A genomic sequence and expression diversity catalogue of BCG

Although the Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor in this variability may be the diversity of the BCG strains that are used around the world, particularly the changes in the genomic material and the resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression at the protein level across five representative BCG strains of the four tandem duplication groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and indels across fourteen BCG strains. The distribution of SNPs across the BCG lineages allowed clustering of these strains to generate a linear phylogeny and refining the previous genealogies of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may reflect in altered immunogenicity and possibly vaccine efficacy. Together, the presented datasets represent the most comprehensive catalogue of genomic variation across a global collection of BCG strains.