title: Relaxed selection drives a noisy noncoding transcriptome in members of the Mycobacterium tuberculosis complex.
abstract: Related species are often used to understand the molecular underpinning of virulence through examination of a shared set of biological features attributable to a core genome of orthologous genes. An important but insufficiently studied issue, however, is the extent to which the regulatory architectures are similarly conserved. A small number of studies have compared the primary transcriptomes of different bacterial species, but few have compared closely related species with clearly divergent evolutionary histories. We addressed the impact of differing modes of evolution within the genus Mycobacterium through comparison of the primary transcriptome of M. marinum with that of a closely related lineage, M. bovis. Both are thought to have evolved from an ancestral generalist species, with M. bovis and other members of the M. tuberculosis complex having subsequently undergone downsizing of their genomes during the transition to obligate pathogenicity. M. marinum, in contrast, has retained a large genome, appropriate for an environmental organism, and is a broad-host-range pathogen. We also examined changes over a shorter evolutionary time period through comparison of the primary transcriptome of M. bovis with that of another member of the M. tuberculosis complex (M. tuberculosis) which possesses an almost identical genome but maintains a distinct host preference. Importance: Our comparison of the transcriptional start site (TSS) maps of M. marinum and M. bovis uncovers a pillar of conserved promoters, noncoding RNA (NCRNA), and a genome-wide signal in the -35 promoter regions of both species. We identify evolutionarily conserved transcriptional attenuation and highlight its potential contribution to multidrug resistance mediated through the transcriptional regulator whiB7. We show that a species population history is reflected in its transcriptome and posit relaxed selection as the main driver of an abundance of canonical -10 promoter sites in M. bovis relative to M. marinum. It appears that transcriptome composition in mycobacteria is driven primarily by the availability of such sites and that their frequencies diverge significantly across the mycobacterial clade. Finally, through comparison of M. bovis and M. tuberculosis, we illustrate that single nucleotide polymorphism (SNP)-driven promoter differences likely underpin many of the transcriptional differences between M. tuberculosis complex lineages.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Dinan
authors.affiliation: Wellcome Trust Cell Biology Centre, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pin
authors.initials: P
authors.lastname: Tong
authors.affiliation: UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lohan
authors.affiliation: UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Conlon
authors.forename: Aleksandra A
authors.initials: AA
authors.lastname: Miranda-CasoLuengo
authors.affiliation: UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Kerri M
authors.initials: KM
authors.lastname: Malone
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Gordon
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland brendan.loftus@ucd.ie.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Loftus
mesh_terms: D019143:Evolution, Molecular; D016680:Genome, Bacterial / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
references.citation: Nature. 2010 Mar 11;464(7286):250-5
references.pmid: 20164839
references.citation: PLoS One. 2013 Nov 14;8(11):e79411
references.pmid: 24244498
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7877-82
references.pmid: 12788972
references.citation: Nat Methods. 2013 Dec;10(12):1211-2
references.pmid: 24097270
references.citation: J Bacteriol. 2011 Nov;193(22):6305-14
references.pmid: 21908667
references.citation: Nucleic Acids Res. 2010 Oct;38(19):6637-51
references.pmid: 20525796
references.citation: RNA. 2013 Jan;19(1):74-84
references.pmid: 23169799
references.citation: PLoS One. 2007 Aug 15;2(8):e745
references.pmid: 17710145
references.citation: Tuberculosis (Edinb). 2007 Jul;87(4):347-59
references.pmid: 17433778
references.citation: PLoS Biol. 2008 Dec 16;6(12):e311
references.pmid: 19090620
references.citation: Tuberculosis (Edinb). 2010 Sep;90(5):311-8
references.pmid: 20810321
references.citation: Microbiology (Reading). 2007 Oct;153(Pt 10):3323-3336
references.pmid: 17906132
references.citation: PLoS Genet. 2012;8(8):e1002867
references.pmid: 22912590
references.citation: PLoS Pathog. 2011 Nov;7(11):e1002342
references.pmid: 22072964
references.citation: Nat Rev Microbiol. 2006 Sep;4(9):670-81
references.pmid: 16912712
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Antimicrob Agents Chemother. 2013 Apr;57(4):1857-65
references.pmid: 23380727
references.citation: Genome Res. 2012 Apr;22(4):721-34
references.pmid: 22377718
references.citation: Genome Res. 2008 May;18(5):729-41
references.pmid: 18403782
references.citation: Int J Med Microbiol. 2013 Dec;303(8):674-7
references.pmid: 24189285
references.citation: Mol Microbiol. 1997 Dec;26(5):991-1003
references.pmid: 9426136
references.citation: Genome Biol. 2009;10(3):R25
references.pmid: 19261174
references.citation: Cell Rep. 2013 Nov 27;5(4):1121-31
references.pmid: 24268774
references.citation: BMC Genomics. 2013 Mar 05;14:145
references.pmid: 23496945
references.citation: Nat Commun. 2014 Mar 24;5:3501
references.pmid: 24662426
references.citation: Annu Rev Microbiol. 2008;62:53-70
references.pmid: 18785837
references.citation: Mol Microbiol. 2009 Feb;71(4):811-24
references.pmid: 19170872
references.citation: J Biol Chem. 2013 Nov 29;288(48):34514-28
references.pmid: 24126912
references.citation: Nucleic Acids Res. 2010 Jul;38(12):4067-78
references.pmid: 20181675
references.citation: J Biol Chem. 2012 Jan 2;287(1):299-310
references.pmid: 22069311
references.citation: Nature. 2001 Feb 22;409(6823):1007-11
references.pmid: 11234002
references.citation: Genome Biol. 2010;11(9):R97
references.pmid: 20920266
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3134-9
references.pmid: 24453212
references.citation: Genome Res. 2009 Sep;19(9):1639-45
references.pmid: 19541911
references.citation: BMC Bioinformatics. 2009 May 20;10:154
references.pmid: 19457249
references.citation: BMC Genomics. 2013 Oct 17;14:710
references.pmid: 24134787
references.citation: Tuberculosis (Edinb). 2013 Jan;93(1):18-25
references.pmid: 23273318
references.citation: PLoS Genet. 2010 Sep 09;6(9):e1001115
references.pmid: 20838599
references.citation: mBio. 2012 Aug 07;3(4):
references.pmid: 22872780
references.citation: Mol Cell. 2011 Sep 16;43(6):880-91
references.pmid: 21925377
references.citation: Genome Biol. 2011 Oct 11;12(10):R98
references.pmid: 21989159
references.citation: Nat Methods. 2008 Jul;5(7):621-8
references.pmid: 18516045
references.citation: Mol Cell. 2013 Dec 12;52(5):629-42
references.pmid: 24239289
references.citation: Genome Biol Evol. 2013;5(10):1849-62
references.pmid: 24115728
references.citation: BMC Genomics. 2012 Mar 28;13:120
references.pmid: 22452820
references.citation: Infect Immun. 2009 Oct;77(10):4654-67
references.pmid: 19651861
references.citation: PLoS One. 2012;7(12):e51950
references.pmid: 23284830
references.citation: Trends Microbiol. 2011 Apr;19(4):156-61
references.pmid: 21277778
references.citation: Mol Cell. 2008 Apr 25;30(2):190-202
references.pmid: 18439898
references.citation: PLoS One. 2013 Sep 16;8(9):e74209
references.pmid: 24066122
references.citation: Science. 2003 Nov 21;302(5649):1401-4
references.pmid: 14631042
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12200-5
references.pmid: 16103351