Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC

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Fine-Tuning the Clock The Relationship Between Variability in Per3 and Circadian Phenotype in Mammals

Malcolm von Schantz1, Donna Robilliard1, Oliver Wood1, Marcel Smits2, Adrian Williams3, Debra J Skene1, Jo Arendt1, and Simon N Archer1
1Centre for Chronobiology, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK; 2Department of Neurology and Sleep-Wake Disorders, Hospital de Gelderse Vallei, 6710 Ede, the Netherlands; 3Lane Fox Unit, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
Telephone: 01144-1483-686468
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Circadian rhythms are an attractive system for studying the relationship between genotype and phenotype because they are created by a set of genes that are mostly uniquely dedicated to the process. In addition to the limited number of genes involved, and the limited and mostly controllable number of confounding factors between genotype and phenotype, the amenability of this system is increased by the fact that phenotype can also be determined non-invasively and quantitatively through parameters such as free-running period length (tau) and morning/evening (diurnal) preference.

The Period (Per) genes are a central part of the molecular machinery that creates circadian rhythms in animals. Initially identified in mutant Drosophila with abnormal circadian rhythms, Per genes were identified in mammals through RT-PCR with nested degenerated primers against putative conserved domains, and three orthologues have been identified in mammals, Per1, 2, and 3. Period genes have also been cloned from birds, zebrafish, and Xenopus.

Whilst the roles of Per1 and 2 in mammals are clearly defined, by knockout mouse studies, the function of Per3 remains harder to define. Per3 knockouts display a circadian period length only half an hour shorter than the wildtype. However, polymorphisms in Per3 have been reported in human subjects and they have been suggested to be associated with delayed sleep phase syndrome (DSPS).

We have analysed inter- and intraspecific variability in the Per3 gene, and have identified a region with particular variability, a stretch of tandem amino acid cluster repeats that is present in human but partially absent in murine Per3. We demonstrated a polymorphism in this region between mouse strains displaying different tau. We also showed that a polymorphism in the number of amino acid cluster repeats associates with diurnal preference in human subjects. Bioinformatic analysis showed that this polymorphic region contains recognition patterns for phosphorylation both by casein kinase e, which was previously known to be intimately involved in the regulation of circadian rhythms, and glycogen synthase kinase 3, which was not. In vitro phosphorylation experiments showed that PER3 is phosphorylated by both kinases. We hypothesise that this region of Per3 is important for the fine-tuning of circadian rhythms, both in terms of intraspecific variability and in terms of the genetic differences that makes species diurnal and nocturnal.

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