One Hundred Years of Influenza A Evolution

Leveraging the simplicity of raw nucleotide distances, we provide an intuitive window into the evolution of the human influenza A \`nonstructural' (NS) gene. In an analysis suggested by the eminent Danish biologist Freddy B. Christiansen, we illustrate the existence of a continuous genetic \``backbone'' of influenza A NS genes, steadily increasing in distance to the 1918 root over more than a century. Interestingly, the 2009 influenza pandemic represents a clear departure from this enduring genetic backbone. Utilizing nucleotide distance maps and phylogenetic analyses, we illustrate remaining uncertainties regarding the origin of the 2009 pandemic, highlighting the complexity of influenza evolution. The NS gene is interesting precisely because it experiences neutral genetic drift over long periods of time time, while sudden deviations from this drift pattern can indicate changes in other genes via the hitchhiking effect. Our approach employs two measures based on genotypic distance - the rooted temporal Hamming map and the unrooted temporal Hamming distribution - to analyze the evolutionary dynamics of the NS gene. The rooted Hamming map elucidates distances between a reference sequence and all other sequences over time. In contrast, the unrooted temporal Hamming distribution captures the distribution of genotypic distances between simultaneously circulating viruses, thereby revealing patterns of sequence diversity and epi-evolutionary dynamics. Our study aims to supplement traditional tree-based phylogenetic inference with these direct temporal distance-based measures, offering transparent insights into the evolution of the influenza NS gene. ### Competing Interest Statement The authors have declared no competing interest.