Natural Selection and Recombination at Host-interacting Lipoprotein Loci Drive Genome Diversification of Lyme Disease and Related Bacteria

Importance: Lyme disease (also called Lyme borreliosis in Europe), a condition caused by spirochete bacteria of the genus , transmitted by hard-bodied ticks, is currently the most prevalent and rapidly expanding tick-borne disease in the United States and Europe. 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 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 genomes to identify determinants of human pathogenicity.