Adaptive evolution to cellular stress is a process implicated in a wide range of biological and clinical phenomena. Two major routes of adaptation have been identified: non-genetic changes, which allow expression of different phenotypes in novel environments, and genetic variation achieved by selection of fitter phenotypes. While these processes are broadly accepted, their temporal and epistatic features in the context of cellular evolution and emerging drug resistance are contentious. In this manuscript, we generated hypomorphic alleles of the essential nuclear pore complex (NPC) gene NUP58. By dissecting early and long-term mechanisms of adaptation in independent clones, we observed that early physiological adaptation correlated with transcriptome rewiring and upregulation of genes known to interact with the NPC; long-term adaptation and fitness recovery instead occurred via focal amplification of NUP58 and restoration of mutant protein expression. These data support the concept that early phenotypic plasticity allows later acquisition of genetic adaptations to a specific impairment. We propose this approach as a genetic model to mimic targeted drug therapy in human cells and to dissect mechanisms of adaptation.

中文翻译：

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非遗传和遗传重连是适应必需基因的低等位基因的基础


对细胞应激的适应性进化是一个与广泛的生物和临床现象有关的过程。已经确定了两种主要的适应途径：非遗传变化，允许在新环境中表达不同的表型，以及通过选择更适应的表型来实现遗传变异。虽然这些过程被广泛接受，但它们在细胞进化和新出现的耐药性背景下的时间和上位特征存在争议。在这份手稿中，我们生成了必需核孔复合体（NPC）基因NUP58的亚等位基因。通过剖析独立克隆的早期和长期适应机制，我们观察到早期生理适应与转录组重连和已知与 NPC 相互作用的基因上调相关。相反，长期适应和健康恢复是通过NUP58的局部扩增和突变蛋白表达的恢复来实现的。这些数据支持这样的概念：早期表型可塑性允许稍后获得针对特定损伤的遗传适应。我们提出这种方法作为遗传模型来模拟人类细胞的靶向药物治疗并剖析适应机制。