鼠疫耶尔森菌低毒种群基因组多样性和选择压力分析

doi:10.16288/j.yczz.25-318

遗传 ›› 2026, Vol. 48 ›› Issue (8): 828-841.doi: 10.16288/j.yczz.25-318

鼠疫耶尔森菌低毒种群基因组多样性和选择压力分析

张佳怡¹^,²(), 贾艺华²^,³, 穆凯², 崔梦楠², 潘海峰¹, 崔玉军¹^,²(), 武雅蓉²()

¹ 安徽医科大学，公共卫生学院，合肥 230032
² 军事科学院军事医学研究院，病原微生物生物安全全国重点实验室，北京 100071
³ 苏州大学，苏州医学院药学院，苏州 215000

收稿日期:2025-12-03 修回日期:2026-02-06 出版日期:2026-08-20 发布日期:2026-02-27
通讯作者: 崔玉军，博士，研究员，研究方向：微生物进化与溯源。E-mail: cuiyujun.new@gmail.com；
武雅蓉，博士，助理研究员，研究方向：微生物进化与溯源。E-mail: wuyarong525@126.com
作者简介:张佳怡，硕士研究生，专业方向：流行病与卫生统计学。E-mail: 2345010442@stu.ahmu.edu.cn
基金资助:
国家重点研发计划(2024YFC2310100);国家自然科学基金项目(32500006)

Genomic diversity and selection pressure analyses of low-virulence Yersinia pestis lineages

Jiayi Zhang¹^,²(), Yihua Jia²^,³, Kai Mu², Mengnan Cui², Haifeng Pan¹, Yujun Cui¹^,²(), Yarong Wu²()

¹ School of Public Health, Anhui Medical University, Hefei 230032, China
² State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
³ School of Pharmacy, Suzhou Medical College, Soochow University, Suzhou 215000, China

Received:2025-12-03 Revised:2026-02-06 Published:2026-08-20 Online:2026-02-27
Supported by:
National Key Research and Development Program of China(2024YFC2310100);National Natural Science Foundation of China(32500006)

摘要/Abstract

摘要：

鼠疫耶尔森菌(Yersinia pestis)是引发鼠疫的烈性病原体，曾造成三次历史大流行，目前分布于全球多个活跃的自然疫源地，对人类健康与公共安全构成严重威胁。不同型别的鼠疫菌在毒力上存在显著差异，其中 0.PE4 谱系的田鼠型菌株对大型哺乳动物几乎无毒。比较低毒与高毒种群的基因组差异有助于阐明毒力的演化基础，但目前针对低毒种群仍缺乏涵盖多类型变异的系统性群体水平基因组学研究。本研究整合我国历年监测数据及公共数据库中其他国家和地区的菌株基因组，共纳入169株低毒菌株和215株高毒主要谱系代表菌株序列。系统发育与时空分布分析显示，0.PE4低毒种群呈现明显的地理聚集性，其中分布于中国及蒙古国的0.PE4.3亚群进一步分化为3个具有地域特征的三级谱系，并在内蒙古地区形成2个更细分的四级谱系。与高毒主要谱系的比较基因组分析鉴定出低毒种群最近共同祖先及其各亚群分支上固定的变异。其中，81个SNP、19 个Indel和5个大片段缺失为所有低毒菌株所特有，代表了低毒种群最近共同祖先的基因组特征。结合选择压力信号分析，共鉴定出5个受到强选择作用的基因(ail、rovA、tssH、cdiA、alr)，分别与毒力、代谢和适应性相关。本研究重建了全球范围内鼠疫菌低毒种群的精细系统发育拓扑结构，揭示了其进化过程中的关键基因组变异，为鼠疫监测、溯源与毒力演化机制研究提供了重要参考。

关键词: 鼠疫耶尔森菌, 毒力, 低毒种群, 系统发育分析, 比较基因组学, 选择压力

Abstract:

