Evolutionary mechanisms that determine which bacterial genes are carried on plasmids
Authors: Lehtinen Sonja , Huisman Jana S. , Bonhoeffer Sebastian 
Published: August 2020

AbstractThe evolutionary pressures that determine the location (chromosomal or plasmid-borne) of bacterial genes are not fully understood. We investigate these pressures through mathematical modelling in the context of antibiotic resistance, which is often found on plasmids. Our central finding is that gene location is under positive frequency-dependent selection: the higher the frequency of one form of resistance compared to the other, the higher its relative fitness. This can keep moderately beneficial genes on plasmids, despite occasional plasmid loss. For these genes, positive frequency-dependence leads to a priority effect: whichever form is acquired first – through either mutation or horizontal gene transfer – has time to increase in frequency and thus become difficult to displace. Higher rates of horizontal transfer of plasmid-borne than chromosomal genes therefore predict moderately beneficial genes will be found on plasmids. Gene flow between plasmid and chromosome allows chromosomal forms to arise, but positive frequencydependent selection prevents these from establishing. Further modelling shows this effect is particularly pronounced when genes are shared across a large number of species, suggesting antibiotic resistance genes are often found on plasmids because they are moderately beneficial across many species. We also revisit previous theoretical work – relating to the role of local adaptation in explaining gene location and to plasmid persistence – in light of our findings.Impact StatementBacterial genes can either reside on the chromosome or on plasmids, extra-chromosomal genetic structures which can be transferred from cell to cell. The distribution of genes between plasmid and chromosome is not random: certain types of genes are particularly likely to be plasmid-associated. This includes a number of clinically important traits, such as antibiotic resistance and virulence factors. The evolutionary mechanisms that give rise to this pattern are not well understood. Plasmids are occasionally lost during cell replication and thus less reliably inherited than the chromosome, and genes are free to transition between plasmid and chromosome: so what keeps genes on plasmids? We address this question using a mathematical model. The key prediction from our model is that the relative fitness of chromosomal and plasmid-borne genes depends on their relative frequencies (‘positive frequency-dependent selection’). In other words, the fitness of a plasmid-borne gene will be higher in a population in which the chromosomal gene is rare (and vice-versa). This positive-frequency dependence can keep moderately beneficial genes on plasmids, despite occasional plasmid loss. This leads to a priority effect: whichever form of the gene (i.e. plasmid-borne or chromosomal) is acquired first has time to increase in frequency and thus become difficult to displace. Therefore, the relative rate of acquiring the gene on the plasmid vs the chromosome predicts where the gene will be found. Further modelling shows this effect is particularly pronounced when genes are beneficial across a large number of species. All together, the hypothesis that emerges from our work is that plasmid-borne genes are moderately beneficial; functional across a large number of species; and rarely acquired through chromosomal mutation. We suggest traits like antibiotic resistance are often found on plasmids because these genes commonly fulfill these criteria.