title: Nonselective Bottlenecks Control the Divergence and Diversification of Phase-Variable Bacterial Populations.
abstract: Phase variation occurs in many pathogenic and commensal bacteria and is a major generator of genetic variability. A putative advantage of phase variation is to counter reductions in variability imposed by nonselective bottlenecks during transmission. Genomes ofCampylobacter jejuni, a widespread food-borne pathogen, contain multiple phase-variable loci whose rapid, stochastic variation is generated by hypermutable simple sequence repeat tracts. These loci can occupy a vast number of combinatorial expression states (phasotypes) enabling populations to rapidly access phenotypic diversity. The imposition of nonselective bottlenecks can perturb the relative frequencies of phasotypes, changing both within-population diversity and divergence from the initial population. Using bothin vitrotesting ofC. jejunipopulations and a simple stochastic simulation of phasotype change, we observed that single-cell bottlenecks produce output populations of low diversity but with bimodal patterns of either high or low divergence. Conversely, large bottlenecks allow divergence only by accumulation of diversity, while interpolation between these extremes is observed in intermediary bottlenecks. These patterns are sensitive to the genetic diversity of initial populations but stable over a range of mutation rates and number of loci. The qualitative similarities of experimental andin silicomodeling indicate that the observed patterns are robust and applicable to other systems where localized hypermutation is a defining feature. We conclude that while phase variation will maintain bacterial population diversity in the face of intermediate bottlenecks, narrow transmission-associated bottlenecks could produce host-to-host variation in bacterial phenotypes and hence stochastic variation in colonization and disease outcomes.IMPORTANCETransmission and within-host spread of pathogenic organisms are associated with selective and nonselective bottlenecks that significantly reduced population diversity. In several bacterial pathogens, hypermutable mechanisms have evolved that mediate high-frequency reversible switching of specific phenotypes, such as surface structures, and hence counteract bottleneck-associated reductions in population diversity. Here, we investigated how combinations of hypermutable simple sequence repeats interact with nonselective bottlenecks by using a stochastic computer model and experimental data forCampylobacter jejuni, a food-borne pathogen. We find that bottleneck size qualitatively alters the output populations, with large bottlenecks maintaining population diversity while small bottlenecks produce dramatic shifts in the prevalence of particular variants. We conclude that narrow bottlenecks are capable of producing host-to-host variation in repeat-controlled bacterial phenotypes, leading to a potential for stochastic person-to-person variations in disease outcome forC. jejuniand other organisms with similar hypermutable mechanisms.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Aidley
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Shweta
authors.initials: S
authors.lastname: Rajopadhye
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Nwanekka M
authors.initials: NM
authors.lastname: Akinyemi
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Lea
authors.initials: L
authors.lastname: Lango-Scholey
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jones
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom cdb12@le.ac.uk.
authors.forename: Christopher D
authors.identifier: 0000-0002-5564-2145
authors.initials: CD
authors.lastname: Bayliss
mesh_terms: D000073537:Biological Variation, Population; D016123:Campylobacter jejuni / Q000145:classification* / Q000235:genetics* / Q000502:physiology; D003198:Computer Simulation; D014644:Genetic Variation; D005828:Genetics, Population