title: Evidence for diversifying selection in a set of Mycobacterium tuberculosis genes in response to antibiotic- and nonantibiotic-related pressure.
abstract: Tuberculosis (TB) is a global health problem estimated to kill 1.4 million people per year. Recent advances in the genomics of the causative agents of TB, bacteria known as the Mycobacterium tuberculosis complex (MTBC), have allowed a better comprehension of its population structure and provided the foundation for molecular evolution analyses. These studies are crucial for a better understanding of TB, including the variation of vaccine efficacy and disease outcome, together with the emergence of drug resistance. Starting from the analysis of 73 publicly available genomes from all the main MTBC lineages, we have screened for evidences of positive selection, a set of 576 genes previously associated with drug resistance or encoding membrane proteins. As expected, because antibiotics constitute strong selective pressure, some of the codons identified correspond to the position of confirmed drug-resistance-associated substitutions in the genes embB, rpoB, and katG. Furthermore, we identified diversifying selection in specific codons of the genes Rv0176 and Rv1872c coding for MCE1-associated transmembrane protein and a putative l-lactate dehydrogenase, respectively. Amino acid sequence analyses showed that in Rv0176, sites undergoing diversifying selection were in a predicted antigen region that varies between "modern" lineages and "ancient" MTBC/BCG strains. In Rv1872c, some of the sites under selection are predicted to impact protein function and thus might result from metabolic adaptation. These results illustrate that diversifying selection in MTBC is happening as a consequence of both antibiotic treatment and other evolutionary pressures.
authors: Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal. nosorio@ecsaude.uminho.pt
authors: Nuno S
authors: NS
authors: Osório
authors: Fernando
authors: F
authors: Rodrigues
authors: Sebastien
authors: S
authors: Gagneux
authors: Jorge
authors: J
authors: Pedrosa
authors: Marta
authors: M
authors: Pinto-Carbó
authors: António G
authors: AG
authors: Castro
authors: Douglas
authors: D
authors: Young
authors: Iñaki
authors: I
authors: Comas
authors: Margarida
authors: M
authors: Saraiva
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D024881:Drug Resistance, Bacterial; D019143:Evolution, Molecular; D005798:Genes, Bacterial; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins
keywords: Mycobacterium; computational molecular biology; diversifying selection; drug resistance; evolution; genetic diversity; genomics; phylogeny; positive selection; tuberculosis