遗传中心的变异和选择的最优性
Optimality of mutation and selection in germinal centers
摘要：
B细胞在一个典型的生殖中心的种群动力学理论在揭示亲和力成熟是如何实现的方面可以发挥重要作用。然而，现有的模型遇到了一些冲突与实验。为了解决这些冲突，我们提出了一个粗粒度的模型来计算亲和力成熟过程中的B细胞群体发展，该模型允许对其参数空间进行全面分析，以寻找突变率、选择强度和初始抗体-抗原结合水平的最佳值，从而最大限度地提高亲和力。通过这些优化的参数，该模型与实验观察结果相容，例如~100倍亲和力改善、突变数量、超突变率和“全或无”现象。此外，我们研究了最佳参数背后的原因。与体内高突变率一致的最佳突变率是在积累足够的有益突变和避免太多的有害或致命突变之间的权衡的结果。最优选择强度作为亲和力改善的需要和通过群体瓶颈的要求之间的平衡而演变。这些发现指出了这样的结论，即通过进化已经优化了生发中心，以有效和快速地产生强亲和力抗体。此外，我们还研究了由于B细胞迁移在生发中心之间的迁移而导致的亲和力改善的增强。这些结果有助于我们进一步认识脑胚中心的功能。
英文摘要：
The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.
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