Abstract
Clock is a semidominant mutation identified from an N-ethyl-N-nitrosourea mutagenesis screen in mice. Mice carrying the Clock mutation exhibit abnormalities of circadian behavior, including lengthening of endogenous period and loss of rhythmicity. To identify the gene affected by this mutation, we have generated a high-resolution genetic map (>1800 meioses) of the Clock locus. We report that Clock is 0.7 cM distal of Kit on mouse chromosome 5. Mapping shows that Clock lies within the W(19H) deletion. Complementation analysis of different Clock and W(19H) compound genotypes indicates that the Clock mutation behaves as an antimorph. This antimorphic behavior of Clock strongly argues that Clock defines a gene centrally involved in the mammalian circadian system.
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- Antoch M. P., Song E. J., Chang A. M., Vitaterna M. H., Zhao Y., Wilsbacher L. D., Sangoram A. M., King D. P., Pinto L. H., Takahashi J. S. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell. 1997 May 16;89(4):655–667. doi: 10.1016/s0092-8674(00)80246-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aronson B. D., Johnson K. A., Loros J. J., Dunlap J. C. Negative feedback defining a circadian clock: autoregulation of the clock gene frequency. Science. 1994 Mar 18;263(5153):1578–1584. doi: 10.1126/science.8128244. [DOI] [PubMed] [Google Scholar]
- Baylies M. K., Bargiello T. A., Jackson F. R., Young M. W. Changes in abundance or structure of the per gene product can alter periodicity of the Drosophila clock. 1987 Mar 26-Apr 1Nature. 326(6111):390–392. doi: 10.1038/326390a0. [DOI] [PubMed] [Google Scholar]
- Brunkow M. E., Nagle D. L., Bernstein A., Bucan M. A 1.8-Mb YAC contig spanning three members of the receptor tyrosine kinase gene family (Pdgfra, Kit, and Flk1) on mouse chromosome 5. Genomics. 1995 Jan 20;25(2):421–432. doi: 10.1016/0888-7543(95)80042-k. [DOI] [PubMed] [Google Scholar]
- Copeland N. G., Jenkins N. A., Gilbert D. J., Eppig J. T., Maltais L. J., Miller J. C., Dietrich W. F., Weaver A., Lincoln S. E., Steen R. G. A genetic linkage map of the mouse: current applications and future prospects. Science. 1993 Oct 1;262(5130):57–66. doi: 10.1126/science.8211130. [DOI] [PubMed] [Google Scholar]
- DeBry R. W., Seldin M. F. Human/mouse homology relationships. Genomics. 1996 May 1;33(3):337–351. doi: 10.1006/geno.1996.0209. [DOI] [PubMed] [Google Scholar]
- Dickinson W. J. Molecules and morphology: where's the homology? Trends Genet. 1995 Apr;11(4):119–121. doi: 10.1016/s0168-9525(00)89015-0. [DOI] [PubMed] [Google Scholar]
- Dietrich W. F., Lander E. S., Smith J. S., Moser A. R., Gould K. A., Luongo C., Borenstein N., Dove W. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell. 1993 Nov 19;75(4):631–639. doi: 10.1016/0092-8674(93)90484-8. [DOI] [PubMed] [Google Scholar]
- Dietrich W. F., Miller J. C., Steen R. G., Merchant M., Damron D., Nahf R., Gross A., Joyce D. C., Wessel M., Dredge R. D. A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nat Genet. 1994 Jun;7(2 Spec No):220–245. doi: 10.1038/ng0694supp-220. [DOI] [PubMed] [Google Scholar]
- Dietrich W. F., Miller J., Steen R., Merchant M. A., Damron-Boles D., Husain Z., Dredge R., Daly M. J., Ingalls K. A., O'Connor T. J. A comprehensive genetic map of the mouse genome. Nature. 1996 Mar 14;380(6570):149–152. doi: 10.1038/380149a0. [DOI] [PubMed] [Google Scholar]
- Dietrich W., Katz H., Lincoln S. E., Shin H. S., Friedman J., Dracopoli N. C., Lander E. S. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992 Jun;131(2):423–447. doi: 10.1093/genetics/131.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dunlap J. C. Genetic analysis of circadian clocks. Annu Rev Physiol. 1993;55:683–728. doi: 10.1146/annurev.ph.55.030193.003343. [DOI] [PubMed] [Google Scholar]
- Dunlap J. C. Genetics and molecular analysis of circadian rhythms. Annu Rev Genet. 1996;30:579–601. doi: 10.1146/annurev.genet.30.1.579. [DOI] [PubMed] [Google Scholar]
- Duttlinger R., Manova K., Berrozpe G., Chu T. Y., DeLeon V., Timokhina I., Chaganti R. S., Zelenetz A. D., Bachvarova R. F., Besmer P. The Wsh and Ph mutations affect the c-kit expression profile: c-kit misexpression in embryogenesis impairs melanogenesis in Wsh and Ph mutant mice. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3754–3758. doi: 10.1073/pnas.92.9.3754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feldman J. F., Hoyle M. N. Isolation of circadian clock mutants of Neurospora crassa. Genetics. 1973 Dec;75(4):605–613. doi: 10.1093/genetics/75.4.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geissler E. N., Cheng S. V., Gusella J. F., Housman D. E. Genetic analysis of the dominant white-spotting (W) region on mouse chromosome 5: identification of cloned DNA markers near W. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9635–9639. doi: 10.1073/pnas.85.24.9635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geissler E. N., Ryan M. A., Housman D. E. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell. 1988 Oct 7;55(1):185–192. doi: 10.1016/0092-8674(88)90020-7. [DOI] [PubMed] [Google Scholar]
