Point mutations of homologs as an adaptive solution to the gene loss

Gene loss is common and has been reported to shape genome evolution (Albalat and Cañestro, 2016; Shen et al., 2018). Comparative genomics is a powerful tool to understand the mechanism by which a genome adapts after gene loss. Experimentally introducing gene loss can also be used to study the mechanism of adaptation. Yeast is commonly used as a model organism to study genome adaptation mechanisms upon exposure to various stresses or selective pressures (Dragosits and Mattanovich, 2013), including gene loss (Ravichandran et al., 2018).

Previous studies showed that aneuploidy can be employed as a short-term solution to acute stress in yeast (Pavelka et al., 2010; Tsai and Nelliat, 2019). Similarly, aneuploidy was also observed in cancer cells under the stresses induced by drug treatment (Lukow et al., 2021) and the environmental stress such as heat (Yona et al., 2012). In some cases, as demonstrated in Saccharomyces cerevisiae, such short-term solutions were eventually replaced by more refined ones, such as point mutations. In one such model, the loss of ULP2 was shown to invariably induce an increase in copy number on chromosome I and the overexpression of CLN3 and CCR4 on chromosome I was able to rescue the defect caused by loss of ULP2 (Ryu et al., 2016). However, eventually the aneuploidy was replaced by mutations in SUMO-ligating enzymes (Ryu et al., 2018), which likely caused a decrease in SUMOylation and compensated for the defect caused by the loss of ULP2, the SUMOylation-deconjugating enzyme.

Interestingly, Ryu et al. (2018)identified only one long-term compensatory strategy in all their independent evolutionary experiments, which involves mutations in upstream SUMOylation conjugation pathway genes (UBA2 and UBC9) (Ryu et al., 2018). However, normally multiple distinct evolutionary strategies are available to cope with different stresses (Huang et al., 2018). Furthermore, previous studies have reported that mutant proteins encoded by engineered ULP1 (temperature-sensitive mutants and truncated proteins) can potentially compensate for defects caused by the loss of ULP2 (Li and Hochstrasser, 2003; Lewis et al., 2007). However, no compensatory mutations in ULP1 have been observed in previous evolutionary experiments (Ryu et al., 2018). Therefore, in this study, additional mechanisms of genome adaptation were explored by repeating genome evolution using the ULP2 gene loss model. In addition to the previously reported mutations in SUMO-ligating enzymes, we identified two independent mutations in the ULP1 gene homolog of two separately evolved clones. Experiments confirmed the fitness advantages of these two mutations in ULP1. Moreover, by analyzing genomes from the yeast gene knockout library and naturally isolated strains, we showed that mutations in homologous genes might be a common mechanism to adapt to gene loss.

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