Dynamic Large-Scale Chromosomal Rearrangements Fuel Rapid Adaptation in Yeast Populations

Abstract

Large-scale genome rearrangements have been observed in cells adapting to various selective conditions during laboratory evolution experiments. However, it remains unclear whether these types of mutations can be stably maintained in populations and how they impact the evolutionary trajectories. Here we show that chromosomal rearrangements contribute to extremely high copper tolerance in a set of natural yeast strains isolated from Evolution Canyon (EC), Israel. The chromosomal rearrangements in EC strains result in segmental duplications in chromosomes 7 and 8, which increase the copy number of genes involved in copper regulation, including the crucial transcriptional activator CUP2 and the metallothionein CUP1. The copy number of CUP2 is correlated with the level of copper tolerance, indicating that increasing dosages of a single transcriptional activator by chromosomal rearrangements has a profound effect on a regulatory pathway. By gene expression analysis and functional assays, we identified three previously unknown downstream targets of CUP2: PHO84, SCM4, and CIN2, all of which contributed to copper tolerance in EC strains. Finally, we conducted an evolution experiment to examine how cells maintained these changes in a fluctuating environment. Interestingly, the rearranged chromosomes were reverted back to the wild-type configuration at a high frequency and the recovered chromosome became fixed in less selective conditions. Our results suggest that transposon-mediated chromosomal rearrangements can be highly dynamic and can serve as a reversible mechanism during early stages of adaptive evolution.

Author Summary

Large-scale chromosomal rearrangements are often associated with dramatic phenotypic changes such as cancer cell formation. It has been speculated that large-scale chromosomal rearrangements may play a crucial role at the early stages of adaptation, since they can quickly change the expression level of multiple genes or even a whole pathway by changing the gene copy number. Nonetheless, it remains unclear whether such mutations can be stably maintained in populations, especially in a fluctuating environment. Here we characterize an adaptive copper-tolerant phenotype in a wild yeast population. We discovered that the adaptive phenotype was contributed to by two large-scale chromosomal rearrangements, which increased the copy number of key components of copper regulation, including a crucial transcriptional activator, Cup2. We further identified three previously unknown downstream targets of Cup2 that also contributed to copper tolerance. Finally, we conducted an evolution experiment to test the stability of the rearranged chromosomes under conditions of relaxed selection. We found that the rearranged chromosomes returned back to the original configuration at a high frequency, and the wild type-like chromosome became fixed in all the evolved cultures. Our results suggest that chromosomal rearrangements can provide a reversible mechanism for cells when adapting to a fluctuating environment.