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Diosgenin, mainly produced by Dioscorea species, is a traditional precursor of most hormonal drugs in the pharmaceutical industry. The mechanisms that underlie the origin and evolution of diosgenin biosynthesis in plants remain unclear. After sequencing the whole genome of Dioscorea zingiberensis , we revealed the evolutionary trajectory of the diosgenin biosynthetic pathway in Dioscorea and demonstrated the de novo biosynthesis of diosgenin in a yeast cell factory. First, we found that P450 gene duplication and neo-functionalization, driven by positive selection, played important roles in the origin of the diosgenin biosynthetic pathway. Subsequently, we found that the enrichment of diosgenin in the yam lineage was regulated by CpG islands, which evolved to regulate gene expression in the diosgenin pathway and balance the carbon flux between the biosynthesis of diosgenin and starch. Finally, by integrating genes from plants, animals, and yeast, we heterologously synthesized diosgenin to 10 mg/l in genetically-engineered yeast. Our study not only reveals the origin and evolutionary mechanisms of the diosgenin biosynthetic pathway in Dioscorea , but also introduces an alternative approach for the production of diosgenin through synthetic biology.

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