Evolutionary trajectories, early diversification and species-specific amplification of the metazoan Inhibitor of Apoptosis (IAP) repertoire

Abstract IAP proteins play central roles in regulating apoptosis and diverse cellular processes, influencing cancer biology, or stress resistance in economically important species, highlighting their major biomedical and ecological relevance. Despite this importance, IAP evolutionary diversity and history remain largely unexplored. Here, we present a large-scale comparative analysis of 2,843 IAP proteins from 312 species spanning all major animal lineages, revealing striking variation in IAP repertoire size and exceptional architectural diversity. We show that IAP expansion has repeatedly emerged through lineage-specific duplication events, seemingly shaped by different duplication dynamics with more recent gene family expansions in arthropods compared to molluscs and chordates. Expression data show that IAP expansion supports distinct strategies. Bivalves and gastropods mobilize multiple IAP subfamilies in response to biotic and abiotic stress, whereas aphids exhibit differential IAP expression associated with polyphenism. These contrasting patterns indicate that heterogeneous selective pressures have recurrently reshaped IAP repertoires, promoting lineage- and species-specific functional diversification. Despite this diversification, phylogenetic analyses reveal the maintenance of a core set of three IAP types. Survivin/Deterin-like and Bruce-like IAPs emerged early in metazoans and remained structurally conserved, although Bruce-like IAPs were independently lost in chelicerates, most nematodes and some hemipteran insects. RING-containing IAPs also originated early but followed more dynamic evolutionary trajectories, being lost in nematodes and platyhelminths while expanding in other lineages through domain acquisition (e.g., gnathostomes) or repeated domain duplication and loss (e.g., molluscs and insects). Our findings establish a comprehensive evolutionary framework for metazoan IAPs, linking lineage-specific diversification to structural innovation and functional specialization.