RT Journal Article SR Electronic T1 A two-hit epistasis model prevents core genome disharmony in recombining bacteria JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.03.15.435406 DO 10.1101/2021.03.15.435406 A1 Aidan J. Taylor A1 Guillaume Méric A1 Koji Yahara A1 Ben Pascoe A1 Leonardos Mageiros A1 Evangelos Mourkas A1 Jessica K Calland A1 Santeri Puranen A1 Matthew D. Hitchings A1 Keith A. Jolley A1 Carolin M. Kobras A1 Nicola J. Williams A1 Arnoud H. M. van Vliet A1 Julian Parkhill A1 Martin C. J. Maiden A1 Jukka Corander A1 Laurence D Hurst A1 Daniel Falush A1 Xavier Didelot A1 David J. Kelly A1 Samuel K. Sheppard YR 2022 UL http://biorxiv.org/content/early/2022/05/10/2021.03.15.435406.abstract AB Recombination of short DNA fragments via horizontal gene transfer (HGT) can both introduce beneficial alleles and create disharmony in coadapted genomes (negative epistasis). Owing to a lack of protracted intragenomic co-evolution, negative epistatic costs of HGT into non-core (accessory) bacterial genomes are likely to be minimal. By contrast, for the core genome, recombination is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma, we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and Campylobacter coli, that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings (negative epistasis). However, multiple HGT events enable recovery of the recipient genome’s co-adaption between the alleles, even in core metabolism genes (e.g. formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred and independently reinstated in a new genetic background. There is a strong resemblance to the two-hit cancer model. Whether it be by multiple mutations or multiple HGT events, immediate harmful effects from an initial event need not preclude adaptive evolution. The fitness peak jumping problem in asexual lineages is thus less of problem than envisaged.Competing Interest StatementThe authors have declared no competing interest.