Collateral fitness effects of mutations
Collateral fitness effects of mutations
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DOI：
10.1073/pnas.1918680117
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发表时间：
2020-05-26
影响因子：
11.1
通讯作者：
Ostermeier, Marc
中科院分区：
文献类型：
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作者：
Mehlhoff, Jacob D.;Stearns, Frank W.;Ostermeier, Marc
突变适应度效应的分布在制约蛋白质进化中起着核心作用。突变导致适合度效应的潜在机制通常归因于蛋白质特定活性或丰度的变化。在这里，我们揭示了突变的附带适应效应的重要性，我们将其定义为不是由于蛋白质执行其生理功能的能力的变化而产生的影响。我们在没有抗生素的情况下，通过生长竞争实验全面地测量了大肠杆菌TEM1β-内酰胺酶抗生素耐药基因错义突变的侧枝适合度效应。至少42%的TEM1错义突变是有害的，这表明对于某些蛋白质来说，伴随适应性的影响就像对蛋白质活性和丰度的影响一样频繁。有害突变导致翻译后加工不当、不正确的二硫键形成、蛋白质聚集、基因表达改变以及对细胞表型的多效性影响。在含有低浓度抗生素的环境中，与抗生素耐药性的有害影响相比，在TEM-1中出现有害的附带健身效应更频繁。有害的附带适应性效应令人惊讶地普遍存在，这表明它们可能在限制蛋白质进化方面发挥作用，特别是对于高表达的蛋白质，对于间歇性选择其生理功能的蛋白质，以及其对适应性的贡献被缓冲以抵御对蛋白质活性和蛋白质丰度的有害影响的蛋白质。
The distribution of fitness effects of mutation plays a central role in constraining protein evolution. The underlying mechanisms by which mutations lead to fitness effects are typically attributed to changes in protein specific activity or abundance. Here, we reveal the importance of a mutation's collateral fitness effects, which we define as effects that do not derive from changes in the protein's ability to perform its physiological function. We comprehensively measured the collateral fitness effects of missense mutations in the Escherichia coli TEM-1 beta-lactamase antibiotic resistance gene using growth competition experiments in the absence of antibiotic. At least 42% of missense mutations in TEM-1 were deleterious, indicating that for some proteins collateral fitness effects occur as frequently as effects on protein activity and abundance. Deleterious mutations caused improper posttranslational processing, incorrect disulfide-bond formation, protein aggregation, changes in gene expression, and pleiotropic effects on cell phenotype. Deleterious collateral fitness effects occurred more frequently in TEM-1 than deleterious effects on antibiotic resistance in environments with low concentrations of the antibiotic. The surprising prevalence of deleterious collateral fitness effects suggests they may play a role in constraining protein evolution, particularly for highly expressed proteins, for proteins under intermittent selection for their physiological function, and for proteins whose contribution to fitness is buffered against deleterious effects on protein activity and protein abundance.