A detailed predictive model of the mammalian circadian clock

Abstract

Experimental data on the circadian (≈24-h) clock in mammalian cells are vast, diverse, and detailed. Mathematical models are therefore needed to piece these data together and to study overall clock behavior. Previous models have focused on Neurospora or Drosophila or can be converted to a Drosophila model simply by renaming variables. Those models used Hill-type terms for transcription regulation and Michaelis–Menten type or delay terms for posttranslation regulation. Recent mammalian experimental data call into question some of the assumptions in these approaches. Moreover, gene duplication has led to more proteins in the mammalian system than in lower organisms. Here we develop a detailed distinctly mammalian model by using mass action kinetics. Parameters for our model are found from experimental data by using a coordinate search method. The model accurately predicts the phase of entrainment, amplitude of oscillation, and shape of time profiles of clock mRNAs and proteins and is also robust to parameter changes and mutations.