| First Author | Keenan BT | Year | 2021 |
| Journal | Curr Biol | Volume | 31 |
| Issue | 23 | Pages | 5238-5248.e7 |
| PubMed ID | 34653361 | Mgi Jnum | J:317426 |
| Mgi Id | MGI:6854394 | Doi | 10.1016/j.cub.2021.09.049 |
| Citation | Keenan BT, et al. (2021) The dihydropyrimidine dehydrogenase gene contributes to heritable differences in sleep in mice. Curr Biol 31(23):5238-5248.e7 |
| abstractText | Many aspects of sleep are heritable, but only a few sleep-regulating genes have been reported. Here, we leverage mouse models to identify and confirm a previously unreported gene affecting sleep duration-dihydropyrimidine dehydrogenase (Dpyd). Using activity patterns to quantify sleep in 325 Diversity Outbred (DO) mice-a population with high genetic and phenotypic heterogeneity-a linkage peak for total sleep in the active lights off period was identified on chromosome 3 (LOD score = 7.14). Mice with the PWK/PhJ ancestral haplotype at this location demonstrated markedly reduced sleep. Among the genes within the linkage region, available RNA sequencing data in an independent sample of DO mice supported a highly significant expression quantitative trait locus for Dpyd, wherein reduced expression was associated with the PWK/PhJ allele. Validation studies were performed using activity monitoring and EEG/EMG recording in Collaborative Cross mouse strains with and without the PWK/PhJ haplotype at this location, as well as EEG and EMG recording of sleep and wake in Dpyd knockout mice and wild-type littermate controls. Mice lacking Dpyd had 78.4 min less sleep during the lights-off period than wild-type mice (p = 0.007; Cohen's d = -0.94). There was no difference in other measured behaviors in knockout mice, including assays evaluating cognitive-, social-, and affective-disorder-related behaviors. Dpyd encodes the rate-limiting enzyme in the metabolic pathway that catabolizes uracil and thymidine to beta-alanine, an inhibitory neurotransmitter. Thus, data support beta-alanine as a neurotransmitter that promotes sleep in mice. |
