title: The Bioinformatics Analysis of Comparative Genomics ofMycobacterium tuberculosisComplex (MTBC) Provides Insight into Dissimilarities between Intraspecific Groups Differing in Host Association, Virulence, and Epitope Diversity.
abstract: Tuberculosis now exceeds HIV as the top infectious disease cause of mortality, and is caused by theMycobacterium tuberculosiscomplex (MTBC). MTBC strains have highly conserved genome sequences (similarity >99%) but dramatically different phenotypes. To analyze the relationship between genotype and phenotype, we conducted the comparative genomic analysis on 12 MTBC strains representing different lineages (i.e.,Mycobacterium bovis;M. bovisBCG;M. microti;M. africanum;M. tuberculosisH37Rv;M. tuberculosisH37Ra, and sixM. tuberculosisclinical isolates). The analysis focused on the three aspects of pathogenicity: host association, virulence, and epitope variations. Host association analysis indicated that eightmce3genes, two enoyl-CoA hydratases, and five PE/PPE family genes were present only in human isolates; these may have roles in host-pathogen interactions. There were 15 SNPs found on virulence factors (including five SNPs in three ESX secretion proteins) only in the Beijing strains, which might be related to their more virulent phenotype. A comparison between the virulent H37Rv and non-virulent H37Ra strains revealed three SNPs that were likely associated with the virulence attenuation of H37Ra: S219L (PhoP), A219E (MazG) and a newly identified I228M (EspK). Additionally, a comparison of animal-associated MTBC strains showed that the deletion of the first four genes (i.e.,pe35, ppe68, esxB, esxA), rather than all eight genes of RD1, might play a central role in the virulence attenuation of animal isolates. Finally, by comparing epitopes among MTBC strains, we found that four epitopes were lost only in the Beijing strains; this may render them better capable of evading the human immune system, leading to enhanced virulence. Overall, our comparative genomic analysis of MTBC strains reveals the relationship between the highly conserved genotypes and the diverse phenotypes of MTBC, provides insight into pathogenic mechanisms, and facilitates the development of potential molecular targets for the prevention and treatment of tuberculosis.
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Xinmiao
authors.initials: X
authors.lastname: Jia
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Mengxing
authors.initials: M
authors.lastname: Dong
authors.affiliation: National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute Beijing, China.
authors.forename: Suting
authors.initials: S
authors.lastname: Chen
authors.affiliation: National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute Beijing, China.
authors.forename: Lingna
authors.initials: L
authors.lastname: Lv
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of Sciences Beijing, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Cao
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of Sciences Beijing, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Xiangli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute Beijing, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shang
authors.affiliation: National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute Beijing, China.
authors.forename: Guirong
authors.initials: G
authors.lastname: Wang
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University Changchun, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute Beijing, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Huang
authors.affiliation: CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China; Sino-Danish College, University of Chinese Academy of SciencesBeijing, China; Collaborative Innovation Center for Genetics and DevelopmentShanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
mesh_terms: D000818:Animals; D019295:Computational Biology; D000939:Epitopes / Q000235:genetics*; D016680:Genome, Bacterial; D054884:Host-Pathogen Interactions; D006801:Humans; D009161:Mycobacterium / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D011110:Polymorphism, Genetic; D037521:Virulence Factors / Q000235:genetics*
chemical_list: D000939:Epitopes; D037521:Virulence Factors
keywords: Mycobacterium tuberculosis complex (MTBC); PacBio; comparative genomics; epitope; host association; pathogenicity; tuberculosis (TB); virulence