Epistasis and co-adaptation in bacterial genome evolution

Precise genotype-phenotype mapping is essential in applied microbiology, from engineering genetically modified strains to developing tailored strategies for antimicrobial therapies. Comparative genomics often treats genes as independent contributors to phenotypes, and gene knockout and complementation remain the gold standard to validate genotype-phenotype associations in microorganisms. However, genes do not act in isolation, and complex gene-gene interactions, that is, epistatic interactions, are essential for the evolution and function of bacterial genomes. Recent advances in high-throughput genomics and experimental techniques have enabled systematic screens of epistasis in bacteria at scale, revealing mechanisms underlying epistasis and co-adaptation in laboratory and wild populations. Here we review how microbial genomics is moving beyond gene-centric models towards integrated analyses of potentiating, compensatory and context-dependent variation. The timely incorporation of interaction-based perspectives into population-scale analyses will improve genotype-phenotype mapping and the understanding of the complex traits that shape the microbial world.