- Haldi M. L., Strickland C., Lim P., VanBerkel V., Chen X., Noya D., Korenberg J. R., Husain Z., Miller J., Lander E. S. A comprehensive large-insert yeast artificial chromosome library for physical mapping of the mouse genome. Mamm Genome. 1996 Oct;7(10):767–769. doi: 10.1007/s003359900228. [DOI] [PubMed] [Google Scholar]
- Hall J. C. Genetics of circadian rhythms. Annu Rev Genet. 1990;24:659–697. doi: 10.1146/annurev.ge.24.120190.003303. [DOI] [PubMed] [Google Scholar]
- Konopka R. J., Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1971 Sep;68(9):2112–2116. doi: 10.1073/pnas.68.9.2112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Konopka R. J., Hamblen-Coyle M. J., Jamison C. F., Hall J. C. An ultrashort clock mutation at the period locus of Drosophila melanogaster that reveals some new features of the fly's circadian system. J Biol Rhythms. 1994 Winter;9(3-4):189–216. doi: 10.1177/074873049400900303. [DOI] [PubMed] [Google Scholar]
- Kozak C. A., Bucan M., Goffinet A., Stephenson D. A. Encyclopedia of the mouse genome V. Mouse chromosome 5. Mamm Genome. 1996;6(Spec No):S97–112. [PubMed] [Google Scholar]
- Lyon M. F., Glenister P. H., Loutit J. F., Evans E. P., Peters J. A presumed deletion covering the W and Ph loci of the mouse. Genet Res. 1984 Oct;44(2):161–168. doi: 10.1017/s0016672300026367. [DOI] [PubMed] [Google Scholar]
- Manly K. F. A Macintosh program for storage and analysis of experimental genetic mapping data. Mamm Genome. 1993;4(6):303–313. doi: 10.1007/BF00357089. [DOI] [PubMed] [Google Scholar]
- McClung C. R., Fox B. A., Dunlap J. C. The Neurospora clock gene frequency shares a sequence element with the Drosophila clock gene period. Nature. 1989 Jun 15;339(6225):558–562. doi: 10.1038/339558a0. [DOI] [PubMed] [Google Scholar]
- Moser A. R., Pitot H. C., Dove W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990 Jan 19;247(4940):322–324. doi: 10.1126/science.2296722. [DOI] [PubMed] [Google Scholar]
- 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. 1995 Nov 3;270(5237):805–808. doi: 10.1126/science.270.5237.805. [DOI] [PubMed] [Google Scholar]
- Okazaki Y., Okuizumi H., Ohsumi T., Nomura O., Takada S., Kamiya M., Sasaki N., Matsuda Y., Nishimura M., Tagaya O. A genetic linkage map of the Syrian hamster and localization of cardiomyopathy locus on chromosome 9qa2.1-b1 using RLGS spot-mapping. Nat Genet. 1996 May;13(1):87–90. doi: 10.1038/ng0596-87. [DOI] [PubMed] [Google Scholar]
- 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. 1994 Mar 18;263(5153):1603–1606. doi: 10.1126/science.8128246. [DOI] [PubMed] [Google Scholar]
- Smith E. A., Seldin M. F., Martinez L., Watson M. L., Choudhury G. G., Lalley P. A., Pierce J., Aaronson S., Barker J., Naylor S. L. Mouse platelet-derived growth factor receptor alpha gene is deleted in W19H and patch mutations on chromosome 5. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4811–4815. doi: 10.1073/pnas.88.11.4811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stephenson D. A., Mercola M., Anderson E., Wang C. Y., Stiles C. D., Bowen-Pope D. F., Chapman V. M. Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):6–10. doi: 10.1073/pnas.88.1.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takahashi J. S. Molecular neurobiology and genetics of circadian rhythms in mammals. Annu Rev Neurosci. 1995;18:531–553. doi: 10.1146/annurev.ne.18.030195.002531. [DOI] [PubMed] [Google Scholar]
- Takahashi J. S., Pinto L. H., Vitaterna M. H. Forward and reverse genetic approaches to behavior in the mouse. Science. 1994 Jun 17;264(5166):1724–1733. doi: 10.1126/science.8209253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vitaterna M. H., King D. P., Chang A. M., Kornhauser J. M., Lowrey P. L., McDonald J. D., Dove W. F., Pinto L. H., Turek F. W., Takahashi J. S. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science. 1994 Apr 29;264(5159):719–725. doi: 10.1126/science.8171325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wehr T. A., Rosenthal N. E. Seasonality and affective illness. Am J Psychiatry. 1989 Jul;146(7):829–839. doi: 10.1176/ajp.146.7.829. [DOI] [PubMed] [Google Scholar]
- Yu Q., Jacquier A. C., Citri Y., Hamblen M., Hall J. C., Rosbash M. Molecular mapping of point mutations in the period gene that stop or speed up biological clocks in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1987 Feb;84(3):784–788. doi: 10.1073/pnas.84.3.784. [DOI] [PMC free article] [PubMed] [Google Scholar]