Sustained Limit Cycles in the Logistic Two-Gene Genetic Oscillator: A Delay-Driven Hopf Bifurcation
逻辑双基因遗传振荡器中的持续极限环:延迟驱动的Hopf分岔
Ismail Belgacem
AI总结 本文研究了具有转录延迟的逻辑斯蒂双基因负反馈振荡器的持续极限环行为,揭示了延迟驱动的Hopf分岔机制。通过引入转录延迟并分析雅可比矩阵的迹,证明当总延迟超过临界值时系统失去稳定性并产生周期振荡,给出了Hopf分岔频率和临界延迟的显式表达式。研究还展示了振荡幅值与延迟的关系,并通过数值模拟验证了理论结果,为理解生物节律等现象提供了数学基础。
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逻辑双基因负反馈振荡器对所有生物参数值都是局部渐近稳定的,因为雅可比矩阵的迹一致为负。然而,真实的生物振荡器(昼夜节律、分节时钟、Hes1、p53)依赖于延迟。我们将逻辑双基因模型扩展为具有转录延迟$τ_1$和$τ_2$的延迟微分系统,并证明当总延迟$τ=τ_1+τ_2$穿过显式临界值$τ_c$时,平衡点通过Hopf分岔失去稳定性。Hopf频率$ω_c$和$τ_c$由逻辑导数以闭式形式计算;环路增益条件$AB>γ_1γ_2$是充分必要的;横截性条件$\mathrm{Re}(dμ/dτ)|_{τ_c}>0$具有参数一致的正下界;并且分岔全局持续。延迟之和的对称性将分析简化为标量参数$τ$。数值模拟确认了三个区域(阻尼、小极限环、松弛),超临界振幅标度$A\sim c\sqrt{τ-τ_c}$,以及深松弛周期渐近$T\sim 2τ+C_\infty$,其中偏移量$C_\infty$为闭式。对于对称阈值环路,通过Lindstedt-Poincaré约化证明超临界性,得到闭式振幅和频率定律;对于一般非对称环路,它给出闭式第一李雅普诺夫系数和显式临界性判据。校准至p53-Mdm2数据后,闭式Hopf周期与观测振荡的误差在3%以内,与标准Hill函数模型的误差在几个百分点内。该分析扩展到循环$N$基因环路,具有闭式横截性率(对每个$N$有效),并且在对称情况下,显式的延迟诱导Hopf窗口为$γ^N<Λ<γ^N\sec^N(π/N)$。
The logistic two-gene negative-feedback oscillator is locally asymptotically stable for all biological parameter values, since the trace of the Jacobian is uniformly negative. Real biological oscillators (circadian rhythms, the segmentation clock, Hes1, p53) nevertheless rely on delays. We extend the logistic two-gene model to a delay-differential system with transcriptional delays $τ_1$ and $τ_2$, and prove that the equilibrium loses stability through a Hopf bifurcation as the total delay $τ=τ_1+τ_2$ crosses an explicit critical value $τ_c$. The Hopf frequency $ω_c$ and $τ_c$ are computed in closed form from the logistic derivatives; the loop-gain condition $AB>γ_1γ_2$ is necessary and sufficient; the transversality $\mathrm{Re}(dμ/dτ)|_{τ_c}>0$ admits a parameter-uniform positive lower bound; and the bifurcation persists globally. A sum-of-delays symmetry reduces the analysis to the scalar parameter $τ$. Numerical simulations confirm three regimes (damped, small limit cycle, relaxation), the supercritical amplitude scaling $A\sim c\sqrt{τ-τ_c}$, and the deep-relaxation period asymptote $T\sim 2τ+C_\infty$ with closed-form offset $C_\infty$. For the symmetric-threshold loop, supercriticality is proved by a Lindstedt--Poincaré reduction yielding closed-form amplitude and frequency laws; for the general asymmetric loop it delivers a closed-form first Lyapunov coefficient and an explicit criticality criterion. Calibrated to p53--Mdm2 data, the closed-form Hopf period matches the observed oscillation within $3\%$, and the standard Hill-function model within a few percent. The analysis extends to cyclic $N$-gene loops, with a closed-form transversality rate valid for every $N$ and -- in the symmetric case -- an explicit delay-induced-Hopf window $γ^N<Λ<γ^N\sec^N(π/N)$.