Natural selection and recombination at host-interacting lipoprotein loci drive genome diversification of Lyme disease and related bacteria
Authors: Akther Saymon , Mongodin Emmanuel F. , Morgan Richard D. , Di Lia , Yang Xiaohua , Golovchenko Maryna , Rudenko Natalie , Margos Gabriele , Hepner Sabrina , Fingerle Volker , Kawabata Hiroki , Norte Ana Cláudia , de Carvalho Isabel Lopes , Núncio Maria Sofia , Marques Adriana , Schutzer Steven E. , Fraser Claire M. , Luft Benjamin J. , Casjens Sherwood R. , Qiu Weigang 
Published: August 2024

Lyme disease, caused by spirochetes in the
Borrelia burgdorferi sensu lato
clade within the
Borrelia
genus, is transmitted by
Ixodes
ticks and is currently the most prevalent and rapidly expanding tick-borne disease in Europe and North America. We report complete genome sequences of 47 isolates that encompass all established species in this clade while highlighting the diversity of the widespread human pathogenic species
B. burgdorferi
. A similar set of plasmids has been maintained throughout
Borrelia
divergence, indicating that they are a key adaptive feature of this genus. Phylogenetic reconstruction of all sequenced
Borrelia
genomes revealed the original divergence of Eurasian and North American lineages and subsequent dispersals that introduced
B. garinii, B. bavariensis, B. lusitaniae, B. valaisiana,
and
B. afzelii
from East Asia to Europe and
B. burgdorferi
and
B. finlandensis
from North America to Europe. Molecular phylogenies of the universally present core replicons (chromosome and cp26 and lp54 plasmids) are highly consistent, revealing a strong clonal structure. Nonetheless, numerous inconsistencies between the genome and gene phylogenies indicate species dispersal, genetic exchanges, and rapid sequence evolution at plasmid-borne loci, including key host-interacting lipoprotein genes. While localized recombination occurs uniformly on the main chromosome at a rate comparable to mutation, lipoprotein-encoding loci are recombination hotspots on the plasmids, suggesting adaptive maintenance of recombinant alleles at loci directly interacting with the host. We conclude that within- and between-species recombination facilitates adaptive sequence evolution of host-interacting lipoprotein loci and contributes to human virulence despite a genome-wide clonal structure of its natural populations.

IMPORTANCE

Lyme disease (also called Lyme borreliosis in Europe), a condition caused by spirochete bacteria of the genus
Borrelia
, transmitted by hard-bodied
Ixodes
ticks, is currently the most prevalent and rapidly expanding tick-borne disease in the United States and Europe.
Borrelia
interspecies and intraspecies genome comparisons of Lyme disease-related bacteria are essential to reconstruct their evolutionary origins, track epidemiological spread, identify molecular mechanisms of human pathogenicity, and design molecular and ecological approaches to disease prevention, diagnosis, and treatment. These Lyme disease-associated bacteria harbor complex genomes that encode many genes that do not have homologs in other organisms and are distributed across multiple linear and circular plasmids. The functional significance of most of the plasmid-borne genes and the multipartite genome organization itself remains unknown. Here we sequenced, assembled, and analyzed whole genomes of 47
Borrelia
isolates from around the world, including multiple isolates of the human pathogenic species. Our analysis elucidates the evolutionary origins, historical migration, and sources of genomic variability of these clinically important pathogens. We have developed web-based software tools (BorreliaBase.org) to facilitate dissemination and continued comparative analysis of
Borrelia
genomes to identify determinants of human pathogenicity.