Genomic Analysis of Mycobacterium tuberculosis Isolates and Construction of a Beijing Lineage Reference Genome

Woei Fuh Wang, Mei Yeh Jade Lu, Ting Jen Rachel Cheng, Yi Ching Tang, Yu Chuan Teng, Teh Yang Hwa, Yi Hua Chen, Meng Yun Li, Mei Hua Wu, Pei Chun Chuang, Ruwen Jou, Chi Huey Wong, Wen Hsiung Li, Rachel Whitaker, George Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, kills over 1 million people worldwide annually. Development of drug resistance (DR) in the pathogen is a major challenge for TB control. We conducted whole-genome analysis of seven Taiwan M. tuberculosis isolates: One drug susceptible (DS) and five DR Beijing lineage isolates and one DR Euro-American lineage isolate. Developing a new method for DR mutation identification and applying it to the next-generation sequencing (NGS) data from the 6 Beijing lineage isolates, we identified 13 known and 6 candidate DR mutations and provided experimental support for 4 of them. We assembled the genomes of one DS and two DR Beijing lineage isolates and the Euro-American lineage isolate using NGS data. Moreover, using both PacBio and NGS sequencing data, we obtained a high-quality assembly of an extensive DR Beijing lineage isolate. Comparative analysis of these five newly assembled genomes and two published complete genomes revealed a large number of genetic changes, including gene gains and losses, indels and translocations, suggesting rapid evolution of M. tuberculosis. We found the MazEF toxin-antitoxin system in all the seven isolates studied and several interesting mutations in MazEF proteins. Finally, we used the four assembled Beijing lineage genomes to construct a high-quality Beijing lineage reference genome that is DS and contains all the genes in the four genomes. It contains 212 genes not found in the standard reference H37Rv, which is Euro-American. It is therefore a better reference than H37Rv for the Beijing lineage, the predominant lineage in Asia.

Original languageEnglish (US)
Pages (from-to)3890-3905
Number of pages16
JournalGenome biology and evolution
Volume12
Issue number2
DOIs
StatePublished - Feb 8 2020

Keywords

  • Beijing lineage reference
  • Mycobacterium tuberculosis
  • TB genomes
  • drug resistance

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics

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