Genome architecture shapes evolutionary adaptation to DNA replication stress

Evolutionary adaptation to perturbations in DNA replication follows reproducible trajectories that lead to changes in three important aspects of genome maintenance: DNA replication, the DNA damage checkpoint, and sister chromatid cohesion. We asked how these trajectories depend on a population's genome architecture by testing whether ploidy or the ability to perform homologous recombination influence the evolutionary fate of the budding yeast, Saccharomyces cerevisiae, as it adapts to constitutive DNA replication stress, a condition that characterizes many cancer cells. In all three genome architectures, adaptation happens within 1000 generations at rates that are linearly correlated with the initial fitness defect of the ancestors. Which genes are mutated depends on the frequency at which mutations occur and the selective advantage they confer. The recombination-deficient strain amplifies adaptive chromosomal regions less often, whereas the selective advantage of loss-of-function mutations, such as those that inactivate the DNA damage checkpoint, is reduced in diploids because of the presence of a second, wild-type copy of the gene. Despite these differences, selection targets the same three functional modules in all three architectures, suggesting that genome architecture controls which genes are mutated but not which modules are modified.