Novel influenza A viruses of the H7N9 subtype [A(H7N9)] emerged in the spring of 2013 in China and have infected 163 people as of January 10, 2014; fifty of them died of the severe respiratory infection caused by these viruses. Phylogenetic studies have indicated that the novel A(H7N9) viruses emerged from reassortment of H7, N9 and H9N2 viruses. Inspections of protein sequences from A(H7N9) virusesand their immediate predecessorsrevealed several amino acid changes in A(H7N9) viruses that may have facilitated transmission and replication in the novel host.Since mutations that occurred more ancestrally may also have contributed to the genesis of A(H7N9) viruses,weinferred historical evolutionary events leading to the novel viruses. We identified a number ofamino acid changes on the evolutionary path to A(H7N9) viruses, including substitutions that may be associated with host range, replicative ability, and/or host responses to infection. The biological significance of these amino acid changes can be tested in future studies.

IMPORTANCE:

The novel influenza A viruses of the H7N9 subtype [A(H7N9)], which first emerged in the spring of 2013, cause severe respiratory infections in humans. Here, we performed a comprehensive evolutionary analysis of the progenitors of A(H7N9) viruses to identify amino acid changes thatmay have been critical for the emergence of A(H7N9) viruses and their ability to infect humans. We provide a list of potentially important amino acid changes which can be tested for their significance in influenza virus host range, replicative ability, and/or host responses to infection.