Holland, M.; Rutkowski, R.; Levin, T.

Caspase-1 and its related protease homologs are key players in inflammation and innate immunity. Because some pro-inflammatory caspases can detect microbial molecules and can be targets of pathogen antagonists, we hypothesized that some of these genes could be involved in evolutionary arms races between hosts and pathogens. If so, rapid caspase evolution may lead to differences in activity and function between primates and rodents and thus discrepancies between humans and animal model studies. Here, we characterize the evolutionary history of caspase-1 and its close relatives across 15 primate and 21 rodent species. While caspase-1 has been retained in all these taxa, we find that it has evolved rapidly at the sequence level in primates. At the same time, the other members of the caspase-1 subfamily (caspase-4, -5, -11, -12, and CARD16, 17, and 18) each have unique evolutionary trajectories. Whereas caspase-4 is found across primates, we identified multiple instances of pseudogenization and gene loss in caspase-5, caspase-11, and the CARDs. Because caspases-4 and -11 bind and recognize cytosolic LPS in the non-canonical inflammasome pathway, we expected that these proteins would be most likely to evolve rapidly. Instead, we found that these two proteins are largely conserved, whereas caspase-4s close paralog, caspase-5, showed significant indications of positive selection. Caspase-12 is thought to be a non-functional pseudogene in humans. We find this extends across primates, although most rodents retain an intact, and likely functional, caspase-12. Finally, unlike rodents, primate caspases have undergone many, repeated rounds of gene duplication, gene conversion, and gene loss leading to a highly dynamic pro-inflammatory caspase repertoire. We discuss the potential implications of this evolutionary history for our understanding of caspase gene functions.