Abstract
Circadian rhythms and sleep are two separate but intimately related processes. Circadian rhythms are generated through the precisely controlled, cyclic expression of a number of genes designated clock genes. Genetic variability in these genes has been associated with a number of phenotypic differences in circadian as well as sleep parameters, both in mouse models and in humans. Diurnal preferences as determined by the selfreported Horne-Östberg (HÖ) questionnaire, has been associated with polymorphisms in the human genes CLOCK, PER1, PER2 and PER3. Circadian rhythm-related sleep disorders have also been associated with mutations and polymorphisms in clock genes, with the advanced type cosegrating in an autosomal dominant inheritance pattern with mutations in the genes PER2 and CSNK1D, and the delayed type associating without discernible Mendelian inheritance with polymorphisms in CLOCK and PER3. Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep loss, confirming the close association between the processes of circadian rhythms and sleep at the genetic level.
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Alvarez J. D., Hansen A., Ord T., Bebas P., Chappell P. E., Giebultowicz J. M. et al. 2008 The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice. J. Biol. Rhythms 23, 26–36.
Ancoli-Israel S., Schnierow B., Kelsoe J. and Fink R. 2001 A pedigree of one family with delayed sleep phase syndrome. Chronobiol. Int. 18, 831–840.
Archer S. N., Robilliard D. L., Skene D. J., Smits M., Williams A., Arendt J. and von Schantz M. 2003 A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 26, 413–415.
Bae K., Jin X., Maywood E. S., Hastings M. H., Reppert S. M. and Weaver D. R. 2001 Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30, 525–536.
Bunger M. K., Wilsbacher L. D., Moran S. M., Clendenin C., Radcliffe L. A., Hogenesch J. B. et al. 2000 Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017.
Bunger M. K., Walisser J. A., Sullivan R., Manley P. A., Moran S. M., Kalscheur V. L. et al. 2005 Progressive arthropathy in mice with a targeted disruption of theMop3/Bmal-1 locus. Genesis 41, 122–132.
Campbell S. S. and Murphy P. J. 2007 Delayed sleep phase disorder in temporal isolation. Sleep 30, 1225–1228.
Carpen J. D., Archer S. N., Skene D. J., Smits M. G. and von Schantz M. 2005 A single-nucleotide polymorphism in the 5′-untranslated region of the hPER2 gene is associated with diurnal preference. J. Sleep Res. 14, 293–297.
Carpen J. D., von Schantz M., Smits M., Skene D. J. and Archer S. N. 2006 A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans. J. Hum. Genet. 51, 1122–1125.
Chu L. W., Zhu Y., Yu K., Zheng T., Yu H., Zhang Y. et al. 2007 Variants in circadian genes and prostate cancer risk: a population-based study in China. Prostate Cancer Prostatic Dis. 11, 342–348.
Ciarleglio C. M., Ryckman K. K., Servick S. V., Hida A., Robbins S., Wells N. et al. 2008 Genetic differences in human circadian clock genes among worldwide populations. J. Biol. Rhythms 23, 330–340.
Cirelli C. and Bushey D. 2008 Sleep and wakefulness in Drosophila melanogaster. Ann. N. Y. Acad. Sci. 1129, 323–329.
Constance C. M., Green C. B., Tei H. and Block G. D. 2002 Bulla gouldiana period exhibits unique regulation at the mRNA and protein levels. J. Biol. Rhythms 17, 413–427.
Czeisler C. A., Duffy J. F., Shanahan T. L., Brown E. N., Mitchell J. F., Rimmer D. W. et al. 1999 Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284, 2177–2181.
Debruyne J. P., Noton E., Lambert C. M., Maywood E. S., Weaver D. R. and Reppert S. M. 2006 A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50, 465–477.
Doi M., Hirayama J. and Sassone-Corsi P. 2006 Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508.
Dudley C. A., Erbel-Sieler C., Estill S. J., Reick M., Franken P., Pitts S. and McKnight S. L. 2003 Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 301, 379–383.
Duffy J. F. and Czeisler C. A. 2002 Age-related change in the relationship between circadian period, circadian phase, and diurnal preference in humans. Neurosci. Lett. 318, 117–120.
Duffy J. F., Rimmer D. W. and Czeisler C. A. 2001 Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase. Behav. Neurosci. 115, 895–899.
Ebisawa T., Uchiyama M., Kajimura N., Mishima K., Kamei Y., Katoh M. et al. 2001 Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep. 2, 342–346.
Franken P., Dudley C. A., Estill S. J., Barakat M., Thomason R., O’Hara B. F. and McKnight S. L. 2006 NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions. Proc. Natl. Acad. Sci. USA 103, 7118–7123.
