Title

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

Document Type

Article

Publication Date

12-6-2021

Publication Title

Current biology : CB

Keywords

JMG

JAX Source

Curr Biol 2021 Dec 6; 31(23):5238-5248.e7

Volume

31

Issue

23

First Page

5238

Last Page

5248

ISSN

1879-0445

PMID

34653361

DOI

https://doi.org/10.1016/j.cub.2021.09.049

Abstract

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.

Comments

We gratefully acknowledge the contribution of the Genome Technologies Service at The Jackson Laboratory for expert assistance with the gene expression described in this publication.

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