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Intersexuality in female moles Female moles are intersexual and develop masculinizing ovotestes, a distinctive trait among mammals. Real et al. investigated the origin of this trait by sequencing the Iberian mole genome and applying comparative strategies that integrate transcriptomic, epigenetic, and chromatin interaction data. They identified mole-specific genomic rearrangements that alter the three-dimensional regulatory landscape of the androgen-converting gene CYP17A1 and the pro-testicular factor gene FGF9, both of which show distinct expression patterns in mole gonads. The use of transgenic mice confirms the capability of these factors to increase circulating testosterone levels and to induce gonadal masculinization. This study highlights how integrative approaches can reveal the phenotypic impact of genomic variation. Science, this issue p. 208 Phylogenomic analyses identify altered regulation at the CYP17A1 and FGF9 loci that contribute to ovotestis formation in moles. Linking genomic variation to phenotypical traits remains a major challenge in evolutionary genetics. In this study, we use phylogenomic strategies to investigate a distinctive trait among mammals: the development of masculinizing ovotestes in female moles. By combining a chromosome-scale genome assembly of the Iberian mole, Talpa occidentalis, with transcriptomic, epigenetic, and chromatin interaction datasets, we identify rearrangements altering the regulatory landscape of genes with distinct gonadal expression patterns. These include a tandem triplication involving CYP17A1, a gene controlling androgen synthesis, and an intrachromosomal inversion involving the pro-testicular growth factor gene FGF9, which is heterochronically expressed in mole ovotestes. Transgenic mice with a knock-in mole CYP17A1 enhancer or overexpressing FGF9 showed phenotypes recapitulating mole sexual features. Our results highlight how integrative genomic approaches can reveal the phenotypic impact of noncoding sequence changes.