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Genetics is one of the various approaches adopted to understand and control mammalian sleep. Reverse genetics, which is usually applied to analyze sleep in gene-deficient mice, has been the mainstream field of genetic studies on sleep for the past three decades and has revealed that various molecules, including orexin, are involved in sleep regulation. Recently, forward genetic studies in humans and mice have identified gene mutations responsible for heritable sleep abnormalities, such as SIK3, NALCN, DEC2, the neuropeptide S receptor, and β1 adrenergic receptor. Furthermore, the protein kinase A-SIK3 pathway was shown to represent the intracellular neural signaling for sleep need. Large-scale genome-wide analyses of human sleep have been conducted, and many gene loci associated with individual differences in sleep have been found. The development of genome-editing technology and gene transfer by an adeno-associated virus has updated and expanded the genetic studies on mammals. These efforts are expected to elucidate the mechanisms of sleep–wake regulation and develop new therapeutic interventions for sleep disorders.


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Hunt for mammalian sleep-regulating genes

Show Author's information Hiromasa Funato1,2( )Masashi Yanagisawa1,3,4( )
 International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
 Department of Anatomy, Faculty of Medicine, Toho University, Ota-ku, Tokyo 951-8585, Japan
 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75390, Texas, USA
 Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan

Abstract

Genetics is one of the various approaches adopted to understand and control mammalian sleep. Reverse genetics, which is usually applied to analyze sleep in gene-deficient mice, has been the mainstream field of genetic studies on sleep for the past three decades and has revealed that various molecules, including orexin, are involved in sleep regulation. Recently, forward genetic studies in humans and mice have identified gene mutations responsible for heritable sleep abnormalities, such as SIK3, NALCN, DEC2, the neuropeptide S receptor, and β1 adrenergic receptor. Furthermore, the protein kinase A-SIK3 pathway was shown to represent the intracellular neural signaling for sleep need. Large-scale genome-wide analyses of human sleep have been conducted, and many gene loci associated with individual differences in sleep have been found. The development of genome-editing technology and gene transfer by an adeno-associated virus has updated and expanded the genetic studies on mammals. These efforts are expected to elucidate the mechanisms of sleep–wake regulation and develop new therapeutic interventions for sleep disorders.

Keywords:

