Non-genetic and genetic rewiring underlie adaptation to hypomorphic alleles of an essential gene

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.

Automated summary

This research explores the mechanisms of early physiological adaptation and long-term adaptive evolution in cells under stress by generating hypomorphic alleles of the essential nuclear pore complex gene NUP58. The study demonstrates that early physiological adaptation is linked to transcriptome rewiring and upregulation of interacting genes, while long-term adaptation occurs through focal amplification of NUP58 and restoration of mutant protein expression. These findings suggest a model for mimicking targeted drug therapy and dissecting mechanisms of adaptation in human cells.