Effective polyploidy causes phenotypic delay and influences bacterial evolvability.
Effective polyploidy causes phenotypic delay and influences bacterial evolvability.
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DOI：
10.1371/journal.pbio.2004644
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发表时间：
2018-03
期刊：
影响因子：
9.8
通讯作者：
Bonhoeffer S
中科院分区：
文献类型：
--
作者：
Sun L;Alexander HK;Bogos B;Kiviet DJ;Ackermann M;Bonhoeffer S
在20世纪40年代至50年代，细菌中的突变是否在表达其相应的突变表型之前表现出明显的延迟进行了深入讨论，但由于缺乏支持性证据以及与波动测试中观察到的突变分布不相容，讨论最终减弱。尽管缺乏直接证据，但人们普遍认为细菌的表型延迟可以忽略不计。在这里，我们重新讨论了利用重组工程将抗生素抗性突变引入大肠杆菌的问题。coli中，然后随时间追踪相应突变表型的表达。与先前的假设相反，我们发现了三到四代的大量中位数表型延迟。我们提供的证据表明，这种延迟的主要来源是多叉复制导致细胞有效地多倍体，从而野生型基因拷贝瞬时掩盖了同一细胞中隐性突变基因拷贝的表型。使用建模和模拟的方法，我们探讨了波动测试和测序为基础的方法估计突变率的有效多倍性的后果。对于隐性突变，尽管存在显著的表型延迟，但可以准确估计每个拷贝或每个基因组的突变率。然而，每个小区的速率不能通过现有的方法来估计。最后，通过一个数学模型，我们发现有效的多倍性增加了常设遗传变异（SGV）中代价高昂的隐性突变的频率，从而增加了它们对进化适应的潜在贡献，同时大大降低了从头隐性突变拯救面临严峻环境变化（如抗生素治疗）的种群的机会。总的来说，我们已经确定了表型延迟和有效的多倍性作为以前被忽视的，但在细菌的进化，包括抗生素耐药性的演变的重要组成部分。在细菌细胞中发生基因突变和表现其表型效应之间的时间延迟是多少？我们发现，大肠杆菌中的抗生素耐药性突变显示出三到四代细菌的显着长的表型延迟。这种延迟的主要潜在机制是有效的多倍性。如果突变发生在多倍体细胞的多条染色体中的一条上，则其他染色体上未突变的野生型基因拷贝的存在可能掩盖突变的表型。我们在这里表明，突变率估计需要考虑多倍性，这影响了细菌适应的潜力。一个新的突变可能只在“曾曾孙辈”中有用，这一事实表明，预先存在的突变对于在突发的环境灾难中生存更为重要。
Whether mutations in bacteria exhibit a noticeable delay before expressing their corresponding mutant phenotype was discussed intensively in the 1940s to 1950s, but the discussion eventually waned for lack of supportive evidence and perceived incompatibility with observed mutant distributions in fluctuation tests. Phenotypic delay in bacteria is widely assumed to be negligible, despite the lack of direct evidence. Here, we revisited the question using recombineering to introduce antibiotic resistance mutations into E. coli at defined time points and then tracking expression of the corresponding mutant phenotype over time. Contrary to previous assumptions, we found a substantial median phenotypic delay of three to four generations. We provided evidence that the primary source of this delay is multifork replication causing cells to be effectively polyploid, whereby wild-type gene copies transiently mask the phenotype of recessive mutant gene copies in the same cell. Using modeling and simulation methods, we explored the consequences of effective polyploidy for mutation rate estimation by fluctuation tests and sequencing-based methods. For recessive mutations, despite the substantial phenotypic delay, the per-copy or per-genome mutation rate is accurately estimated. However, the per-cell rate cannot be estimated by existing methods. Finally, with a mathematical model, we showed that effective polyploidy increases the frequency of costly recessive mutations in the standing genetic variation (SGV), and thus their potential contribution to evolutionary adaptation, while drastically reducing the chance that de novo recessive mutations can rescue populations facing a harsh environmental change such as antibiotic treatment. Overall, we have identified phenotypic delay and effective polyploidy as previously overlooked but essential components in bacterial evolvability, including antibiotic resistance evolution. What is the time delay between the occurrence of a genetic mutation in a bacterial cell and manifestation of its phenotypic effect? We show that antibiotic resistance mutations in Escherichia coli show a remarkably long phenotypic delay of three to four bacterial generations. The primary underlying mechanism of this delay is effective polyploidy. If a mutation arises on one of the multiple chromosomes in a polyploid cell, the presence of nonmutated, wild-type gene copies on other chromosomes may mask the phenotype of the mutation. We show here that mutation rate estimation needs to consider polyploidy, which influences the potential for bacterial adaptation. The fact that a new mutation may become useful only in the “great-great-grandchildren” suggests that preexisting mutations are more important for surviving sudden environmental catastrophes.
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DOI：
10.1073/pnas.1210309109
发表时间：
2012-10-09
影响因子：
11.1
作者：
Lee, Heewook;Popodi, Ellen;Foster, Patricia L.
通讯作者：
Foster, Patricia L.
影响因子：
3.2
作者：
Nielsen, Henrik J.;Youngren, Brenda;Austin, Stuart
通讯作者：
Austin, Stuart
影响因子：
9.8
作者：
Cirz, RT;Chin, JK;Romesberg, FE
通讯作者：
Romesberg, FE
影响因子：
2.9
作者：
Kremers, Gert-Jan;Goedhart, Joachim;Gadella, Theodorus W. J., Jr.
通讯作者：
Gadella, Theodorus W. J., Jr.
影响因子：
3.3
作者：
Anderson, JB;Sirjusingh, C;Ricker, N
通讯作者：
Ricker, N