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The following HTML text is provided to enhance online readability. Many aspects of typography translate only awkwardly to HTML. Please use the page image as the authoritative form to ensure accuracy. TABLE 6. The distribution of silent and nonsilent substitutions in the HM vs. non-HM codons
growth in egg culture in addition to being under selection to evade the human immune response. The observation of excess mutations assigned to the terminal branches of the HA tree is consistent with expectations based on two very different hypotheses. HM mutations appear to account for part of the excess. The majority of the excess is of a magnitude consistent with expectations based on our sampling protocol, which is biased against sequencing closely related viruses. Unlike the excess caused by sampling bias, excess mutations attributable to HM change reflect processes other than the ongoing evolution of the virus during replication in the human host, and thus should be identified and extracted before making evolutionary inference based on phylogenetic reconstruction of influenza evolution. We gratefully acknowledge the technical expertise of Huang Jing and critical reviews by C. Bergstrom, B. Levin, A. Moya, and K. Subbarao. This work was supported by National Institutes of Health Grant 1R01AI44474 –01 and by funds provided by the University of California for the conduct of discretionary research by Los Alamos National Laboratory, conducted under the auspices of the U.S. Department of Energy. REFERENCESBush, R. M., Fitch, W. M., Bender, C. A. & Cox, N. J. ( 1999a) Positive selection on the H3 hemagglutinin gene of human influenza virus A. Mol. Biol. Evol. 16, 1457–1465. Bush, R. M., Bender, C. A., Subbaro, K., Cox, N. J. & Fitch, W. M. ( 1999b) Predicting the evolution of human influenza A. Science 286, 1921–1925. Cao, J. X., Ni, H., Wills, M. R., Campbell, G. A., Sil, B. K., Ryman, K. D., Kitchen, I. & Barrett, A. D. ( 1995) Passage of Japanese encephalitis virus in HeLa cells results in attenuation of virulence in mice. J. Gen. Virol. 76, 2757–2764. Graff, J., Normann, A., Feinstone, S. M. & Flehmig, B. ( 1994) Nucleotide sequence of wild-type hepatitis A virus GBM in comparison with two cell culture-adapted variants. J. Virol. 68, 548–554. Itoh, M., Isegawa, Y., Hotta, H. & Homma, M. ( 1997) Isolation of an avirulent mutant of Sendai virus with two amino acid mutations from a highly virulent field strain through adaptation to LLC-MK2 cells. J. Gen. Virol. 78, 3207–3215.
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