title: Effects of DNA replication on mRNA noise.
abstract: There are several sources of fluctuations in gene expression. Here we study the effects of time-dependent DNA replication, itself a tightly controlled process, on noise in mRNA levels. Stochastic simulations of constitutive and regulated gene expression are used to analyze the time-averaged mean and variation in each case. The simulations demonstrate that to capture mRNA distributions correctly, chromosome replication must be realistically modeled. Slow relaxation of mRNA from the low copy number steady state before gene replication to the high steady state after replication is set by the transcript's half-life and contributes significantly to the shape of the mRNA distribution. Consequently both the intrinsic kinetics and the gene location play an important role in accounting for the mRNA average and variance. Exact analytic expressions for moments of the mRNA distributions that depend on the DNA copy number, gene location, cell doubling time, and the rates of transcription and degradation are derived for the case of constitutive expression and subsequently extended to provide approximate corrections for regulated expression and RNA polymerase variability. Comparisons of the simulated models and analytical expressions to experimentally measured mRNA distributions show that they better capture the physics of the system than previous theories.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Peterson
authors.affiliation: Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: John A
authors.initials: JA
authors.lastname: Cole
authors.affiliation: Carl Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Jingyi
authors.initials: J
authors.lastname: Fei
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Taekjip
authors.initials: T
authors.lastname: Ha
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Carl Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801; zan@illinois.edu.
authors.forename: Zaida A
authors.initials: ZA
authors.lastname: Luthey-Schulten
mesh_terms: D000465:Algorithms; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D018628:Gene Dosage; D005786:Gene Expression Regulation; D007700:Kinetics; D008957:Models, Genetic; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D013269:Stochastic Processes; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D004247:DNA; D012321:DNA-Directed RNA Polymerases
keywords: analytical solutions; chromosome replication; master equation; stochastic gene expression; stochastic simulation