The dihydropyrimidine dehydrogenase gene contributes to heritable differences in sleep in mice

Curr Biol. 2021 Dec 6;31(23):5238-5248.e7. doi: 10.1016/j.cub.2021.09.049. Epub 2021 Oct 14.


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 β-alanine, an inhibitory neurotransmitter. Thus, data support β-alanine as a neurotransmitter that promotes sleep in mice.

Keywords: Collaborative Cross; Diversity Outbred; Dpyd; dihydropyrimidine dehydrogenase; genetics; knockout; mice; sleep.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dihydrouracil Dehydrogenase (NADP)* / genetics
  • Haplotypes
  • Mice
  • Mice, Knockout
  • Sleep* / genetics
  • beta-Alanine / genetics


  • beta-Alanine
  • Dihydrouracil Dehydrogenase (NADP)