The PA gene was chosen as a control to the HA because it encodes an internal viral protein and is among the viral genes that are the least likely to be subject to substantial positive selection.

As is generally seen in similar comparisons, gene segments roughly cluster by the sampling date.

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.

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