Opposing Copy Number Variation Dynamics Shape Adaptation to Glucose and Galactose in Diploid Yeast

Adaptation to constant environments is often thought to proceed through point mutations that finetune gene function. However, structural variation, such as gene duplications and deletions, can also reshape genomes and drive rapid phenotypic change. Yet, how these classes of mutations jointly influence long-term adaptation remains unclear. Here we evolve six replicate diploid Saccharomyces cerevisiae populations for 1200 generations in either glucose or galactose and show that adaptation is dominated by large-scale copy number variations (CNVs) rather than single-nucleotide polymorphisms. In glucose, adaptation proceeds through early, extensive telomeric deletions that target carbon-use modules, followed by later compensatory duplications that restore metabolic breadth. In galactose, adaptation is marked instead by persistent telomeric and subtelomeric duplications that reinforce specialization. Opposing selection acted on overlapping sets of genes, with loci deleted during glucose adaptation becoming duplicated during galactose adaptation, linking structural remodeling to divergent physiological strategies. Contrary to models emphasizing SNP accumulation, these findings demonstrate that predictable CNV trajectories dominate genome evolution in stable environments, and that the direction and persistence of such structural changes are constrained by both the ancestral genotype and the regulatory architecture of the cell.