Editing Mycobacterium tuberculosis (section)

==Genome==
The genome of the [[H37Rv]] strain was published in 1998.<ref name="Deciphering the biology of Mycobact"/><ref>{{cite web |url=http://www.sanger.ac.uk/Projects/M_tuberculosis/ |title=''Mycobacterium tuberculosis'' |publisher=Sanger Institute |date=2007-03-29 |access-date=2008-11-16 |archive-date=9 November 2008 |archive-url=https://web.archive.org/web/20081109114150/http://www.sanger.ac.uk/Projects/M_tuberculosis/ |url-status=live}}</ref> Its size is 4 million base pairs, with 3,959 genes; 40% of these genes have had their function characterized, with possible function postulated for another 44%. Within the genome are also six [[pseudogene]]s.{{citation needed|date=May 2024}}

'''Fatty acid metabolism'''. The genome contains 250 genes involved in [[fatty acid]] metabolism, with 39 of these involved in the [[polyketide]] metabolism generating the waxy coat. Such large numbers of conserved genes show the evolutionary importance of the waxy coat to pathogen survival. Furthermore, experimental studies have since validated the importance of a lipid metabolism for'' M. tuberculosis'', consisting entirely of host-derived lipids such as fats and cholesterol. Bacteria isolated from the lungs of infected mice were shown to preferentially use fatty acids over carbohydrate substrates.<ref>{{cite journal | vauthors = Bloch H, Segal W | title = Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro | journal = Journal of Bacteriology | volume = 72 | issue = 2 | pages = 132–41 | date = August 1956 | doi = 10.1128/JB.72.2.132-141.1956 | pmid = 13366889 | pmc = 357869 | url =}}</ref> ''M. tuberculosis'' can also grow on the lipid [[cholesterol]] as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of ''M. tuberculosis'', especially during the chronic phase of infection when other nutrients are likely not available.<ref>{{cite journal | vauthors = Wipperman MF, Sampson NS, Thomas ST | title = Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 49 | issue = 4 | pages = 269–93 | date = 2014 | pmid = 24611808 | pmc = 4255906 | doi = 10.3109/10409238.2014.895700}}</ref>

'''PE/PPE gene families'''. About 10% of the coding capacity is taken up by the ''PE''/''PPE'' gene families that encode acidic, glycine-rich proteins. These proteins have a conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas.<ref>{{cite journal | vauthors = Glickman MS, Jacobs WR | title = Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline | journal = Cell | volume = 104 | issue = 4 | pages = 477–85 | date = February 2001 | pmid = 11239406 | doi = 10.1016/S0092-8674(01)00236-7 | s2cid = 11557497 | doi-access = free}}</ref>

'''Noncoding RNAs'''. [[Mycobacterium tuberculosis sRNA|Nine noncoding sRNAs]] have been characterised in ''M. tuberculosis'',<ref>{{cite journal | vauthors = Arnvig KB, Young DB | title = Identification of small RNAs in Mycobacterium tuberculosis | journal = Molecular Microbiology | volume = 73 | issue = 3 | pages = 397–408 | date = August 2009 | pmid = 19555452 | pmc = 2764107 | doi = 10.1111/j.1365-2958.2009.06777.x}}</ref> with a further 56 predicted in a [[bioinformatics]] screen.<ref>{{cite journal | vauthors = Livny J, Brencic A, Lory S, Waldor MK | title = Identification of 17 Pseudomonas aeruginosa sRNAs and prediction of sRNA-encoding genes in 10 diverse pathogens using the bioinformatic tool sRNAPredict2 | journal = Nucleic Acids Research | volume = 34 | issue = 12 | pages = 3484–93 | year = 2006 | pmid = 16870723 | pmc = 1524904 | doi = 10.1093/nar/gkl453}}</ref>

'''Antibiotic resistance genes'''. In 2013, a study on the genome of several sensitive, ultraresistant, and multiresistant ''M. tuberculosis'' strains was made to study antibiotic resistance mechanisms. Results reveal new relationships and drug resistance genes not previously associated and suggest some genes and intergenic regions associated with drug resistance may be involved in the resistance to more than one drug. Noteworthy is the role of the intergenic regions in the development of this resistance, and most of the genes proposed in this study to be responsible for drug resistance have an essential role in the development of ''M. tuberculosis''.<ref>{{cite journal | vauthors = Zhang H, Li D, Zhao L, Fleming J, Lin N, Wang T, Liu Z, Li C, Galwey N, Deng J, Zhou Y, Zhu Y, Gao Y, Wang T, Wang S, Huang Y, Wang M, Zhong Q, Zhou L, Chen T, Zhou J, Yang R, Zhu G, Hang H, Zhang J, Li F, Wan K, Wang J, Zhang XE, Bi L | title = Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance | journal = Nature Genetics | volume = 45 | issue = 10 | pages = 1255–60 | date = October 2013 | pmid = 23995137 | doi = 10.1038/ng.2735 | s2cid = 14396673}}</ref>

