DPYD links glial lipids and myelination to sleep duration

The regulation of sleep is heritable and conserved across species 1,2 , but the governing genetic mechanisms remain poorly understood. Here, we investigate the role of DPYD —which encodes the pyrimidine catabolic enzyme, dihydropyrimidine dehydrogenase—in sleep. Using a cross-species approach, we show that DPYD and its orthologs act specifically in glia to promote sleep through the regulation of brain lipids. In mouse and zebrafish, we find that DPYD orthologs are enriched in oligodendrocyte lineage cells, and their loss reduces myelination and sleep independent of DPYD s established role in uracil catabolism to β-alanine. Genetic and pharmacological manipulations of myelin in zebrafish show that altering myelination is sufficient to perturb sleep duration. In Drosophila, which lack myelin, we find that the DPYD ortholog acts in ensheathing glia to promote sleep through formation of glial lipid droplets, a proposed evolutionary precursor to myelin. Furthermore, a human GWAS-identified sleep variant 2 resides in a conserved cis-regulatory element that selectively contacts the promoter of DPYD within oligodendrocytes, connecting the human genetic association to oligodendrocyte-specific control of DPYD . Together, these results identify a deeply conserved role for glial lipids in sleep regulation and establish DPYD as a mechanistic link between myelin biology and sleep.