Burst of aneuploidy: a cost of adaptation driven by breakdown of cell cycle control.

Complex genome rearrangements are intriguing because it remains unclear whether they occurred gradually or suddenly, and what promoted or impeded their development. We started by asking whether double loss of heterozygosity (dLOH) involving two different chromosomes is simply the result of two independent single LOH events. We examined hundreds of vegetatively growing diploid yeast strains with gene deletions known to stimulate LOH through different mechanisms. In dozens of these strains, dLOH mutants were overrepresented by tens or even hundreds of times. Interestingly, the (deleted) genes that caused the greatest instability were functionally diverse yet apparently affected the same biological process: cell cycle control. Furthermore, mutants were dominated by aneuploidy, which often involved multiple non-target chromosomes, with virtually no segmental loss, non-homologous recombination, or other small-scale changes. We conclude that the supply of separate, local rearrangements affecting only the required regions is insufficient, even in mutator strains. Consequently, double-pointed selection tends to reveal extensive reassortments resulting from systemic failures in mitotic cell division. Therefore, overcoming multiple adaptation barriers tends to produce aneuploidy, which is often reversible.