Weak pervasive incompatibilities and compensatory adaptation drive hybrid genome evolution in yeast

Species barriers limit gene flow and maintain co-adapted genomes. Interspecific hybridization can break down species barriers to reveal genetic incompatibilities. Although the phenotypic and genomic consequences of hybridization have been extensively studied in many systems, far less is known about the longer-term evolutionary dynamics of highly divergent, mosaic genomes and the extent to which genetic incompatibilities shape their adaptation. In yeast, pre-zygotic barriers are weak but post-zygotic barriers are strong due to mispairing of chromosomes during meiosis. By suppressing anti-recombination genes in meiosis, we generated a panel of 20 haploid recombinant hybrids from a cross between Saccharomyces cerevisiae and its sister species, Saccharomyces paradoxus. Across conditions, these hybrids are, on average, less fit than either parent and show broad phenotypic variation. Inheritance patterns of protein complexes in the hybrid genomes reveal no evidence of pairwise lethality but do support a model of pervasive weak negative genetic interactions in hybrid protein complexes. We show by laboratory evolution that each recombinant genome follows a distinct evolutionary trajectory, and a small subset of hybrid protein complexes and loci show hybrid-specific mutational targeting. Finally, we show that species-of-origin alleles can bias evolutionary outcomes by reshaping selection on interacting genes. Together, our results suggest that strong pairwise incompatibilities are rare, while weak, background-dependent incompatibilities are widespread and shape fitness and adaptation in hybrid genomes.