Structurally informed evolutionary models improve phylogenetic reconstruction for emerging, seasonal, and pandemic influenza viruses

Xueting Qiu; Justin Bahl

inference of viral evolution, due to the disparate immune selection pressure on different 23 functional domains. Accurately reconstructed evolutionary features on specific functional 24 domains can in turn provide biological information on viral protein and immune targets for 25 vaccine design. In this study we developed and evaluated a structurally informed partitioning 26 scheme that accounts for rate variation among immunogenic head and stalk domains of the 27 surface protein hemagglutinin (HA) of influenza viruses. We evaluated the model fit and 28 performance of four different models -HKY, SRD06 codon, HKY with a structurally informed 29 partitioning scheme, SRD06 with a structurally informed partitioning scheme on pandemic 30 A/H1N1pdm09, seasonal A/H1N1postpdm, A/H3N2, B-Yamagata-like and Victoria-like 31 lineages, and two highly pathogenic avian influenza A viruses H5Nx and H7N9. Results showed 32 that structurally informed partitioning with SRD06 performed better for all datasets with 33 decisively statistical support. Significantly faster nucleotide substitution rates for head domain, 34 compared to stalk domain was observed and may provide insight for stalk derived broadly-35 reactive vaccine design. Taken together, integrating a functionally informed partitioning scheme 36 based on protein structures of immune targets allows for significant improvement of 37 phylogenetic analysis and providing important biological insights.