FIGURE 1-5 Change in hemagglutinin (HA) and neuraminidase (NA) proteins over time. The number of amino acid changes from a hypothetical ancestor was plotted versus the date of viral isolation for viruses isolated from 1930 to 1993. Open circles, human HA; closed diamonds, human NA; closed circles, swine HA; open diamonds, swine NA. Regression lines were drawn, extrapolated to the x-intercept and then the 1918 data points, closed square, 1918 HA; closed circle, 1918 NA were added to the graph (arrow).

SOURCES: Reid et al. (1999, 2000); Taubenberger et al. (2000).

reassortment, these evolutionary studies must be performed independently for each gene segment.

A comparison of the complete 1918 HA (Figure 1-5) and NA genes with those of numerous human, swine, and avian sequences demonstrates the following: Phylogenetic analyses based on HA nucleotide changes (either total or synonymous) or HA amino acid changes always place the 1918 HA with the mammalian viruses, not with the avian viruses (Reid et al., 1999). In fact, both synonymous and nonsynonymous changes place the 1918 HA in the human clade. Phylogenetic analyses of total or synonymous NA nucleotide changes also place the 1918 NA sequence with the mammalian viruses, but analysis of nonsynonymous changes or amino acid changes places the 1918 NA with the avian viruses (Reid et al., 2000). Because the 1918 HA and NA have avian features and most analyses place HA and NA near the root of the mammalian clade (close to an ancestor of the avian genes), it is likely that both genes emerged from an avian-like influenza reservoir just prior to 1918 (Reid et al., 1999, 2000, 2003; Fanning and