sleep, forward genetics, reverse genetics, human, mouse, SIK3
Received: 12 March 2022 Revised: 14 April 2022 Accepted: 22 April 2022 Published: 27 May 2022 Issue date: September 2022
References(54)
[1]
Irwin DJ, Lee VMY, Trojanowski JQ. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci 2013, 14(9): 626–636.
[2]
Spiegel K, Leproult R, van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999, 354(9188): 1435–1439.
[3]
Kecklund G, Axelsson J. Health consequences of shift work and insufficient sleep. BMJ 2016, 355: i5210.
[4]
Grandner MA, Fernandez FX. The translational neuroscience of sleep: A contextual framework. Science 2021, 374(6567): 568–573
[5]
Morin CM, Benca R. Chronic insomnia. Lancet 2012, 379(9821): 1129–1141.
[6]
Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007, 8(3): 171–181.
[7]
Adamantidis AR, Gutierrez Herrera C, Gent TC. Oscillating circuitries in the sleeping brain. Nat Rev Neurosci 2019, 20(12): 746–762.
[8]
Liu DQ, Dan Y. A motor theory of sleep-wake control: arousal-action circuit. Annu Rev Neurosci 2019, 42: 27–46.
[9]
Tobler I, Gaus SE, Deboer T, et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 1996, 380(6575): 639–642.
[10]
Zhang J, Obál F Jr, Fang J, et al. Non-rapid eye movement sleep is suppressed in transgenic mice with a deficiency in the somatotropic system. Neurosci Lett 1996, 220(2): 97–100.
[11]
Cirelli C. The genetic and molecular regulation of sleep: from fruit flies to humans. Nat Rev Neurosci 2009, 10(8): 549–560.
[12]
Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999, 98(4): 437–451.
[13]
Mahoney CE, Cogswell A, Koralnik IJ, et al. The neurobiological basis of narcolepsy. Nat Rev Neurosci 2019, 20(2): 83–93.
[14]
Peterson KA, Murray SA. Progress towards completing the mutant mouse null resource. Mamm Genome 2022, 33(1): 123–134.
[15]
Potter PK, Bowl MR, Jeyarajan P, et al. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease. Nat Commun 2016, 7: 12444.
[16]
Sunagawa GA, Sumiyama K, Ukai-Tadenuma M, et al. Mammalian reverse genetics without crossing reveals Nr3a as a short-sleeper gene. Cell Rep 2016, 14(3): 662–677.
[17]
Tatsuki F, Sunagawa GA, Shi S, et al. Involvement of Ca(2+)-dependent hyperpolarization in sleep duration in mammals. Neuron 2016, 90(1): 70–85.
[18]
Niwa Y, Kanda GN, Yamada RG, et al. Muscarinic acetylcholine receptors Chrm1 and Chrm3 are essential for REM sleep. Cell Rep 2018, 24(9): 2231–2247.e7.
[19]
Konopka RJ, Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci USA 1971, 68(9): 2112–2116.
[20]
Allada R, Emery P, Takahashi JS, et al. Stopping time: the genetics of fly and mouse circadian clocks. Annu Rev Neurosci 2001, 24: 1091–1119.
[21]
Funato H. Forward genetic approach for behavioral neuroscience using animal models. Proc Jpn Acad Ser B Phys Biol Sci 2020, 96(1): 10–31.
[22]
Shaw PJ, Cirelli C, Greenspan RJ, et al. Correlates of sleep and waking in Drosophila melanogaster. Science 2000, 287(5459): 1834–1837.
[23]
Hendricks JC, Finn SM, Panckeri KA, et al. Rest in Drosophila is a sleep-like state. Neuron 2000, 25(1): 129–138.
[24]
Cirelli C, Bushey D, Hill S, et al. Reduced sleep in Drosophila shaker mutants. Nature 2005, 434(7037): 1087–1092.
[25]
Miyoshi C, Kim SJ, Ezaki T, et al. Methodology and theoretical basis of forward genetic screening for sleep/wakefulness in mice. Proc Natl Acad Sci USA 2019, 116(32): 16062–16067.
[26]
Hossain MS, Asano F, Fujiyama T, et al. Identification of mutations through dominant screening for obesity using C57BL/6 substrains. Sci Rep 2016, 6: 32453.
[27]
Wang T, Zhan XW, Bu CH, et al. Real-time resolution of point mutations that cause phenovariance in mice. Proc Natl Acad Sci USA 2015, 112(5): E440–E449.
[28]
Quwailid MM, Hugill A, Dear N, et al. A gene-driven ENU-based approach to generating an allelic series in any gene. Mamm Genome 2004, 15(8): 585–591.
[29]
Iwasaki K, Hotta-Hirashima N, Funato H, et al. Protocol for sleep analysis in the brain of genetically modified adult mice. STAR Protoc 2021, 2(4): 100982.
[30]
Choi J, Kim SJ, Fujiyama T, et al. The role of reproductive hormones in sex differences in sleep homeostasis and arousal response in mice. Front Neurosci 2021, 15: 739236.
[31]
Funato H, Miyoshi C, Fujiyama T, et al. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature 2016, 539(7629): 378–383.
[32]
Gottlieb DJ, Hek K, Chen TH, et al. Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Mol Psychiatry 2015, 20(10): 1232–1239.
[33]
Allebrandt KV, Amin N, Müller-Myhsok B, et al. A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila. Mol Psychiatry 2013, 18(1): 122–132.
[34]
Byrne EM, Gehrman PR, Medland SE, et al. A genome-wide association study of sleep habits and insomnia. Am J Med Genet B Neuropsychiatr Genet 2013, 162B(5): 439–451.
[35]
Jones SE, Tyrrell J, Wood AR, et al. Genome-wide association analyses in 128, 266 individuals identifies new morningness and sleep duration loci. PLoS Genet 2016, 12(8): e1006125.
[36]
Lane JM, Liang JJ, Vlasac I, et al. Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nat Genet 2017, 49(2): 274–281.
[37]
Lane JM, Jones SE, Dashti HS, et al. Biological and clinical insights from genetics of insomnia symptoms. Nat Genet 2019, 51(3): 387–393.
[38]
Dashti HS, Jones SE, Wood AR, et al. Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates. Nat Commun 2019, 10(1): 1100.
[39]
Dashti HS, Daghlas I, Lane JM, et al. Genetic determinants of daytime napping and effects on cardiometabolic health. Nat Commun 2021, 12(1): 900.
[40]
Wang HM, Lane JM, Jones SE, et al. Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes. Nat Commun 2019, 10(1): 3503.
[41]
He Y, Jones CR, Fujiki N, et al. The transcriptional repressor DEC2 regulates sleep length in mammals. Science 2009, 325(5942): 866–870.
[42]
Pellegrino R, Kavakli IH, Goel N, et al. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. Sleep 2014, 37(8): 1327–1336.
[43]
Xing LJ, Shi GS, Mostovoy Y, et al. Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. Sci Transl Med 2019, 11(514): eaax2014.
[44]
Shi GS, Xing LJ, Wu D, et al. A rare mutation of β1-adrenergic receptor affects sleep/wake behaviors. Neuron 2019, 103(6): 1044–1055.e7.
[45]
Honda T, Fujiyama T, Miyoshi C, et al. A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice. Proc Natl Acad Sci USA 2018, 115(41): 10458–10463.
[46]
Iwasaki K, Fujiyama T, Nakata S, et al. Induction of mutant Sik3Sleepy allele in neurons in late infancy increases sleep need. J Neurosci 2021, 41(12): 2733–2746.
[47]
Grubbs JJ, Lopes LE, van der Linden AM, et al. A salt-induced kinase is required for the metabolic regulation of sleep. PLoS Biol 2020, 18(4): e3000220.
[48]
Park M, Miyoshi C, Fujiyama T, et al. Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need. Sci Rep 2020, 10(1): 8676.
[49]
Darling NJ, Cohen P. Nuts and bolts of the salt-inducible kinases (SIKs). Biochem J 2021, 478(7): 1377–1397.
[50]
Mikhail C, Vaucher A, Jimenez S, et al. ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness. Sci Signal 2017, 10(463): eaai9219.
[51]
Wang ZQ, Ma J, Miyoshi C, et al. Quantitative phosphoproteomic analysis of the molecular substrates of sleep need. Nature 2018, 558(7710): 435–439.
[52]
Cirelli C, Tononi G. Effects of sleep and waking on the synaptic ultrastructure. Philos Trans R Soc Lond B Biol Sci 2020, 375(1799): 20190235.
[53]
Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol 2020, 38(7): 824–844.
[54]
Li C, Zhang R, Meng XB, et al. Targeted, random mutagenesis of plant genes with dual cytosine and adenine base editors. Nat Biotechnol 2020, 38(7): 875–882.
Publication history
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Publication history

Received: 12 March 2022
Revised: 14 April 2022
Accepted: 22 April 2022
Published: 27 May 2022
Issue date: September 2022

Copyright

© The authors 2022.

Acknowledgements

We thank all Yanagisawa/Funato laboratory members and IIIS members for their kind support, technical assistance, and discussion.

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