Using Simulations to Explore Genetic Networks

正在开发的计算机软件对基因网络进行非数学描述，将其转换为一组微分方程，然后求解方程，以揭示网络成分的浓度如何随时间变化。该程序包括搜索这些参数的值的设施，这些参数使网络产生所需的时空模式。人们发现了一条大大加快搜索速度的捷径：从一个简单的模型开始，这个模型只涉及果蝇的五个体节极性基因的产物，人们发现，这些基因之间最具特征的相互作用不能解释体节极性模式。这个最初的失败指向了几个意想不到的实验结果，并且由此产生的网络对参数值的变化具有惊人的鲁棒性。该网络也可以容易地产生，不同的参数值，除了生物片段极性模式的一些特征模式。这两个结果都可能具有进化意义。这项初步工作将扩大到包括下列目标：a）找出迄今为止发现的转录控制和转录后修饰机制如何以及是否联合收割机来解释在野生型和突变的苍蝇胚胎胚盘中观察到的该网络的时空模式化行为，B）实验测量对该模型的行为有关键影响的某些参数的值，c）通过实验测试由模型确定为所有重要环节的某些转录调节步骤，d）理解在发育后期和通过其他基因的参与进行修饰时，同样的网络建立了前/后室边界的成虫盘。调控基因转化为定量机制模型的方法已经被开发出来。将进行进一步的改进和实验测试。将继续开发并及时提供可作为发育生物学家研究和教学工具的软件。

Computer software being developed takes a non-mathematical description of a gene network, converts it into a set of differential equations, and then solves the equations to reveal how concentrations of network components change over time. The program includes facilities to search for values of these parameters that cause the network to produce the desired spatio-temporal pattern. A short cut which greatly speeds up the search has been found. Starting with a simple model involving products of just five of the segment polarity genes of Drosophila, it has been found that the best-characterized interactions between those genes could not account for the segment polarity pattern. This initial failure pointed to several unexpected experimental results and the resulting network is surprisingly robust to changes in parameter values. The network can also readily produce, with different parameter values, a few characteristic patterns other than the biological segment polarity pattern. Both of these results may have evolutionary implications. This preliminary work will be extended to encompass the following objectives: a) to find out how and if the transcriptional control and post-transcriptional modification mechanisms so far discovered combine to explain the observed spatio-temporal patterning behavior of this network in wild type and mutant fly embryo blastoderms, b) to experimentally measure the values of certain parameters that affect crucially this model's behavior, c) to experimentally test certain transcription regulation steps pinpointed by the model as all important links, d) to comprehend how, later in development and modified by participation of other genes, the same network establishes the anterior/posterior compartment boundary in imaginal discs.A computer simulation approach for integrating known interactions among cross-regulatory genes into a quantitative mechanistic model has been developed. Further refinement and experimental testing will be done. Software that will serve as a tool for developmental biologists in both research and teaching will be continued to be developed and made available in a timely fashion.