New phenotypes can arise from repurposing a gene or regulatory element to a new function through a co-option process. To understand the role of gene regulatory changes in the evolution of an organ, Francisca Martinez Real and colleagues focus on the development of the mole ovotestes, which are fertile ovaries with a sterile testicular portion. First, the authors compare epigenetic and transcriptional datasets in mole ovotestes to analogous datasets in mice ovaries. They identify mole-specific enhancers active in the testicular part of the ovotestis, with one of the top-ranking genes being SALL1, a transcriptional factor involved in cell fate decision. Immunostaining confirms that SALL1 is a marker for the testicular part of mole ovotestis, but is absent in other mammalian ovaries, suggesting that SALL1 expression has been acquired during the evolution of mole ovotestes. Furthermore, by analysing chromosome conformation capture datasets, the authors observe a conservation of the 3D organisation at the SALL1 locus across species, but divergent enhancer activity in moles. Finally, by overexpressing SALL1 in mice ovaries, the authors show that SALL1 can activate kidney-related gene programmes, which are signatures of mole ovotestes formation. Overall, the findings highlight an example of the co-option of gene regulation through changes in enhancer activity.
