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Epistasis and co-adaptation in bacterial genome evolution

Nature Reviews Genetics (2026)Cite this article

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Abstract

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.

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Fig. 1: Hierarchical epistasis of interdependent flagellum genes.
Fig. 2: Inferred gene interaction networks in bacteria.
Fig. 3: Epistasis of long-range suppressor mutations mitigating streptomycin resistance in ribosomal subunits.
Fig. 4: Genome evolution mitigating substitution cost in bacterial adaptation.

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Acknowledgements

E.A.C. is supported by a Biotechnology and Biological Sciences Research Council (BBSRC) grant (BB/W020602/1), awarded to S.K.S. P.S.R. and E.H. are supported by the Ineos Oxbridge Doctoral Initiative on Antimicrobial Resistance.

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  1. Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK

    Elizabeth A. Cummins, Priyanshu Singh Raikwar, Eve Hallett & Samuel K. Sheppard

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  2. Priyanshu Singh Raikwar
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E.A.C., P.S.R. and S.K.S. researched the literature. S.K.S. conceptualized and E.A.C. and S.K.S. wrote the article. All authors made contributions to discussions of the content, contributed to figure design and reviewed and edited the manuscript before submission.

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Glossary

Accessory genes

The complement of strain-dependent (not shared) genes among strains of a given bacterial species.

Antagonistic epistasis

When two mutations have a combined effect that is less severe than expected, meaning one mutation partially offsets or interferes with the effect of the other.

Clonal frame

The portion of a bacterial genome that has been inherited vertically (from parent to offspring) without recombination.

Clonal interference

Competition between different lineages in an asexual population, each carrying distinct beneficial mutations, which slows or alters the fixation of advantageous alleles.

Co-adaptation

The mutual adaption of two or more genes through natural selection, leading to increased interdependence.

Codon usage bias

The non-random preference for certain synonymous codons over others.

Comparative genomics

A genomics approach to reveal evolutionary patterns by identifying genomic similarities and differences between species.

Core genes

The complement of shared genes among strains of a given bacterial species.

Ecotype model

A model which proposes that microbial populations form distinct, ecologically specialized groups that diversify by mutation but are kept uniform by periodic selection.

Epistasis

A phenotypic phenomenon in which the effect of one gene (the ‘epistatic’ gene) masks or alters the expression of another gene (the ‘hypostatic’ gene). It is distinct from additive effects, in which multiple genes contribute independently to a trait.

Epistatic effect size

The strength of interaction between genes in influencing a trait, beyond their individual additive effects — it shows how much one gene modifies another’s impact.

Functional genomics

The study of a gene’s function and interactions with other genes in the context of a single organism, typically linking genotype to phenotype through experimental methods.

Horizontal gene transfer

(HGT). Non-sexual transfer of genetic material from one organism to another that is distinct from parent–offspring inheritance.

Linkage disequilibrium

The non-random association of alleles at different genetic loci in a population.

Modern Synthesis

A unifying framework in evolutionary biology for the theory of natural selection and Mendel’s laws of heredity.

Natural competence

The genetically programmed ability to take up extracellular environmental DNA in both natural and laboratory settings.

Negative selection

A form of natural selection that reduces the frequency of disadvantageous alleles within a population.

Neutral diversification

An increase in genetic variation within a population not driven by natural selection.

Non-synonymous mutation

A nucleotide change in a coding sequence that alters the encoded amino acid, potentially affecting the structure and function of the resulting protein.

Pangenome

The entire collection of genes present within a given bacterial species.

Pleiotropy

When a single gene influences multiple unrelated phenotypic traits.

Positive selection

A form of natural selection that increases the frequency of beneficial alleles within a population.

Purifying selection

Natural selection that removes harmful mutations, thereby preserving existing biological function.

Sign epistasis

A phenomenon that occurs when the fitness effect (‘sign’) of a mutation — beneficial, neutral or deleterious — depends on which other alleles are present at another locus. A mutation that is advantageous in one genetic background can be harmful (or neutral) in another, so the ‘sign’ of its effect flips according to the genotype context.

Sympatric

Populations or species that occur in the same geographic area and thus have the potential to encounter one another (that is, their ranges overlap without physical barriers).

Synonymous mutation

A change in a DNA sequence that alters a codon but does not change the amino acid it codes for.

Synteny

The conservation of blocks of genetic loci on the same chromosome across different species or strains.

Synthetically lethal

A term to describe a genetic interaction in which the simultaneous mutation or deletion of two genes leads to cell death, whereas mutation of either gene alone does not affect viability.

Transmission genetics

Also known as Mendelian genetics. The study of how genes are passed from one generation to the next.

Transposon

Mobile DNA sequences that can change their position within a genome, often duplicating themselves and sometimes altering or disrupting nearby genes in the process.

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Cummins, E.A., Raikwar, P.S., Hallett, E. et al. Epistasis and co-adaptation in bacterial genome evolution. Nat Rev Genet (2026). https://doi.org/10.1038/s41576-026-00941-7

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