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Reference genome and comparative genome analysis for the WHO reference strain for Mycobacterium bovis BCG Danish, the present tuberculosis vaccine

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Abstract
Background: Mycobacterium bovis bacillus Calmette-Guerin (M. bovis BCG) is the only vaccine available against tuberculosis (TB). In an effort to standardize the vaccine production, three substrains, i.e. BCG Danish 1331, Tokyo 172-1 and Russia BCG-1 were established as the WHO reference strains. Both for BCG Tokyo 172-1 as Russia BCG-1, reference genomes exist, not for BCG Danish. In this study, we set out to determine the completely assembled genome sequence for BCG Danish and to establish a workflow for genome characterization of engineering-derived vaccine candidate strains.ResultsBy combining second (Illumina) and third (PacBio) generation sequencing in an integrated genome analysis workflow for BCG, we could construct the completely assembled genome sequence of BCG Danish 1331 (07/270) (and an engineered derivative that is studied as an improved vaccine candidate, a SapM KO), including the resolution of the analytically challenging long duplication regions. We report the presence of a DU1-like duplication in BCG Danish 1331, while this tandem duplication was previously thought to be exclusively restricted to BCG Pasteur. Furthermore, comparative genome analyses of publicly available data for BCG substrains showed the absence of a DU1 in certain BCG Pasteur substrains and the presence of a DU1-like duplication in some BCG China substrains. By integrating publicly available data, we provide an update to the genome features of the commonly used BCG strains. Conclusions: We demonstrate how this analysis workflow enables the resolution of genome duplications and of the genome of engineered derivatives of the BCG Danish vaccine strain. The BCG Danish WHO reference genome will serve as a reference for future engineered strains and the established workflow can be used to enhance BCG vaccine standardization.
Keywords
Tuberculosis, Live vaccines, BCG, Next-generation sequencing, Complete genomic sequence, Genetic differences, Tandem duplications, BACILLUS-CALMETTE-GUERIN, SEQUENCE, REPLICATION, IDENTIFICATION, SMEGMATIS, PROGRAM, PROTEIN

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MLA
Borgers, Katlyn, et al. “Reference Genome and Comparative Genome Analysis for the WHO Reference Strain for Mycobacterium Bovis BCG Danish, the Present Tuberculosis Vaccine.” BMC GENOMICS, vol. 20, 2019.
APA
Borgers, K., Ou, J.-Y., Zheng, P.-X., Tiels, P., Van Hecke, A., Plets, E., … Lin, Y.-C. (2019). Reference genome and comparative genome analysis for the WHO reference strain for Mycobacterium bovis BCG Danish, the present tuberculosis vaccine. BMC GENOMICS, 20.
Chicago author-date
Borgers, Katlyn, Jheng-Yang Ou, Po-Xing Zheng, Petra Tiels, Annelies Van Hecke, Evelyn Plets, Gitte Michielsen, Nele Festjens, Nico Callewaert, and Yao-Cheng Lin. 2019. “Reference Genome and Comparative Genome Analysis for the WHO Reference Strain for Mycobacterium Bovis BCG Danish, the Present Tuberculosis Vaccine.” BMC GENOMICS 20.
Chicago author-date (all authors)
Borgers, Katlyn, Jheng-Yang Ou, Po-Xing Zheng, Petra Tiels, Annelies Van Hecke, Evelyn Plets, Gitte Michielsen, Nele Festjens, Nico Callewaert, and Yao-Cheng Lin. 2019. “Reference Genome and Comparative Genome Analysis for the WHO Reference Strain for Mycobacterium Bovis BCG Danish, the Present Tuberculosis Vaccine.” BMC GENOMICS 20.
Vancouver
1.
Borgers K, Ou J-Y, Zheng P-X, Tiels P, Van Hecke A, Plets E, et al. Reference genome and comparative genome analysis for the WHO reference strain for Mycobacterium bovis BCG Danish, the present tuberculosis vaccine. BMC GENOMICS. 2019;20.
IEEE
[1]
K. Borgers et al., “Reference genome and comparative genome analysis for the WHO reference strain for Mycobacterium bovis BCG Danish, the present tuberculosis vaccine,” BMC GENOMICS, vol. 20, 2019.
@article{8631425,
  abstract     = {Background: Mycobacterium bovis bacillus Calmette-Guerin (M. bovis BCG) is the only vaccine available against tuberculosis (TB). In an effort to standardize the vaccine production, three substrains, i.e. BCG Danish 1331, Tokyo 172-1 and Russia BCG-1 were established as the WHO reference strains. Both for BCG Tokyo 172-1 as Russia BCG-1, reference genomes exist, not for BCG Danish. In this study, we set out to determine the completely assembled genome sequence for BCG Danish and to establish a workflow for genome characterization of engineering-derived vaccine candidate strains.ResultsBy combining second (Illumina) and third (PacBio) generation sequencing in an integrated genome analysis workflow for BCG, we could construct the completely assembled genome sequence of BCG Danish 1331 (07/270) (and an engineered derivative that is studied as an improved vaccine candidate, a SapM KO), including the resolution of the analytically challenging long duplication regions. We report the presence of a DU1-like duplication in BCG Danish 1331, while this tandem duplication was previously thought to be exclusively restricted to BCG Pasteur. Furthermore, comparative genome analyses of publicly available data for BCG substrains showed the absence of a DU1 in certain BCG Pasteur substrains and the presence of a DU1-like duplication in some BCG China substrains. By integrating publicly available data, we provide an update to the genome features of the commonly used BCG strains.
Conclusions: We demonstrate how this analysis workflow enables the resolution of genome duplications and of the genome of engineered derivatives of the BCG Danish vaccine strain. The BCG Danish WHO reference genome will serve as a reference for future engineered strains and the established workflow can be used to enhance BCG vaccine standardization.},
  articleno    = {561},
  author       = {Borgers, Katlyn and Ou, Jheng-Yang and Zheng, Po-Xing and Tiels, Petra and Van Hecke, Annelies and Plets, Evelyn and Michielsen, Gitte and Festjens, Nele and Callewaert, Nico and Lin, Yao-Cheng},
  issn         = {1471-2164},
  journal      = {BMC GENOMICS},
  keywords     = {Tuberculosis,Live vaccines,BCG,Next-generation sequencing,Complete genomic sequence,Genetic differences,Tandem duplications,BACILLUS-CALMETTE-GUERIN,SEQUENCE,REPLICATION,IDENTIFICATION,SMEGMATIS,PROGRAM,PROTEIN},
  language     = {eng},
  pages        = {14},
  title        = {Reference genome and comparative genome analysis for the WHO reference strain for Mycobacterium bovis BCG Danish, the present tuberculosis vaccine},
  url          = {http://dx.doi.org/10.1186/s12864-019-5909-5},
  volume       = {20},
  year         = {2019},
}

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