Adaptive Mutations: A Consequence of Prokaryotic Differentiation

1988年，约翰·凯恩斯和他的合作者发现了所谓的“适应性突变”。这些观察结果后来得到一系列研究人员的支持，表明一些突变是针对特定的环境挑战或情况而产生的。产生这些“适应性突变体”的机制的本质已经引起了激烈的争论。现在看来，这些突变是分化为高度可变状态的细胞亚群的结果。这种分化的遗传控制尚未阐明。对细菌枯草芽孢杆菌模型系统的初步研究表明，在该生物中，调节高度可变状态发展的遗传机制(S)与调节产孢子和竞争能力(摄取胞外DNA)的机制重叠。这个项目将利用孢子形成和能力发展过程的遗传控制知识来描述负责产生“适应性突变”的分子机制。利用目前已有的信息，产生“适应性”突变的一个可行假设是，在压力下，一小部分细胞分化为高度可变状态，而这些细胞缺乏功能上的DNA错配修复系统。这个项目的研究旨在利用已经开发的遗传和分子生物学技术来检验这一假设，这些技术已经被开发用于分析革兰氏阳性芽胞形成菌枯草芽孢杆菌的分化。描述这一系统对于我们理解压力诱导的遗传多样性机制在物种中所起的作用至关重要。

In 1988, John Cairns and his collaborators discovered so-called "adaptive mutations" These observations, later enhanced by a series of investigators, suggested that some mutants arose in response to specific environmental challenges or situations. The nature of the mechanism that generates these "adaptive mutants" has been hotly debated. It now appears that these mutations are the result of a sub-population of cells that differentiate into a hypermutable state. The genetic control for this differentiation has not yet been elucidated. Preliminary investigations with the bacterial Bacillus subtilis model system indicate that in this organism the genetic mechanism(s) that regulate the development of the hypermutable state overlap with the mechanisms that regulate the processes of sporulation and competence (uptake of extracellular DNA). This project will utilize the knowledge of the genetic control of the processes of sporulation and competence development to delineate the molecular mechanisms responsible for the generation of "adaptive mutations." Using the information that is currently available, a working hypothesis for the generation of "adaptive" mutations would be that under stress, a small subset of cells differentiate into a hypermutable state, and these cells lack a functional DNA mismatch repair system. The research in this project is aimed at testing this hypothesis by utilizing the genetic and molecular biological techniques that have been developed for analyzing differentiation in the Gram-positive, spore forming bacterium Bacillus subtilis. Delineating this system is critical to our understanding of the role played by stress-induced genetic diversity mechanisms in species