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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 .
It has been emphasized that the phylogenetic tree for the HA1 of H3N2 isolates has a distinct, "ladder-like" shape, with a prominent trunk (the path from the root to the base of the latest included cluster of isolates) and, typically, short side branches .
This study supported earlier findings of positive selection for those amino acid positions involved in receptor and antibody binding and, more specifically, for a subset of 18 amino acid sites in HA1. found that 9 of these 18 positions showed evidence of positive selection only in the internal branches and not the terminal branches (i.e.
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.
the tips) of a phylogenetic tree generated from the entire set of HA1 sequences.
Given this bias, it has been proposed that these positions would be useful in predicting future dominant epidemic variants .
Associated with this is a major branching of the PA tree with one subtree comprised of isolates primarily from 2001–2003 and another subtree with isolates from 19–2005.The subtrees corresponding to sequences from isolates prior to 1994 are collapsed to focus on isolates from 1994 through 2005 and portions of the trees are labeled ("Wuhan", "Middle Sydney", etc.) with names derived from antigenically distinctive isolates that dominated during particular time intervals.Approximate positions of the vaccine isolates are indicated by red asterisks and blue, italicized labels.A number of parallel amino acid replacements – the same amino acid substitution occurring independently in different lineages – were also detected in H3N2 HA.These parallel mutations were, largely, associated with periods of rapid fitness change, indicating that there are major limitations on evolutionary pathways during antigenic change.