Segmental copy number amplifications are stable in the absence of selection

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Abstract

Copy number variants (CNVs) are duplications and deletions of DNA sequences that contribute to genetic variation between individuals and underlie rapid adaptive evolution. Increases in gene copy number can confer a strong selective advantage in some circumstances, but CNVs can also incur fitness costs. Prior research has shown that experimental evolution of Saccharomyces cerevisiae in nutrient-limited chemostats recurrently selects for amplifications of nutrient transporter genes, including GAP1, MEP2, and PUT4 in glutamine, ammonium and proline limited conditions, respectively. However, the fate of these CNVs upon return of the organism to a non-selective environment, is unknown. To investigate the fitness costs and stability of CNVs upon reversal of the original selection pressure, we studied 15 unique CNV lineages that had been selected in different nitrogen-limited chemostats, including both segmental amplifications and whole-chromosome aneuploidies. We studied the stability of CNVs using a fluorescent CNV reporter system during propagation in nutrient-rich media using serial dilution of batch cultures for 110-220 generations. We found that only one-third of CNV lineages repeatedly underwent loss of CNVs and reversion to a single-copy genotype. All lineages containing aneuploidies showed rapid reversion dynamics, whereas lineages containing segmental amplifications were remarkably stable – only one of 11 strains reverted to a single copy. Pairwise competitive fitness assays revealed strong fitness defects associated with reverting CNVs in the nutrient-rich environment but minimal fitness defects in lineages that did not revert. Reversion of CNVs led to increased fitness. Using simulation-based inference to estimate reversion rates and fitness effects we find that negative selection is the primary driver of CNV loss although aneuploid reversion rates are high with estimates of 10 −5 to 10 −3 . Whole-genome sequencing of clones isolated from evolved populations revealed that reversion of both aneuploids and a segmental amplification left no evidence of prior existence of the CNV, making the genomes of revertants indistinguishable from the single-copy ancestor. Our findings provide novel evidence of the low fitness cost and high stability of most segmental CNVs upon removal of the selection pressure, and that gene amplifications with large fitness costs are readily reversible, highlighting the significance of CNVs for genome evolution as well as rapid and reversible adaptation to transient selection pressures.

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