Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Circadian rhythm genetics: from flies to mice to humans

Nature Genetics volume 26, pages 23–27 (2000)Cite this article

Abstract

A successful genetic dissection of the circadian regulation of behaviour has been achieved through phenotype-driven mutagenesis screens in flies and mice. Cloning and biochemical analysis of these evolutionarily conserved proteins has led to detailed molecular insight into the clock mechanism. Few behaviours enjoy the degree of understanding that exists for circadian rhythms at the genetic, cellular and anatomical levels. The circadian clock has so eagerly spilled her secrets that we may soon know the unbroken chain of events from gene to behaviour. It will likely be fruitful to wield this uncommon degree of knowledge to attack one of the most challenging problems in genetics: the basis of complex human behavioural disorders. We review here the genetic screens that provided the entreé into the heart of the circadian clock, the model of the clock mechanism that has resulted, and the prospects for using the homologues as candidate genes in studies of human circadian dysrhythmias.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sequence of intracellular events at the core of the circadian clock.
Figure 2: Animal model of a human behavioural disorder.

Similar content being viewed by others

References

  1. Hastings, M. & Maywood, E.S. Circadian clocks in the mammalian brain. Bioessays 22, 23–31 (2000).

    Article  CAS  Google Scholar 

  2. King, D.P. & Takahashi, J.S. Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713–742 (2000).

    Article  CAS  Google Scholar 

  3. Sakamoto, K. et al. Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. J. Biol. Chem. 273, 27039–27042 (1998).

    Article  CAS  Google Scholar 

  4. Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000).

    Article  CAS  Google Scholar 

  5. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    Article  CAS  Google Scholar 

  6. Akashi, M. & Nishida, E. Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev. 14, 645–649 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Dunlap, J.C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999).

    Article  CAS  Google Scholar 

  8. Hall, J.C. Genetics of biological rhythms in drosophila. Adv. Genet. 38, 135–184 (1998).

    Article  CAS  Google Scholar 

  9. Sehgal, A., Price, J.L., Man, B. & Young, M.W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–1606 (1994).

    Article  CAS  Google Scholar 

  10. Price, J.L. et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95 (1998).

    Article  CAS  Google Scholar 

  11. Allada, R., White, N.E., So, W.V., Hall, J.C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791–804 (1998).

    Article  CAS  Google Scholar 

  12. Rutila, J.E. et al. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–814 (1998).

    Article  CAS  Google Scholar 

  13. Rutila, J.E. et al. The timSL mutant of the Drosophila rhythm gene timeless manifests allele-specific interactions with period gene mutants. Neuron 17, 921–929 (1996).

    Article  CAS  Google Scholar 

  14. Stanewsky, R. et al. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell 95, 681–692 (1998).

    Article  CAS  Google Scholar 

  15. Newby, L.M. & Jackson, F.R. A new biological rhythm mutant of Drosophila melanogaster that identifies a gene with an essential embryonic function. Genetics 135, 1077–1090 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rothenfluh, A., Young, M.W. & Saez, L. A timeless-independent function for period proteins in the Drosophila clock. Neuron 26, 505–514 (2000).

    Article  CAS  Google Scholar 

  17. Konopka, R.J. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971).

    Article  CAS  Google Scholar 

  18. Vitaterna, M.H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725 (1994).

    Article  CAS  Google Scholar 

  19. Lowrey, P.L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492 (2000).

    Article  CAS  Google Scholar 

  20. Darlington, T.K. et al. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280, 1599–1603 (1998).

    Article  CAS  Google Scholar 

  21. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    Article  CAS  Google Scholar 

  22. Hogenesch, J.B., Gu, Y.Z., Jain, S. & Bradfield, C.A. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    Article  CAS  Google Scholar 

  23. Ralph, M.R. & Menaker, M. A mutation of the circadian system in golden hamsters. Science 241, 1225–1227 (1988).

    Article  CAS  Google Scholar 

  24. Hamblen, M.J., White, N.E., Emery, P.T., Kaiser, K. & Hall, J.C. Molecular and behavioral analysis of four period mutants in Drosophila melanogaster encompassing extreme short, novel long, and unorthodox arrhythmic types. Genetics 149, 165–178 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Myers, M.P., Wager-Smith, K., Wesley, C.S., Young, M.W. & Sehgal, A. Positional cloning and sequence analysis of the Drosophila clock gene, timeless. Science 270, 805–808 (1995).

    Article  CAS  Google Scholar 

  26. Yu, Q. et al. Molecular mapping of point mutations in the period gene that stop or speed up biological clocks in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 84, 784–788 (1987).

    Article  CAS  Google Scholar 

  27. Renn, S.C., Park, J.H., Rosbash, M., Hall, J.C. & Taghert, P.H. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99, 791–802 (1999).

    Article  CAS  Google Scholar 

  28. Hochgeschwender, U. & Brennan, M.B. The impact of genomics on mammalian neurobiology. Bioessays 21, 157–163 (1999).

    Article  CAS  Google Scholar 

  29. Scully, A.L. & Kay, S.A. Time flies for Drosophila. Cell 100, 297–300 (2000).

    Article  CAS  Google Scholar 

  30. Suri, V., Lanjuin, A. & Rosbash, M. TIMELESS-dependent positive and negative autoregulation in the Drosophila circadian clock. EMBO J. 18, 675–686 (1999).

    Article  CAS  Google Scholar 

  31. Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57–68 (1999).

    Article  CAS  Google Scholar 

  32. Ripperger, J.A., Shearman, L.P., Reppert, S.M. & Schibler, U. CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. Genes Dev. 14, 679–689 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lakin-Thomas, P.L. Circadian rhythms: new functions for old clock genes. Trends Genet. 16,135–142 (2000).

