Institute of General Microbiology, Kiel University, Kiel, Germany.
Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany.
PLoS Pathog. 2020 Sep 30;16(9):e1008357. doi: 10.1371/journal.ppat.1008357. eCollection 2020 Sep.
In genome evolution, genetic variants are the source of diversity, which natural selection acts upon. Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. This suggests that epistatic interactions between indels and substitutions affect antibiotic resistance and compensatory evolution in MTB.
在基因组进化中，遗传变异是多样性的来源，自然选择作用于这些遗传变异。人类结核病（TB）的治疗会对感染的结核分枝杆菌（MTB）菌株中赋予抗生素耐药性的变异体产生强烈的选择压力。MTB 对治疗的反应已经得到了深入研究，主要归因于点突变。然而，插入和缺失（indels）对 MTB 基因组进化的频率和贡献仍知之甚少。在这里，我们分析了多药耐药 MTB 爆发，以确定是否存在高质量的 indels 和替换。我们发现，indels 在赋予抗生素耐药性的基因中显著富集。此外，我们表明 indels 在爆发期间是可遗传的，并遵循一个分子钟，其进化率为 5.37e-9 indels/site/年，比替换率低 23 倍。遗传的 indels 可能与相关生物途径中的基因中的替换同时发生；例如铁储存和对二线抗生素的耐药性。这表明 indels 和替换之间的上位性相互作用影响 MTB 的抗生素耐药性和补偿进化。
