biostudies-literatureUnknown17(10)Mordier JAgence Nationale de la RechercheInstitute of GeneticsFondation pour la Recherche MédicaleSCHLAFEN proteins are a large family of RNase-related enzymes carrying essential immune and developmental functions. Despite these important roles, Schlafen genes display varying degrees of evolutionary conservation in mammals. While this appears to influence their molecular activities, a detailed understanding of these evolutionary innovations is still lacking. Here, we used in-depth phylogenomic approaches to characterize the evolutionary trajectories and selective forces shaping mammalian Schlafen genes. We traced lineage-specific Schlafen amplifications and found that recent duplicates evolved under distinct selective forces, supporting repeated subfunctionalization cycles. Codon-level natural selection analyses in primates and rodents identified recurrent positive selection over SchlaGenome biology and evolutionevaf172https://www.ebi.ac.uk/biostudies/studies/S-EPMC12492265biostudies-literatureRecurrent Evolutionary Innovations in Rodent and Primate Schlafen Genes.PMC12492265Molaro AFraisse MMordier JCohen-Tannoudji MfalseRecurrent Evolutionary Innovations in Rodent and Primate Schlafen Genes.SCHLAFEN proteins are a large family of RNase-related enzymes carrying essential immune and developmental functions. Despite these important roles, Schlafen genes display varying degrees of evolutionary conservation in mammals. While this appears to influence their molecular activities, a detailed understanding of these evolutionary innovations is still lacking. Here, we used in-depth phylogenomic approaches to characterize the evolutionary trajectories and selective forces shaping mammalian Schlafen genes. We traced lineage-specific Schlafen amplifications and found that recent duplicates evolved under distinct selective forces, supporting repeated subfunctionalization cycles. Codon-level natural selection analyses in primates and rodents identified recurrent positive selection over Schla2025-01-01T00:00:00Z2025 Sep2026-05-09T03:10:53.864Z2026-05-09T03:08:02.125ZS-EPMC124922654097195410.1093/gbe/evaf172