title: Mycobacterium tuberculosis Complex Exhibits Lineage-Specific Variations Affecting Protein Ductility and Epitope Recognition.
abstract: The advent of whole-genome sequencing has provided an unprecedented detail about the evolution and genetic significance of species-specific variations across the whole Mycobacterium tuberculosis Complex. However, little attention has been focused on understanding the functional roles of these variations in the protein coding sequences. In this work, we compare the coding sequences from 74 sequenced mycobacterial species including M. africanum, M. bovis, M. canettii, M. caprae, M. orygis, and M. tuberculosis. Results show that albeit protein variations affect all functional classes, those proteins involved in lipid and intermediary metabolism and respiration have accumulated mutations during evolution. To understand the impact of these mutations on protein functionality, we explored their implications on protein ductility/disorder, a yet unexplored feature of mycobacterial proteomes. In agreement with previous studies, we found that a Gly71Ile substitution in the PhoPR virulence system severely affects the ductility of its nearby region in M. africanum and animal-adapted species. In the same line of evidence, the SmtB transcriptional regulator shows amino acid variations specific to the Beijing lineage, which affects the flexibility of the N-terminal trans-activation domain. Furthermore, despite the fact that MTBC epitopes are evolutionary hyperconserved, we identify strain- and lineage-specific amino acid mutations affecting previously known T-cell epitopes such as EsxH and FbpA (Ag85A). Interestingly, in silico studies reveal that these variations result in differential interaction of epitopes with the main HLA haplogroups.
authors.affiliation: Estación Experimental de Aula Dei-Consejo Superior de Investigaciones Científicas (EEAD-CSIC), Zaragoza, Spain.|Grupo de Bioquímica, Biofísica y Biología Computacional (BIFI, UNIZAR), Unidad Asociada I+D+i al CSIC, Zaragoza, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Yruela
authors.affiliation: Estación Experimental de Aula Dei-Consejo Superior de Investigaciones Científicas (EEAD-CSIC), Zaragoza, Spain.|Grupo de Bioquímica, Biofísica y Biología Computacional (BIFI, UNIZAR), Unidad Asociada I+D+i al CSIC, Zaragoza, Spain.|Fundación ARAID, Aragón, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Contreras-Moreira
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Magalhães
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Nuno S
authors.initials: NS
authors.lastname: Osório
authors.affiliation: Grupo de Genética de Micobacterias, Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.|CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.|Instituto de Biocomputación y Física de Sistemas Complejos (BIFI-UNIZAR), Zaragoza, Spain.|Servicio de Microbiología Hospital Universitario Miguel Servet, ISS Aragón, Zaragoza, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gonzalo-Asensio
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000939:Epitopes / Q000235:genetics; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D013045:Species Specificity
chemical_list: D000939:Epitopes
keywords: Mycobacterium; coding sequences; epitope polymorphisms; epitope-HLA binding; lineages; protein ductility