TY - JOUR
T1 - Effects of DNA replication on mRNA noise
AU - Peterson, Joseph R.
AU - Cole, John A.
AU - Fei, Jingyi
AU - Ha, Taekjip
AU - Luthey-Schulten, Zaida A.
N1 - Funding Information:
We thank Dr. Rob Phillips and his laboratory for supplying the experimental mRNA data from ref. 23. We acknowledge the Texas Advanced Computing Center at The University of Texas at Austin for providing HPC resources that have contributed to the research results reported within this paper. This work is supported by the National Science Foundation (NSF) Graduate Research Fellowship Program under Grant DGE-1144245 (to J.R.P.), by the National Institutes of Health Grants GM112659 and 9 P41 GM104601-23, and by NSF (Center for the Physics of Living Cells) Grant PHY-1430124. T.H. is an investigator with the Howard Hughes Medical Institute. We acknowledge computing allocation (TG-MCA03S027) provided by Extreme Science and Engineering Discovery Environment, which is supported by NSF Grant ACI-1053575.
PY - 2015/12/29
Y1 - 2015/12/29
N2 - 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.
AB - 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.
KW - Analytical solutions
KW - Chromosome replication
KW - Master equation
KW - Stochastic gene expression
KW - Stochastic simulation
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U2 - 10.1073/pnas.1516246112
DO - 10.1073/pnas.1516246112
M3 - Article
C2 - 26669443
AN - SCOPUS:84952690966
SN - 0027-8424
VL - 112
SP - 15886
EP - 15891
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -