Negative trade-offs shape the evolution of dosage sensitivity

Dominance is a relationship between alleles of a given gene, in which the fitness effect of one allele masks the contribution of the second allele. The evolutionary forces shaping dominance have been intensely debated. In particular, it is unclear whether dominance can evolve as a direct response to selection on heterozygote mutants with low fitness. To investigate this issue, we performed laboratory evolution with over 120 diploid heterozygote gene knockout bakers yeast strains, all of which initially displayed reduced fitness (i.e haploinsufficient). Compensatory evolution following gene dosage reduction was rapid and pervasive: almost half of the genotypes reached near wild-type fitness after 320 generations. This process was driven by restoring gene dosage through gene duplication or by point mutations in functionally related genes elsewhere in the genome. The accumulated genomic mutations reduced fitness in specific genetic and environmental settings. Our work indicates that gene dosage sensitivity can be rapidly mitigated during evolution. However, the associated mutations have potential fitness costs that could pose a barrier to the evolution of dominance in sexual populations.