Bull James J, Wilke Claus O
Institute for Cellular and Molecular Biology, Center for Computational Biology and Bioinformatics, University of Texas, Austin, Texas 78712, USA.
Genetics. 2008 Oct;180(2):1061-70. doi: 10.1534/genetics.108.091413. Epub 2008 Sep 9.
Lethal mutagenesis, the killing of a microbial pathogen with a chemical mutagen, is a potential broad-spectrum antiviral treatment. It operates by raising the genomic mutation rate to the point that the deleterious load causes the population to decline. Its use has been limited to RNA viruses because of their high intrinsic mutation rates. Microbes with DNA genomes, which include many viruses and bacteria, have not been considered for this type of treatment because their low intrinsic mutation rates seem difficult to elevate enough to cause extinction. Surprisingly, models of lethal mutagenesis indicate that bacteria may be candidates for lethal mutagenesis. In contrast to viruses, bacteria reproduce by binary fission, and this property ensures their extinction if subjected to a mutation rate >0.69 deleterious mutations per generation. The extinction threshold is further lowered when bacteria die from environmental causes, such as washout or host clearance. In practice, mutagenesis can require many generations before extinction is achieved, allowing the bacterial population to grow to large absolute numbers before the load of deleterious mutations causes the decline. Therefore, if effective treatment requires rapid population decline, mutation rates >>0.69 may be necessary to achieve treatment success. Implications for the treatment of bacteria with mutagens, for the evolution of mutator strains in bacterial populations, and also for the evolution of mutation rate in cancer are discussed.
致死性诱变，即用化学诱变剂杀死微生物病原体，是一种潜在的广谱抗病毒治疗方法。它的作用原理是将基因组突变率提高到有害负荷导致种群数量下降的程度。由于RNA病毒具有较高的固有突变率，其应用仅限于RNA病毒。具有DNA基因组的微生物，包括许多病毒和细菌，尚未被考虑用于这类治疗，因为它们较低的固有突变率似乎很难提高到足以导致灭绝的程度。令人惊讶的是，致死性诱变模型表明细菌可能是致死性诱变的候选对象。与病毒不同，细菌通过二分裂进行繁殖，并且如果每代受到>0.69个有害突变的突变率，这一特性将确保它们灭绝。当细菌因环境原因（如被冲走或被宿主清除）死亡时，灭绝阈值会进一步降低。在实际操作中，诱变可能需要许多代才能实现灭绝，这使得细菌种群在有害突变负荷导致数量下降之前能够增长到很大规模。因此，如果有效的治疗需要细菌种群数量迅速下降，可能需要>>0.69的突变率才能取得治疗成功。本文还讨论了诱变剂治疗细菌、细菌种群中突变菌株的进化以及癌症中突变率进化的相关问题。
