title: Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder.
abstract: OBJECTIVE
  To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression.
  
  
  METHODS
  Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position -874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence.
  
  
  METHODS
  N/A.
  
  
  METHODS
  DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n=23).
  
  
  METHODS
  N/A.
  
  
  RESULTS
  We verified three single nucleotide polymorphisms (G -320T, C -319A, G -294A), and found a novel variable number tandem repeat (VNTR) polymorphism (-318 1/2 VNTR). The -320T and -319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (-703 to -605, and -283 to -80).
  
  
  CONCLUSIONS
  Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.
authors.affiliation: Faculty of Health and Medical Sciences, University ofSurrey, Guildford, Surrey, UK. simon.archer@surrey.ac.uk
authors.forename: Simon N
authors.initials: SN
authors.lastname: Archer
authors.forename: Jayshan D
authors.initials: JD
authors.lastname: Carpen
authors.forename: Mark
authors.initials: M
authors.lastname: Gibson
authors.forename: Gim Hui
authors.initials: GH
authors.lastname: Lim
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Johnston
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Skene
authors.forename: Malcolm
authors.initials: M
authors.lastname: von Schantz
mesh_terms: D000328:Adult; D000483:Alleles; D002940:Circadian Rhythm / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D056950:Period Circadian Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics*; D020080:Tandem Repeat Sequences / Q000235:genetics
chemical_list: C512644:PER3 protein, human; D056950:Period Circadian Proteins; D004247:DNA; D008156:Luciferases
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