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TABLE 6. The distribution of silent and nonsilent substitutions in the HM vs. non-HM codons

All branches

Obs non-HM

Exp HM

Obs HM

χ2

Nonsilent sub

478

142.76

268

109.88

Silent sub

560

167.24

42

93.79

Sum

1038

310.00

310

203.67

The HM codons showed a significant excess of nonsilent substitutionsas opposed to silent substitutions compared to expectations basedon the non-HM codon set (P < 0.05, df = 1).

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.

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