文章摘要
陶必林,王钰婷,李忠奇,吴继周,王建明.基于全基因组测序估算结核分枝杆菌分子钟[J].中华流行病学杂志,2022,43(9):1462-1468
基于全基因组测序估算结核分枝杆菌分子钟
Estimation of molecular clock of Mycobacterium tuberculosis based on whole genome sequencing data
收稿日期:2022-04-08  出版日期:2022-09-09
DOI:10.3760/cma.j.cn112338-20220408-00272
中文关键词: 结核病;分子钟;突变率;全基因组测序
英文关键词: Tuberculosis;Molecular clock;Mutation rate;Whole genome sequencing
基金项目:国家自然科学基金(81973103);江苏卫生健康委员会医学科研项目(ZDB2020013);南京市重大科技专项(2021-11005)
作者单位E-mail
陶必林 南京医科大学公共卫生学院全球健康中心流行病学系, 南京 211166  
王钰婷 南京医科大学公共卫生学院全球健康中心流行病学系, 南京 211166  
李忠奇 南京医科大学公共卫生学院全球健康中心流行病学系, 南京 211166  
吴继周 南京医科大学公共卫生学院全球健康中心流行病学系, 南京 211166  
王建明 南京医科大学公共卫生学院全球健康中心流行病学系, 南京 211166
南京医科大学姑苏学院流行病学系, 南京 211166 
jmwang@njmu.edu.cn 
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中文摘要:
      目的 基于全基因组测序数据,通过内源性激活期间菌株基因组突变分析,开展结核分枝杆菌(MTB)分子钟研究。方法 筛选MTB内源性激活全基因组研究文献,下载全基因组测序数据,提取初治-复发配对样本单核苷酸多态性(SNP)差异和菌株分离时间,运用Poisson回归模型拟合初治-复发时间间隔与差异SNP的关系,计算MTB分子钟,估算突变率。结果 若MTB传代时间为18 h,0~2年短期内源性激活突变率为6.47×10-10(95%CI:5.59×10-10~7.44×10-10),明显高于2~14年长期内源性激活突变率(3.27×10-10,95%CI:2.88×10-10~3.69×10-10)。0~、1~、2~、3~、5~、7~14年突变率分别为7.10×10-10、6.06×10-10、4.24×10-10、5.34×10-10、2.59×10-10、1.26×10-10结论 内源性激活复发期间,MTB突变率随初治-复发时间间隔增加而下降,本研究从微观层面验证了临床实践观察到的初治结核病2年内易复发现象。
英文摘要:
      Objective To analyze the genomic mutation of Mycobacterium tuberculosis (M.tuberculosis) isolated in endogenous activation period and estimate the molecular clock based on the whole genome sequencing data.Methods Literatures of the whole genome research of endogenous reactivated tuberculosis were retrieved,and the corresponding whole genome sequencing data were downloaded.We extracted the single nucleotide polymorphisms (SNPs) and strain isolation time of initial treatment and relapse of tuberculosis cases,explored the relationship between the different SNPs and interval between initial treatment and relapse by Poisson regression model,calculated the M.tuberculosis molecular clock,and estimated the mutation rate.Results When the generation time of M.tuberculosis was 18 hours,the mutation rate in 0-2 years,i.e.short-term endogenous activation,was 6.47×10-10(95%CI:5.59×10-10-7.44×10-10),which was significantly higher than that in 2-14 years in long term endogenous activation (3.27×10-10,95%CI:2.88×10-10-3.69×10-10).The mutation rates of 0-,1-,2-,3-,5-and 7-14 years were 7.10×10-10,6.06×10-10,4.24×10-10,5.34×10-10,2.59×10-10 and 1.26×10-10 respectively.Conclusions In the period of endogenous reactivation,the mutation rate of M.tuberculosis decreases with the interval time between initial treatment and relapse,which verifies the clinically observed phenomenon that the relapse often occurs within two years after the initial treatment of tuberculosis.
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