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MBE Advance Access published online on July 3, 2006
Molecular Biology and Evolution, doi:10.1093/molbev/msl050
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© The Author 2006. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Accepted June 28, 2006

Research Article

Natural Selection on the Influenza Virus Genome

Yoshiyuki Suzuki 1 *

1 Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, 1111 Yata, Mishima-shi, Shizuoka-ken 411-8540, Japan

* To whom correspondence should be addressed.
Yoshiyuki Suzuki, E-mail: yossuzuk{at}lab.nig.ac.jp


  Abstract

Influenza viruses are the etiological agents of influenza. Although vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections, the generation of escape mutants has been reported. To develop vaccines and drugs that are less susceptible to the generation of escape mutants, it is important to understand the evolutionary mechanisms of the viruses. Here natural selection operating on all the proteins encoded by the H3N2 human influenza A virus genome was inferred by comparing the numbers of synonymous (dS [DS]) and nonsynonymous (dN [DN]) substitutions per site. Natural selection was also inferred for the groups of functional amino acid sites involved in B-cell epitopes (BCEs), T-cell epitopes (TCEs), drug resistance, and growth in eggs. The entire region of PB1-F2 was positively selected, and positive selection also appeared to operate on BCEs, TCEs, and growth in eggs. The frequency of escape mutant generation appeared to be positively correlated with the dN/dS (DN/DS) values for the targets of vaccines and drugs, suggesting that the amino acid sites under strong functional constraint are suitable targets. In particular, TCEs may represent candidate targets, since the dN/dS (DN/DS) values were small and negative selection was inferred for many of them.

Keywords: Influenza virus; genome; positive selection; negative selection; vaccine; drug.
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