Spence, MatthewMortimer, MatthewBuckle, AshleyMinh, Bui QuangJackson, Colin2023-12-082023-12-080737-4038http://hdl.handle.net/1885/307740Serine protease inhibitors (serpins) are found in all kingdoms of life and play essential roles in multiple physiological processes. Owing to the diversity of the superfamily, phylogenetic analysis is challenging and prokaryotic serpins have been speculated to have been acquired from Metazoa through horizontal gene transfer due to their unexpectedly high homology. Here, we have leveraged a structural alignment of diverse serpins to generate a comprehensive 6,000-sequence phylogeny that encompasses serpins from all kingdoms of life. We show that in addition to a central "hub"of highly conserved serpins, there has been extensive diversification of the superfamily into many novel functional clades. Our analysis indicates that the hub proteins are ancient and are similar because of convergent evolution, rather than the alternative hypothesis of horizontal gene transfer. This work clarifies longstanding questions in the evolution of serpins and provides new directions for research in the field of serpin biology.Funding by the Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science and the Centre of Excellence in Synthetic Biology is gratefully acknowledged. This project was undertaken with the assistance of resources and services from the National Computational Infrastructure (NCI), which is supported by the Australian Government.application/pdfen-AU© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.https://creativecommons.org/licenses/by/4.0/serpinphylogeneticsevolution202110.1093/molbev/msab0812022-09-04Creative Commons Attribution 4.0 International License