Genomics Research Center (one of The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
BMC Evol Biol. 2010 Sep 13;10:277. doi: 10.1186/1471-2148-10-277.
All life forms need both high genetic stability to survive as species and a degree of mutability to evolve for adaptation, but little is known about how the organisms balance the two seemingly conflicting aspects of life: genetic stability and mutability. The DNA mismatch repair (MMR) system is essential for maintaining genetic stability and defects in MMR lead to high mutability. Evolution is driven by genetic novelty, such as point mutation and lateral gene transfer, both of which require genetic mutability. However, normally a functional MMR system would strongly inhibit such genomic changes. Our previous work indicated that MMR gene allele conversion between functional and non-functional states through copy number changes of small tandem repeats could occur spontaneously via slipped-strand mis-pairing during DNA replication and therefore may play a role of genetic switches to modulate the bacterial mutability at the population level. The open question was: when the conversion from functional to defective MMR is prohibited, will bacteria still be able to evolve by accepting laterally transferred DNA or accumulating mutations?
To prohibit allele conversion, we "locked" the MMR genes through nucleotide replacements. We then scored changes in bacterial mutability and found that Salmonella strains with MMR locked at the functional state had significantly decreased mutability. To determine the generalizability of this kind of mutability 'switching' among a wider range of bacteria, we examined the distribution of tandem repeats within MMR genes in over 100 bacterial species and found that multiple genetic switches might exist in these bacteria and may spontaneously modulate bacterial mutability during evolution.
MMR allele conversion through repeats-mediated slipped-strand mis-pairing may function as a spontaneous mechanism to switch between high genetic stability and mutability during bacterial evolution.
所有生命形式都需要高度的遗传稳定性才能作为物种生存，同时也需要一定程度的可变性来适应进化，但对于生物体如何平衡遗传稳定性和可变性这两个看似矛盾的方面，人们知之甚少。DNA 错配修复（MMR）系统对于维持遗传稳定性至关重要，而 MMR 缺陷会导致高突变率。进化是由遗传新颖性驱动的，例如点突变和水平基因转移，两者都需要遗传可变性。然而，通常情况下，功能正常的 MMR 系统会强烈抑制这种基因组变化。我们之前的工作表明，通过小串联重复序列的拷贝数变化，MMR 基因等位基因可以在功能和非功能状态之间自发转换，这种转换是通过 DNA 复制过程中的单链滑动错配发生的，因此可能作为遗传开关在群体水平上调节细菌的可变性。目前仍存在一个悬而未决的问题：当从功能到缺陷 MMR 的转换被禁止时，细菌是否仍然能够通过接受水平转移的 DNA 或积累突变来进化？
为了禁止等位基因转换，我们通过核苷酸替换“锁定”了 MMR 基因。然后，我们对细菌可变性的变化进行了评分，发现 MMR 功能状态被锁定的沙门氏菌菌株的可变性显著降低。为了确定这种可变性“开关”在更广泛的细菌范围内的通用性，我们检查了超过 100 种细菌中 MMR 基因内串联重复的分布，发现这些细菌中可能存在多种遗传开关，并且在进化过程中可能会自发调节细菌的可变性。
通过重复介导的单链滑动错配的 MMR 等位基因转换可能是细菌进化过程中在高遗传稳定性和可变性之间切换的一种自发机制。
