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

Abstract

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.

Disruption of Leishmania flagellum attachment zone architecture causes flagellum loss

“…The likely many close protein–protein interactions involved in FAZ assembly and function suggest that compensatory changes in other interacting and non‐interacting proteins may well be expected in this system. The exact nature of these changes has still to be identified, and whether they result from genomic and/or transcriptomic changes (Targa et al., 2021 ). Work in yeast showed that there was a preference for changes to genes functionally related to the deleted gene, so there is the potential that these mutants harbour changes in genes important for FAZ assembly and cell morphogenesis (Farkas et al., 2022 ; Helsen et al., 2020 ; Szamecz et al., 2014 ; Venkataram et al., 2016 ).…”