Groeger J. A., Viola A. U., Lo J. C. Y., von Schantz M., Archer S. N. and Dijk D. J. 2008 Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. Sleep 31, 1159–1167.
Hankins M. W., Peirson S. N. and Foster R. G. 2008 Melanopsin: an exciting photopigment. Trends Neurosci. 31, 27–36.
Hogenesch J. B., Gu Y. Z., Moran S. M., Shimomura K., Radcliffe L. A., Takahashi J. S. and Bradfield C. A. 2000 The basic helixloop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors. J. Neurosci. 20, RC83.
Horne J. A. and Östberg O. 1976 A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int. J. Chronobiol. 4, 97–110.
Iwase T., Kajimura N., Uchiyama M., Ebisawa T., Yoshimura K., Kamei Y. et al. 2002 Mutation screening of the human Clock gene in circadian rhythm sleep disorders. Psychiatry Res. 109, 121–128.
Jenkins A., Archer S. N. and von Schantz M. 2005 Expansion during primate radiation of a variable number tandem repeat coding region of the circadian clock gene Period3. J. Biol Rhythms 20, 470–472.
Johansson C., Willeit M., Smedh C., Ekholm J., Paunio T., Kieseppa T. et al. 2003 Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 28, 734–739.
Jones C. R., Campbell S. S., Zone S. E., Cooper F., DeSano A., Murphy P. J. et al. 1999 Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat. Med. 5, 1062–1065.
Jones K. H. S., Ellis J., von Schantz M., Skene D. J., Dijk D. J. and Archer S. N. 2007 Age-related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities. J. Sleep Res. 16, 12–16.
Kafka F. 1912 Die Verwandlung. Kurt Wolff Verlag, Leipzig.
Katzenberg D., Young T., Finn L., Lin L., King D. P., Takahashi J. S., and Mignot E. 1998 A CLOCK polymorphism associated with human diurnal preference. Sleep 21, 569–576.
King D. P., Zhao Y., Sangoram A. M., Wilsbacher L. D., Tanaka M., Antoch M. P. et al. 1997 Positional cloning of the mouse circadian Clock gene. Cell 89, 641–653.
Konopka R. J. and Benzer S. 1971 Clock mutants of Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 68, 2112–2116.
Lamont E. W., Legault-Coutu D., Cermakian N. and Boivin D. B. 2007 The role of circadian clock genes in mental disorders. Dialogues Clin. Neurosci. 9, 333–342.
Lockley S. W., Skene D. J., Arendt J., Tabandeh H., Bird A. C. and Defrance R. 1997 Relationship between melatonin rhythms and visual loss in the blind. J. Clin. Endocrinol. Metab. 82, 3763–3770.
Lowrey P. L., Shimomura K., Antoch M. P., Yamazaki S., Zemenides P. D., Ralph M. R. et al. 2000 Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492.
Matsuo M., Shino Y., Yamada N., Ozeki Y. and Okawa M. 2007 A novel SNP in hPer2 associates with diurnal preference in a healthy population. Sleep Biol. Rhythms 5, 141–145.
Meng Q. J., Logunova L., Maywood E. S., Gallego M., Lebiecki J., Brown T. M. et al. 2008 Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58, 78–88.
Nadkarni N. A., Weale M. E., von Schantz M. and Thomas M. G. 2005 Evolution of a length polymorphism in the human PER3 gene, a component of the circadian system. J. Biol. Rhythms 20, 490–499.
Naylor E., Bergmann B. M., Krauski K., Zee P. C., Takahashi J. S., Vitaterna M. H. and Turek F. W. 2000 The circadian clock mutation alters sleep homeostasis in the mouse. J. Neurosci. 20, 8138–8143.
Ohno S. 1970 Evolution by gene duplication. Springer, Berlin.
Partonen T., Treutlein J., Alpman A., Frank J., Johansson C., Depner M. et al. 2007 Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann. Med. 39, 229–238.
Pedrazzoli M., Louzada F. M., Pereira D. S., Benedito-Silva A. A., Lopez A. R., Martynhak B. J. et al. 2007 Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population. Chronobiol. Int. 24, 1–8.
Pereira D. S., Tufik S., Louzada F. M., Benedito-Silva A. A., Lopez A. R., Lemos N. A. et al. 2005 Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? Sleep 28, 29–32.
Preitner N., Damiola F., Lopez-Molina L., Zakany J., Duboule D., Albrecht U. and Schibler U. 2002 The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260.
Ralph M. R., Foster R. G., Davis F. C. and Menaker M. 1990 Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978.
