Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints.
Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints.
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DOI：
10.1371/journal.pone.0007407
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发表时间：
2009-10-12
期刊：
影响因子：
3.7
通讯作者：
Archer JA
中科院分区：
文献类型：
--
作者：
Niemann S;Köser CU;Gagneux S;Plinke C;Homolka S;Bignell H;Carter RJ;Cheetham RK;Cox A;Gormley NA;Kokko-Gonzales P;Murray LJ;Rigatti R;Smith VP;Arends FP;Cox HS;Smith G;Archer JA
结核分枝杆菌复合体(MTBC)是结核病(TB)的病原体，具有低序列多样性的特点，使其成为基因单态病原体的经典例子之一。由于DNA序列变异有限，用于流行病学目的的临床MTBC分离株的常规基因分型依赖于基于流动和重复遗传元素的高度区分性的DNA指纹分析方法。根据标准观点，具有相同指纹模式的分离株被认为是同一细菌克隆的直系后代，很可能反映了个别患者中正在进行的传播或疾病复发。在这里，我们进一步研究了这一假设，并使用大规模平行全基因组测序方法比较了来自高发区(乌兹别克斯坦卡拉卡尔帕克斯坦)的一个快速传播的结核分枝杆菌北京基因型克隆的一个药物敏感株(K-1)和一个多药耐药株(K-2)。两个分离株在24个Miru-VNTR基因座中有23个具有相同的IS6110 RFLP图谱和相同的等位基因。我们产生了2,390万(K-1)和3,300万(K-2)成对的50bp纯度过滤读数，分别对应于483.5倍和656.1倍的平均覆盖率。与实验室毒株H37Rv相比，两株北京分离株都有1,209个SNPs。这两个北京分离株存在130个SNP和一个大片段缺失。敏感株有55个特异性SNPs，而MDR变异体有75个特异性SNPs，其中包括5个已知的与耐药性相关的突变。我们的结果表明，具有相同DNA指纹模式的结核分枝杆菌分离株可以包含大量的基因组多样性。由于传统的MTBC基因分型没有捕捉到这种异质性，结核病传播动力学的某些方面可能会被遗漏或误解。此外，如果循环克隆的总体多样性有限，使用标准的基因分型工具可能不可能有效区分疾病复发和外源性再感染。这些发现对抗结核新药的临床试验具有重要意义。
Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB), is characterized by low sequence diversity making this bacterium one of the classical examples of a genetically monomorphic pathogen. Because of this limited DNA sequence variation, routine genotyping of clinical MTBC isolates for epidemiological purposes relies on highly discriminatory DNA fingerprinting methods based on mobile and repetitive genetic elements. According to the standard view, isolates exhibiting the same fingerprinting pattern are considered direct progeny of the same bacterial clone, and most likely reflect ongoing transmission or disease relapse within individual patients. Here we further investigated this assumption and used massively parallel whole-genome sequencing to compare one drug-susceptible (K-1) and one multidrug resistant (MDR) isolate (K-2) of a rapidly spreading M. tuberculosis Beijing genotype clone from a high incidence region (Karakalpakstan, Uzbekistan). Both isolates shared the same IS6110 RFLP pattern and the same allele at 23 out of 24 MIRU-VNTR loci. We generated 23.9 million (K-1) and 33.0 million (K-2) paired 50 bp purity filtered reads corresponding to a mean coverage of 483.5 fold and 656.1 fold respectively. Compared with the laboratory strain H37Rv both Beijing isolates shared 1,209 SNPs. The two Beijing isolates differed by 130 SNPs and one large deletion. The susceptible isolate had 55 specific SNPs, while the MDR variant had 75 specific SNPs, including the five known resistance-conferring mutations. Our results suggest that M. tuberculosis isolates exhibiting identical DNA fingerprinting patterns can harbour substantial genomic diversity. Because this heterogeneity is not captured by traditional genotyping of MTBC, some aspects of the transmission dynamics of tuberculosis could be missed or misinterpreted. Furthermore, a valid differentiation between disease relapse and exogenous reinfection might be impossible using standard genotyping tools if the overall diversity of circulating clones is limited. These findings have important implications for clinical trials of new anti-tuberculosis drugs.
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影响因子：
15.8
作者：
Farmer PE;Nizeye B;Stulac S;Keshavjee S
通讯作者：
Keshavjee S
影响因子：
11.8
作者：
Cox, HS;Orozco, JD;Aziz, M
通讯作者：
Aziz, M
影响因子：
9.4
作者：
Kamerbeek, J;Schouls, L;vanEmbden, J
通讯作者：
vanEmbden, J
影响因子：
11.8
作者：
Cowley, Donna;Govender, Dhirendra;Nicol, Mark P.
通讯作者：
Nicol, Mark P.
DOI：
10.1196/annals.1425.009
发表时间：
2008-01-01
期刊：
REDUCING THE IMPACT OF POVERTY ON HEALTH AND HUMAN DEVELOPMENT: SCIENTIFIC APPROACHES
影响因子：
--
作者：
Keshavjee, S.;Gelmanova, I. Y.;Shin, S. S.
通讯作者：
Shin, S. S.