Pervasive Recombination and Sympatric Genome Diversification Driven by Frequency-Dependent Selection in Borrelia burgdorferi, the Lyme Disease Bacterium

Abstract

How genomic diversity within bacterial populations originates and is maintained in the presence of frequent recombination is a central problem in understanding bacterial evolution. Natural populations of Borrelia burgdorferi, the bacterial agent of Lyme disease, consist of diverse genomic groups co-infecting single individual vertebrate hosts and tick vectors. To understand mechanisms of sympatric genome differentiation in B. burgdorferi, we sequenced and compared 23 genomes representing major genomic groups in North America and Europe. Linkage analysis of .13,500 single-nucleotide polymorphisms revealed pervasive horizontal DNA exchanges. Although three times more frequent than point mutation, recombination is localized and weakly affects genome-wide linkage disequilibrium. We show by computer simulations that, while enhancing population fitness, recombination constrains neutral and adaptive divergence among sympatric genomes through periodic selective sweeps. In contrast, simulations of frequency-dependent selection with recombination produced the observed pattern of a large number of sympatric genomic groups associated with major sequence variations at the selected locus. We conclude that negative frequency-dependent selection targeting a small number of surface-antigen loci (ospC in particular) sufficiently explains the maintenance of sympatric genome diversity in B. burgdorferi without adaptive divergence. We suggest that pervasive recombination makes it less likely for local B. burgdorferi genomic groups to achieve host specialization. B. burgdorferi genomic groups in the northeastern United States are thus best viewed as constituting a single bacterial species, whose generalist nature is a key to its rapid spread and human virulence. G ENETIC discontinuity, the basis of biodiversity, is ubiquitous in prokaryotes as well as in eukaryotes. Most bacterial populations display a highly clonal genetic structure, in which the observable number of multilocus genotypes is far fewer than the number expected under the assumption of free recombination (Maynard Smith et al. 1993). Bacterial clonality was originally thought of as a result of a lack or rarity of recombination among asexually reproducing and independently evolving clones (Ochman and Selander 1984). Since then, molecular surveys of natural bacterial populations using protein electrophoresis, multilocus sequencing typing (MLST), and whole-genome PRJNA3, PRJNA28633, PRJNA19839, PRJNA29359, PRJNA28629, PRJNA29357, PRJNA21003, PRJNA19835, PRJNA28627, PRJNA21001, PRJNA29361, PRJNA28621, PRJNA19837, PRJNA20999, PRJNA28631, PRJNA29363, PRJNA17057, PRJNA19841, PRJNA12554, PRJNA28625, PRJNA29573, PRJNA19843, and PRJNA28635. 1 Present address: Odum School of Ecology, University of Georgia, Athens, GA 30602. sequencing revealed that horizontal genetic exchange is in fact often more frequent than point mutations in bacteria, including species known as strongly clonal (Maynard Smith et al. 1993;Feil and Spratt 2001;Didelot and Maiden 2010;Retc...

Detection of Established Virulence Genes and Plasmids To Differentiate Borrelia burgdorferi Strains

“…This is similar to the finding that the locations of important virulence factor-encoding genes, such as dbpA-dbpB, ospA-ospB, and ospC, are conserved in particular genome segments, even though sizes may be somewhat different due to genetic rearrangements, especially on the outer edges of the linear plasmids. Gene duplication followed by rearrangement and mutations appear to have resulted in the evolution and antigenic variation of a number of B. burgdorferi virulence factors and other proteins (4,28,43,62,82,97,109,110). Often, duplicated genes that encode functionally redundant proteins that exhibit overlapping roles are present in the same operon, with each protein demonstrating altered specificities for host cell factors.…”

Imbalanced presence of Borrelia burgdorferi s.l. multilocus sequence types in clinical manifestations of Lyme borreliosis

“…Recombination is known to maintain sequence polymorphisms within B. burgdorferi s.l. populations (Haven et al, 2011) and the high number of STs can impede the identification of associations with clinical manifestations of LB. The test for recombination (not shown) indicated that this is a frequent event even for chromosomal housekeeping genes, as other studies (Haven et al, 2011) have also revealed.…”

Comparative genetic diversity of Lyme disease bacteria in Northern Californian ticks and their vertebrate hosts

“…The 5S (rrf)-23S (rrl) intergenic spacer region is a tandemly repeated sequence that is unique to B. burgdorferi sensu lato and has been used to differentiate and identify different isolates of Borrelia spirochetes in many different sample types including ticks (Postic et al, 1994;Humphrey et al, 2010), blood meal hosts (Chu et al, 2008) and patients (Postic et al, 1998;Rijpkema et al, 2009). This is in contrast with other markers such as the ospA or ospC genes are not ideal for phylogenetic analyses of inferences because of frequent recombination events (Haven et al, 2011). Previous studies from the northeastern or midwestern US have examined the genetic structure of B. burgdorferi with other genes and found limited genetic structure at a local scale but evidence of regional barriers to gene flow (Qiu et al, 2002;Humphrey et al, 2010).…”