Cao Xin, Cao Cuihua, Chen Zefan, Li Jialin, Yao Zikun, Zheng Yidong, Wu Jinjin, Li Zeling, Hu Yueming, Hao Gaofeng, Zhu Guoqiang, Köster Wolfgang, White Aaron P, Wang Yejun
Youth Innovation Team of Medical Bioinformatics, Shenzhen University Medical School, Shenzhen, Guangdong, China.
Department of Bioinformatics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Appl Environ Microbiol. 2025 Jun 18;91(6):e0055725. doi: 10.1128/aem.00557-25. Epub 2025 May 30.
Several genes in Gram-negative bacteria encoding outer membrane proteins (OMPs) have been reported to show patterns of mosaic evolution featured by a mixture of negative selection and local recombination. Here, we improved a strategy and applied it to screen OMPs under mosaic evolution in at the genome level. In total, 21 OMP families, including 16 new ones, were detected with the typical patterns of mosaic evolution. An absolute majority of the protein families are conserved in for the composition, genomic loci, and the overall structures. Highly variable regions (HVRs) can be recognized, which are frequently located extracellularly within the protruding loops. There is only a limited number of major HVR sequence types, within which positively selected sites can be detected occassionally. Based on the simulated results of multiple models, the OMPs under mosaic evolution are often with good antigenicity, with HVRs of various sequence types coinciding with the B-cell epitopes of the strongest immunogenicity. The study further broadened our understanding of the characteristics of mosaic evolution and the functions of OMPs in Gram-negative bacteria, laying an important foundation for their potential translational applications.IMPORTANCEIt is important to understand the evolutionary mechanisms of bacterial OMP-encoding genes, which would facilitate the development of anti-bacterial reagents. This study made the first genome-wide screening of bacterial OMPs under mosaic evolution and increased the list of candidate OMP families by threefold in , far more than we expected. The study further confirmed the hypothesis about the evolutionary, micro-evolutionary, and structural features of these OMPs and facilitated the functional theory of mosaic evolution. Moreover, the findings of limited HVR sequence types and strong immunogenicity of HVRs paved an important foundation for the application of these OMPs and their HVRs in the development of antibodies or other antibacterial treatment.
据报道，革兰氏阴性菌中几个编码外膜蛋白（OMP）的基因呈现出镶嵌进化模式，其特征是负选择和局部重组相结合。在此，我们改进了一种策略，并将其应用于在基因组水平上筛选处于镶嵌进化状态的OMP。总共检测到21个OMP家族，包括16个新家族，它们具有典型的镶嵌进化模式。绝大多数蛋白质家族在组成、基因组位点和整体结构方面在[具体物种]中是保守的。可以识别出高度可变区域（HVR），这些区域通常位于细胞外的突出环内。主要的HVR序列类型数量有限，在这些类型中偶尔可以检测到正选择位点。基于多种模型的模拟结果，处于镶嵌进化状态的OMP通常具有良好的抗原性，不同序列类型的HVR与免疫原性最强的B细胞表位相吻合。该研究进一步拓宽了我们对革兰氏阴性菌中镶嵌进化特征和OMP功能的理解，为其潜在的转化应用奠定了重要基础。
了解细菌OMP编码基因的进化机制对于促进抗菌试剂的开发很重要。本研究首次在全基因组范围内筛选处于镶嵌进化状态的细菌OMP，并使[具体物种]中候选OMP家族的数量增加了两倍，远远超出我们的预期。该研究进一步证实了关于这些OMP的进化、微观进化和结构特征的假设，并推动了镶嵌进化的功能理论。此外，HVR序列类型有限以及HVR具有强免疫原性的发现为这些OMP及其HVR在抗体开发或其他抗菌治疗中的应用奠定了重要基础。
