Gerland Ulrich, Hwa Terence
Department of Physics, University of California, San Diego, La Jolla, CA 92093-0319, USA.
J Mol Evol. 2002 Oct;55(4):386-400. doi: 10.1007/s00239-002-2335-z.
The mutation and selection of regulatory DNA sequences are presented as an ideal model system of molecular evolution where genotype, phenotype, and fitness can be explicitly and independently characterized. In this theoretical study, we construct an explicit model for the evolution of regulatory sequences, making use of the known biophysics of the binding of regulatory proteins to DNA sequences, under the assumption that fitness of a sequence depends only on its binding affinity to the regulatory protein. The model is confined to the mean field (i.e., infinite population size) limit. Using realistic values for all parameters, we determine the minimum fitness advantage needed to maintain a binding sequence, demonstrating explicitly the "error threshold" below which a binding sequence cannot survive the accumulated effect of mutation over long time. The commonly observed "fuzziness" in binding motifs arises naturally as a consequence of the balance between selection and mutation in our model. In addition, we devise a simple model for the evolution of multiple binding sequences in a given regulatory region. We find the number of evolutionarily stable binding sequences to increase in a step-like fashion with increasing fitness advantage, if multiple regulatory proteins can synergistically enhance gene transcription. We discuss possible experimental approaches to resolve open questions raised by our study.
调控DNA序列的突变与选择被视为分子进化的理想模型系统，在此系统中，基因型、表型和适应性能够得到明确且独立的表征。在这项理论研究中，我们利用调控蛋白与DNA序列结合的已知生物物理学知识，构建了一个调控序列进化的明确模型，假设序列的适应性仅取决于其与调控蛋白的结合亲和力。该模型局限于平均场（即无限种群规模）极限。使用所有参数的实际值，我们确定了维持结合序列所需的最小适应性优势，明确展示了“错误阈值”，低于此阈值，结合序列无法在长时间的突变累积效应下存活。我们模型中选择与突变之间的平衡自然导致了结合基序中常见的“模糊性”。此外，我们设计了一个给定调控区域内多个结合序列进化的简单模型。如果多个调控蛋白能够协同增强基因转录，我们发现进化稳定结合序列的数量会随着适应性优势的增加呈阶梯状增加。我们讨论了解决我们研究中提出的开放性问题的可能实验方法。
