title: To Be or Not to Be a Pseudogene: A Molecular Epidemiological Approach to the mclx Genes and Its Impact in Tuberculosis.
abstract: Tuberculosis presents a myriad of symptoms, progression routes and propagation patterns not yet fully understood. Whereas for a long time research has focused solely on the patient immunity and overall susceptibility, it is nowadays widely accepted that the genetic diversity of its causative agent, Mycobacterium tuberculosis, plays a key role in this dynamic. This study focuses on a particular family of genes, the mclxs (Mycobacterium cyclase/LuxR-like genes), which codify for a particular and nearly mycobacterial-exclusive combination of protein domains. mclxs genes were found to be pseudogenized by frameshift-causing insertion(s)/deletion(s) in a considerable number of M. tuberculosis complex strains and clinical isolates. To discern the functional implications of the pseudogenization, we have analysed the pattern of frameshift-causing mutations in a group of M. tuberculosis isolates while taking into account their microbial-, patient- and disease-related traits. Our logistic regression-based analyses have revealed disparate effects associated with the transcriptional inactivation of two mclx genes. In fact, mclx2 (Rv1358) pseudogenization appears to be primarily driven by the microbial phylogenetic background, being mainly related to the Euro-American (EAm) lineage; on the other hand, mclx3 (Rv2488c) presents a higher tendency for pseudogenization among isolates from patients born on the Western Pacific area, and from isolates causing extra-pulmonary infections. These results contribute to the overall knowledge on the biology of M. tuberculosis infection, whereas at the same time launch the necessary basis for the functional assessment of these so far overlooked genes.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Lopes Santos
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal; National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: Nebenzahl-Guimaraes
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Vaz Mendes
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Correia-Neves
mesh_terms: D005260:Female; D005798:Genes, Bacterial / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D016680:Genome, Bacterial; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification; D010802:Phylogeny; D011544:Pseudogenes / Q000235:genetics*; D012189:Retrospective Studies; D014376:Tuberculosis / Q000382:microbiology*