Yersinia pestis, the causative agent of plague, is a highly virulent pathogen that has caused three historical pandemics and currently persists in multiple active natural foci worldwide, posing a serious threat to human health and public safety. Distinct phylogenetic lineages of Y. pestis exhibit differences in virulence, among which the Microtus biovar within the 0.PE4 lineage is nearly avirulent to large mammals. Comparative genomics between low-virulence and highly virulent populations is therefore key to elucidating the evolutionary basis of virulence. However, comprehensive population-genomic analysis of the low-virulence lineage remains limited, particularly those integrating multiple types of genomic variations. In this study, we analyzed 169 low-virulence strains and 215 representative high-virulence strains collected from long-term national surveillance data in China and public databases. Phylogenetic and spatiotemporal analyses revealed geographic clustering within the low-virulence 0.PE4 lineage. The 0.PE4.3 subclade circulating in China and Mongolia was further subdivided into three regionally associated tertiary lineages, with two more finely resolved quaternary lineages identified specifically in Inner Mongolia. Comparative genomic analyses with representative high-virulence genomes identified mutations fixed in the most recent common ancestor (MRCA) of the low-virulence population and its subclades. Among these, 81 single nucleotide polymorphisms (SNPs), 19 insertion and deletions (Indels), and 5 large fragment losses are shared by all low-virulence strains, defining the genomic features of their MRCA. Together with selection pressure analysis, we identified five genes (ail, rovA, tssH, cdiA, and alr) under strong positive selection, which are involved in virulence, metabolism, and adaptation. Collectively, this study reconstructs the phylogenetic topology of the global low-virulence Y. pestis population and identifies key genomic variations that occurred during its evolutionary process, providing valuable insights for fine-scale tracing and identifying potential molecular targets for elucidating virulence mechanisms.

Key words: Yersinia pestis, virulence, low-virulence lineage, phylogenetic analysis, comparative genomics, selection pressure

张佳怡, 贾艺华, 穆凯, 崔梦楠, 潘海峰, 崔玉军, 武雅蓉. 鼠疫耶尔森菌低毒种群基因组多样性和选择压力分析[J]. 遗传, 2026, 48(8): 828-841.

Jiayi Zhang, Yihua Jia, Kai Mu, Mengnan Cui, Haifeng Pan, Yujun Cui, Yarong Wu. Genomic diversity and selection pressure analyses of low-virulence Yersinia pestis lineages[J]. Hereditas(Beijing), 2026, 48(8): 828-841.

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变异	突变类型	突变个数	占比(%)	总计*
SNP	同义突变	131	20.66	634
	非同义突变	332	52.36
	无义突变	18	2.84
	间区	153	24.13
Indel	移码突变	775	57.75	1,342(1,329)
	非移码突变	254	19.71
	间区	283	23.24

片段	参考	染色体/质粒	起始	终止	长度	基因数	基因编号	基因名	功能
S1	CO92	pMT1质粒	73881	74369	489	1	YPMT1.73	-	磷脂代谢与信号传导
S2	CO92	染色体	2253549	2257250	3702	3	YPO1985、YPO1986、YPO1987	-	糖基化修饰
S3	CO92	染色体	2350433	2352337	1905	1	YPO2071	-	DNA解旋酶DinG样蛋白
S4	CO92	染色体	2370557	2403064	32508	42	YPO2096~YPO2134	tnpA、rzpR、 y1062	噬菌体相关功能
S5	CO92	染色体	2789116	2790121	1006	2	YPO2488、YPO2489	-	DUF2247 家族蛋白
S6	CO92	染色体	1923715	1924944	1230	1	YPO1687	alr	广谱型氨基酸消旋酶
S7	CO92	染色体	2537797	2538729	933	1	YPO2258	araC	AraC 家族转录调控因子
S8	CO92	染色体	3402002	3404908	2907	2	YPO3046、YPO3047	ydeN	硫酸酯酶

鼠疫耶尔森菌低毒种群基因组多样性和选择压力分析

Genomic diversity and selection pressure analyses of low-virulence Yersinia pestis lineages

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