Reick M., Garcia J. A., Dudley C. and McKnight S. L. 2001 NPAS2: an analog of clock operative in the mammalian forebrain. Science 293, 506–509.
Reid K. and Zee P. C. 2005 Circadian disorders of the sleep-wake cycle. In Principles and practice of sleep medicine (ed. M. H. Kryger, T. Roth and W. C. Dement), pp. 691–701. Elsevier Saunders, Philadelphia.
Robilliard D., Archer S. N., Arendt J., Lockley S. W., Hack L. M., English J. et al. 2002 The 3111Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. J. Sleep Res. 11, 305–312.
Roenneberg T., Wirz-Justice A. and Merrow M. 2003 Life between clocks: daily temporal patterns of human chronotypes. J. Biol. Rhythms 18, 80–90.
Roenneberg T., Kumar C. J. and Merrow M. 2007 The human circadian clock entrains to sun time. Curr. Biol. 17, R44–R45.
Satoh K., Mishima K., Inoue Y., Ebisawa T. and Shimizu T. 2003 Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 26, 416–417.
Scott E. M., Carter A. M. and Grant P. J. 2008 Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int. J. Obes. 32, 658–662.
Shearman L. P., Jin X., Lee C., Reppert S. M. and Weaver D. R. 2000 Targeted disruption of the mPer3 gene: subtle effects on circadian clock function. Mol. Cell. Biol. 20, 6269–6275.
Shiromani P. J., Xu M., Winston E. M., Shiromani S. N., Gerashchenko D. and Weaver D. R. 2004 Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R47–R57.
Sookoian S., Castano G., Gemma C., Gianotti T. F. and Pirola C. J. 2007 Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. World J. Gastroenterol. 13, 4242–4248.
Sun Y., Yang Z., Niu Z., Wang W., Peng J., Li Q. et al. 2006 The mortality ofMOP3 deficient mice with a systemic functional failure. J. Biomed. Sci. 13, 845–851.
Taillard J., Philip P., Chastang J. F. and Bioulac B. 2004 Validation of Horne and Östberg morningness-eveningness questionnaire in a middle-aged population of French workers. J. Biol. Rhythms. 19, 76–86.
Takahashi J. S., Hong H. K., Ko C. H. and McDearmon E. L. 2008 The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat. Rev. Genet. 9, 764–775.
Tauber E., Last K. S., Olive P. J. and Kyriacou C. P. 2004 Clock gene evolution and functional divergence. J. Biol. Rhythms 19, 445–458.
Toh K. L., Jones C. R., He Y., Eide E. J., Hinz W.A., Virshup D.M. et al. 2001 An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043.
Uchiyama M., Okawa M., Shibui K., Kim K., Tagaya H., Kudo Y. et al. 2000 Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep-wake syndrome in humans. Neurosci. Lett. 294, 101–104.
van der Horst G. T., Muijtjens M., Kobayashi K., Takano R., Kanno S., Takao M. et al. 1999 Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630.
Viola A. U., Archer S. N., James L. M., Groeger J. A., Lo J. C., Skene D. J. et al. 2007 PER3 polymorphism predicts sleep structure and waking performance. Curr. Biol. 17, 613–618.
Vitaterna M. H., King D. P., Chang A.-M., Kornhauser J. M., Lowrey P. L., McDonald J. D. et al. 1994 Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725.
Wisor J. P., O’Hara B. F., Terao A., Selby C. P., Kilduff T. S., Sancar A. et al. 2002 A role for cryptochromes in sleep regulation. BMC Neurosci. 3, 20.
Xu Y., Padiath Q. S., Shapiro R. E., Jones C. R., Wu S. C., Saigoh N. et al. 2005 Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644.
Yeh C. T., Lu S. C., Tseng I. C., Lai H. Y., Tsao M. L., Huang S. F. and Liaw Y. F. 2003 Antisense overexpression of BMAL2 enhances cell proliferation. Oncogene 22, 5306–5314.
Zhu Y., Brown H. N., Zhang Y., Stevens R. G. and Zheng T. 2005 Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol. Biomarkers Prev. 14, 268–270.
Zou Y., Liao G., Liu Y., Wang Y., Yang Z., Lin Y. et al. 2008 Association of the 54-nucleotide repeat polymorphism of hPer3 with heroin dependence in Han Chinese population. Genes Brain Behav. 7, 26–30.
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Von Schantz, M. Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters. J Genet 87, 513–519 (2008). https://doi.org/10.1007/s12041-008-0074-7
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DOI: https://doi.org/10.1007/s12041-008-0074-7