Collateral fitness effects of mutations
Collateral fitness effects of mutations
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DOI：
10.1101/820068
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发表时间：
2019-10
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通讯作者：
Jacob D. Mehlhoff;Frank W. Stearns;Dahlia Rohm;Buheng Wang;Erh-Yeh Tsou;Nisita Dutta;Meng-Hsuan Hsiao;Courtney E. Gonzalez;Alan F. Rubin;M. Ostermeier
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作者：
Jacob D. Mehlhoff;Frank W. Stearns;Dahlia Rohm;Buheng Wang;Erh-Yeh Tsou;Nisita Dutta;Meng-Hsuan Hsiao;Courtney E. Gonzalez;Alan F. Rubin;M. Ostermeier
突变提供了遗传变异性的来源，而进化正是基于这种变异性而起作用的。有害的蛋白质突变通常被认为是它们如何损害蛋白质执行其生理功能的能力。然而，突变也可能是有害的，如果它们对无数其他细胞过程中的一个产生负面影响。这种附带适应性效应的频率和幅度尚不清楚。我们对细菌蛋白质突变的系统研究发现了广泛的附带适应性效应，这些效应与蛋白质聚集、蛋白质加工不当、蛋白质跨膜转运不完全、不正确的二硫键形成、应激反应途径的诱导以及细胞特性的意外变化有关。突变适应度效应的分布在限制蛋白质进化中起着核心作用。突变导致适应性效应的潜在机制通常归因于蛋白质比活性或丰度的变化。在这里，我们揭示了突变的附带适应性效应的重要性，我们将其定义为不来自蛋白质执行其生理功能的能力变化的效应。我们在没有抗生素的情况下，使用生长竞争实验全面测量了大肠杆菌TEM-1 β-内酰胺酶抗生素耐药基因中错义突变的附带适应性效应。TEM-1中至少有42%的错义突变是有害的，这表明对于某些蛋白质来说，附属适应性效应与对蛋白质活性和丰度的影响一样频繁地发生。有害的突变导致不正确的翻译后加工，不正确的二硫键形成，蛋白质聚集，基因表达的变化，和细胞表型的多效性效应。有害的附带健身效果发生更频繁地在TEM-1比有害的抗生素耐药性的环境中，低浓度的抗生素。令人惊讶的普遍存在的有害的附带健身效果表明，他们可能会发挥作用，限制蛋白质的进化，特别是高度表达的蛋白质，蛋白质的间歇性选择的生理功能，和蛋白质的贡献健身缓冲对蛋白质活性和蛋白质丰度的有害影响。
Significance Mutations provide the source of genetic variability upon which evolution acts. Deleterious protein mutations are commonly thought of in terms of how they compromise the protein’s ability to perform its physiological function. However, mutations might also be deleterious if they cause negative effects on one of the countless other cellular processes. The frequency and magnitude of such collateral fitness effects are unknown. Our systematic study of mutations in a bacterial protein finds widespread collateral fitness effects that were associated with protein aggregation, improper protein processing, incomplete protein transport across membranes, incorrect disulfide-bond formation, induction of stress-response pathways, and unexpected changes in cell properties. 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 β-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.