    Article  CAS  Google Scholar 

  34. Keesler, G.A. et al. Phosphorylation and destabilization of human period I clock protein by human casein kinase I ɛ. Neuroreport 11, 951–955 (2000).

    Article  CAS  Google Scholar 

  35. Hardin, P.E. & Glossop, N.R. Perspectives: neurobiology. The CRYs of flies and mice. Science 286, 2460–2461 (1999).

    Article  CAS  Google Scholar 

  36. Akiyama, M. et al. Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms. J. Neurosci. 19, 1115–1121 (1999).

    Article  CAS  Google Scholar 

  37. Suri, V., Qian, Z., Hall, J.C. & Rosbash, M. Evidence that the TIM light response is relevant to light-induced phase shifts in Drosophila melanogaster. Neuron 21, 225–234 (1998).

    Article  CAS  Google Scholar 

  38. Yang, Z., Emerson, M., Su, H.S. & Sehgal, A. Response of the timeless protein to light correlates with behavioral entrainment and suggests a nonvisual pathway for circadian photoreception. Neuron 21, 215–223 (1998).

    Article  CAS  Google Scholar 

  39. Vitaterna, M.H. et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl Acad. Sci. USA 96, 12114–12119 (1999).

    Article  CAS  Google Scholar 

  40. Blau, J. & Young, M.W. Cycling vrille expression is required for a functional Drosophila clock. Cell 99, 661–671 (1999).

    Article  CAS  Google Scholar 

  41. Park, J.H. et al. Differential regulation of circadian pacemaker output by separate clock genes in drosophila. Proc. Natl Acad. Sci. USA 97, 3608–3613 (2000).

    Article  CAS  Google Scholar 

  42. Franken, P., Lopez-Molina, L., Marcacci, L., Schibler, U. & Tafti, M. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity. J. Neurosci. 20, 617–625 (2000).

    Article  CAS  Google Scholar 

  43. Lopez-Molina, L., Conquet, F., Dubois-Dauphin, M. & Schibler, U. The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. EMBO J. 16, 6762–6771 (1997).

    Article  CAS  Google Scholar 

  44. McNeil, G.P., Zhang, X., Genova, G. & Jackson, F.R. A molecular rhythm mediating circadian clock output in Drosophila. Neuron 20, 297–303 (1998).

    Article  CAS  Google Scholar 

  45. Osiel, S., Golombek, D.A. & Ralph, M.R. Conservation of locomotor behavior in the golden hamster: effects of light cycle and a circadian period mutation. Physiol. Behav. 65, 123–131 (1998).

    Article  CAS  Google Scholar 

  46. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, DSM-IV (American Psychiatric Association, Washington DC, 1994).

  47. Bunney, W.E. & Bunney, B.G. Molecular clock genes in man and lower animals. Possible implications for circadian abnormalities in depression. Neuropsychopharmacology 22, 335–345 (2000).

    Article  CAS  Google Scholar 

  48. American Sleep Disorders Association The International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual (American Sleep Disorders Association, Rochester, Minnesota, 1997).

  49. Hamblen-Coyle, M.J., Wheeler, D.A., Rutila, J.E., Rosbash, M. & Hall, J.C. Behavior of period-altered circadian rhythm mutants of Drosophila in light:dark cycles. J. Insect Behav. 5, 417–446 (1992).

    Article  Google Scholar 

  50. Katzenberg, D. et al. A CLOCK polymorphism associated with human diurnal preference. Sleep 21, 569–576 (1998).

    Article  CAS  Google Scholar 

  51. Jones, C.R. et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nature Med. 5, 1062–1065 (1999).

    Article  CAS  Google Scholar 

  52. Earnest, D.J., Liang, F.Q., Ratcliff, M. & Cassone, V.M. Immortal time: circadian clock properties of rat suprachiasmatic cell lines. Science 283, 693–695 (1999).

    Article  CAS  Google Scholar 

  53. Moldofsky, H., Musisi, S. & Phillipson, E.A. Treatment of a case of advanced sleep phase syndrome by phase advance chronotherapy. Sleep 9, 61–65 (1986).

    Article  CAS  Google Scholar 

  54. Zheng, B. et al. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400, 169–173 (1999).

    Article  CAS  Google Scholar 

  55. Czeisler, C.A. et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284, 2177–2181 (1999).

    Article  CAS  Google Scholar 

  56. Wheeler, D.A., Hamblen-Coyle, M.J., Dushay, M.S. & Hall, J.C. Behavior in light-dark cycles of Drosophila mutants that are arrhythmic, blind, or both. J. Biol. Rhythms 8, 67–94 (1993).

    Article  CAS  Google Scholar 

  57. Emery, P., Stanewsky, R., Hall, J.C. & Rosbash, M. A unique circadian rhythm photoreceptor. Nature 404, 456–457 (2000).

    Article  CAS  Google Scholar 

  58. Thresher, R.J. et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998).

    Article  CAS  Google Scholar 

  59. van der Horst, G.T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Mayford and F. Ceriani for suggestions.

Author information

Authors and Affiliations

  1. Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA

    Karen Wager-Smith & Steve A. Kay

  2. NSF Center for Biological Timing, USA

    Karen Wager-Smith & Steve A. Kay

Authors
  1. Karen Wager-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steve A. Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steve A. Kay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wager-Smith, K., Kay, S. Circadian rhythm genetics: from flies to mice to humans. Nat Genet 26, 23–27 (2000). https://doi.org/10.1038/79134

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79134

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing