Identification of Causal Genes, Networks, and Transcriptional Regulators of REM Sleep and Wake

Sage Bionetworks, Seattle, WA, USA.
Sleep (Impact Factor: 4.59). 11/2011; 34(11):1469-77. DOI: 10.5665/sleep.1378
Source: PubMed


Sleep-wake traits are well-known to be under substantial genetic control, but the specific genes and gene networks underlying primary sleep-wake traits have largely eluded identification using conventional approaches, especially in mammals. Thus, the aim of this study was to use systems genetics and statistical approaches to uncover the genetic networks underlying 2 primary sleep traits in the mouse: 24-h duration of REM sleep and wake.
Genome-wide RNA expression data from 3 tissues (anterior cortex, hypothalamus, thalamus/midbrain) were used in conjunction with high-density genotyping to identify candidate causal genes and networks mediating the effects of 2 QTL regulating the 24-h duration of REM sleep and one regulating the 24-h duration of wake.
Basic sleep research laboratory.
Male [C57BL/6J × (BALB/cByJ × C57BL/6J*) F1] N(2) mice (n = 283).
The genetic variation of a mouse N2 mapping cross was leveraged against sleep-state phenotypic variation as well as quantitative gene expression measurement in key brain regions using integrative genomics approaches to uncover multiple causal sleep-state regulatory genes, including several surprising novel candidates, which interact as components of networks that modulate REM sleep and wake. In particular, it was discovered that a core network module, consisting of 20 genes, involved in the regulation of REM sleep duration is conserved across the cortex, hypothalamus, and thalamus. A novel application of a formal causal inference test was also used to identify those genes directly regulating sleep via control of expression.
Systems genetics approaches reveal novel candidate genes, complex networks and specific transcriptional regulators of REM sleep and wake duration in mammals.

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Available from: Christopher J Winrow, May 13, 2014
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    • "Interestingly, REM sleep expression is not only determined by preceding history but is also subject to circadian rhythmicity (Dijk and Czeisler 1995; Kantor and others 2009). Moreover, in both humans and animals the amount as well as spontaneous EEG activity in REM sleep were shown to be under genetic control (Buckelmuller and others 2006; Franken and others 1998; Millstein and others 2011). "
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    • "Evidence has been found in mice linking DNA variation to variation in 24 h REM sleep, possibly mediated by chronic differences in gene expression (Winrow et al., 2009; Millstein et al., 2011). Here we report an application of the method to identify gene expression features in the hypothalamus associated with variation in 24 h REM sleep in a segregating population of mice. "
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