1] Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [2] State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [3].
Nat Genet. 2013 Oct;45(10):1255-60. doi: 10.1038/ng.2735. Epub 2013 Sep 1.
The worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis threatens to make this disease incurable. Drug resistance mechanisms are only partially understood, and whether the current understanding of the genetic basis of drug resistance in M. tuberculosis is sufficiently comprehensive remains unclear. Here we sequenced and analyzed 161 isolates with a range of drug resistance profiles, discovering 72 new genes, 28 intergenic regions (IGRs), 11 nonsynonymous SNPs and 10 IGR SNPs with strong, consistent associations with drug resistance. On the basis of our examination of the dN/dS ratios of nonsynonymous to synonymous SNPs among the isolates, we suggest that the drug resistance-associated genes identified here likely contain essentially all the nonsynonymous SNPs that have arisen as a result of drug pressure in these isolates and should thus represent a near-complete set of drug resistance-associated genes for these isolates and antibiotics. Our work indicates that the genetic basis of drug resistance is more complex than previously anticipated and provides a strong foundation for elucidating unknown drug resistance mechanisms.
全球耐多药（MDR）和广泛耐药（XDR）结核病的出现威胁着使这种疾病无法治愈。耐药机制仅部分被理解，目前对结核分枝杆菌耐药的遗传基础的理解是否足够全面尚不清楚。在这里，我们对具有不同耐药谱的 161 个分离株进行了测序和分析，发现了 72 个新基因、28 个基因间区（IGR）、11 个非同义 SNP 和 10 个与耐药性具有强一致关联的 IGR SNP。基于我们对分离株中非同义 SNP 与同义 SNP 的 dN/dS 比值的检查，我们认为这里鉴定的耐药相关基因可能包含了由于这些分离株中药物压力而产生的几乎所有非同义 SNP，因此它们代表了这些分离株和抗生素的近完整的耐药相关基因集。我们的工作表明，耐药的遗传基础比以前预期的更为复杂，并为阐明未知的耐药机制提供了坚实的基础。
