Genetic basis of virulence attenuation revealed by comparative genomic analysis of Mycobacterium tuberculosis strain H37Ra versus H37Rv

Huajun Zheng, Liangdong Lu, Bofei Wang, Shiying Pu, Xianglin Zhang, Genfeng Zhu, Wanliang Shi, Zhang Lu, Honghai Wang, Shengyue Wang, Guoping Zhao, Ying Zhang

Research output: Contribution to journalArticle

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading infectious disease despite the availability of chemotherapy and BCG vaccine. The commonly used avirulent M. tuberculosis strain H37Ra was derived from virulent strain H37 in 1935 but the basis of virulence attenuation has remained obscure despite numerous studies. We determined the complete genomic sequence of H37Ra ATCC25177 and compared that with its virulent counterpart H37Rv and a clinical isolate CDC1551. The H37Ra genome is highly similar to that of H37Rv with respect to gene content and order but is 8,445 bp larger as a result of 53 insertions and 21 deletions in H37Ra relative to H37Rv. Variations in repetitive sequences such as IS6110 and PE/PPE/PE-PGRS family genes are responsible for most of the gross genetic changes. A total of 198 single nucleotide variations (SNVs) that are different between H37Ra and H37Rv were identified, yet 119 of them are identical between H37Ra and CDC1551 and 3 are due to H37Rv strain variation, leaving only 76 H37Ra-specific SNVs that affect only 32 genes. The biological impact of missense mutations in protein coding sequences was analyzed in silico while nucleotide variations in potential promoter regions of several important genes were verified by quantitative RT-PCR. Mutations affecting transcription factors and/or global metabolic regulations related to in vitro survival under aging stress, and mutations affecting cell envelope, primary metabolism, in vivo growth as well as variations in the PE/PPE/PE-PGRS family genes, may underlie the basis of virulence attenuation. These findings have implications not only for improved understanding of pathogenesis of M. tuberculosis but also for development of new vaccines and new therapeutic agents. Copyright:

Original languageEnglish (US)
Article numbere2375
JournalPLoS One
Volume3
Issue number6
DOIs
StatePublished - Jun 11 2008

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Mycobacterium tuberculosis
Virulence
virulence
Genes
genomics
Nucleotides
nucleotides
genes
BCG Vaccine
Mutation
Gene Order
Nucleic Acid Repetitive Sequences
BCG vaccine
Missense Mutation
mutation
missense mutation
Genetic Promoter Regions
Computer Simulation
repetitive sequences
strain differences

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Genetic basis of virulence attenuation revealed by comparative genomic analysis of Mycobacterium tuberculosis strain H37Ra versus H37Rv. / Zheng, Huajun; Lu, Liangdong; Wang, Bofei; Pu, Shiying; Zhang, Xianglin; Zhu, Genfeng; Shi, Wanliang; Lu, Zhang; Wang, Honghai; Wang, Shengyue; Zhao, Guoping; Zhang, Ying.

In: PLoS One, Vol. 3, No. 6, e2375, 11.06.2008.

Research output: Contribution to journalArticle

Zheng, Huajun ; Lu, Liangdong ; Wang, Bofei ; Pu, Shiying ; Zhang, Xianglin ; Zhu, Genfeng ; Shi, Wanliang ; Lu, Zhang ; Wang, Honghai ; Wang, Shengyue ; Zhao, Guoping ; Zhang, Ying. / Genetic basis of virulence attenuation revealed by comparative genomic analysis of Mycobacterium tuberculosis strain H37Ra versus H37Rv. In: PLoS One. 2008 ; Vol. 3, No. 6.
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AU - Zhu, Genfeng

AU - Shi, Wanliang

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AU - Zhang, Ying

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AB - Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading infectious disease despite the availability of chemotherapy and BCG vaccine. The commonly used avirulent M. tuberculosis strain H37Ra was derived from virulent strain H37 in 1935 but the basis of virulence attenuation has remained obscure despite numerous studies. We determined the complete genomic sequence of H37Ra ATCC25177 and compared that with its virulent counterpart H37Rv and a clinical isolate CDC1551. The H37Ra genome is highly similar to that of H37Rv with respect to gene content and order but is 8,445 bp larger as a result of 53 insertions and 21 deletions in H37Ra relative to H37Rv. Variations in repetitive sequences such as IS6110 and PE/PPE/PE-PGRS family genes are responsible for most of the gross genetic changes. A total of 198 single nucleotide variations (SNVs) that are different between H37Ra and H37Rv were identified, yet 119 of them are identical between H37Ra and CDC1551 and 3 are due to H37Rv strain variation, leaving only 76 H37Ra-specific SNVs that affect only 32 genes. The biological impact of missense mutations in protein coding sequences was analyzed in silico while nucleotide variations in potential promoter regions of several important genes were verified by quantitative RT-PCR. Mutations affecting transcription factors and/or global metabolic regulations related to in vitro survival under aging stress, and mutations affecting cell envelope, primary metabolism, in vivo growth as well as variations in the PE/PPE/PE-PGRS family genes, may underlie the basis of virulence attenuation. These findings have implications not only for improved understanding of pathogenesis of M. tuberculosis but also for development of new vaccines and new therapeutic agents. Copyright:

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