'''Epigenome'''. [[Single-molecule real-time sequencing]] and subsequent bioinformatic analysis has identified three [[DNA methyltransferase]]s in ''M. tuberculosis,'' <u>'''M'''</u>ycobacterial '''<u>A</u>'''denine '''<u>M</u>'''ethyltransferases A (MamA),<ref name=":11">{{cite journal | vauthors = Shell SS, Prestwich EG, Baek SH, Shah RR, Sassetti CM, Dedon PC, Fortune SM | title = DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis | journal = PLOS Pathogens | volume = 9 | issue = 7 | pages = e1003419 | date = 2013-07-04 | pmid = 23853579 | pmc = 3701705 | doi = 10.1371/journal.ppat.1003419 | doi-access = free}}</ref> B (MamB),<ref>{{cite journal | vauthors = Zhu L, Zhong J, Jia X, Liu G, Kang Y, Dong M, Zhang X, Li Q, Yue L, Li C, Fu J, Xiao J, Yan J, Zhang B, Lei M, Chen S, Lv L, Zhu B, Huang H, Chen F | title = Precision methylome characterization of Mycobacterium tuberculosis complex (MTBC) using PacBio single-molecule real-time (SMRT) technology | journal = Nucleic Acids Research | volume = 44 | issue = 2 | pages = 730–743 | date = January 2016 | pmid = 26704977 | pmc = 4737169 | doi = 10.1093/nar/gkv1498}}</ref> and C (MamC'').<ref name=":12">{{cite journal | vauthors = Modlin SJ, Conkle-Gutierrez D, Kim C, Mitchell SN, Morrissey C, Weinrick BC, Jacobs WR, Ramirez-Busby SM, Hoffner SE, Valafar F | title = Drivers and sites of diversity in the DNA adenine methylomes of 93 ''Mycobacterium tuberculosis'' complex clinical isolates | journal = eLife | volume = 9 | pages = e58542 | date = October 2020 | pmid = 33107429 | doi = 10.7554/eLife.58542 | doi-access = free | veditors = Stallings CL, Soldati-Favre D, Casadesús J | pmc = 7591249}}</ref> ''All three are [[DNA adenine methylase|adenine methyltransferases]], and each are functional in some clinical strains of ''M. tuberculosis''and not in others.''<ref>{{cite journal | vauthors = Phelan J, de Sessions PF, Tientcheu L, Perdigao J, Machado D, Hasan R, Hasan Z, Bergval IL, Anthony R, McNerney R, Antonio M, Portugal I, Viveiros M, Campino S, Hibberd ML, Clark TG | title = Methylation in Mycobacterium tuberculosis is lineage specific with associated mutations present globally | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 160 | date = January 2018 | pmid = 29317751 | doi = 10.1038/s41598-017-18188-y | pmc = 5760664 | bibcode = 2018NatSR...8..160P | hdl = 10362/116703 | hdl-access = free}}</ref><ref name=":12" /> ''Unlike DNA methyltransferases in most bacteria, which invariably methylate the [[adenine]]s at their targeted sequence,<ref>{{cite journal | vauthors = Blow MJ, Clark TA, Daum CG, Deutschbauer AM, Fomenkov A, Fries R, Froula J, Kang DD, Malmstrom RR, Morgan RD, Posfai J, Singh K, Visel A, Wetmore K, Zhao Z, Rubin EM, Korlach J, Pennacchio LA, Roberts RJ | title = The Epigenomic Landscape of Prokaryotes | journal = PLOS Genetics | volume = 12 | issue = 2 | pages = e1005854 | date = February 2016 | pmid = 26870957 | pmc = 4752239 | doi = 10.1371/journal.pgen.1005854 | doi-access = free}}</ref> some strains of ''M. tuberculosis'' carry mutations in MamA that cause partial methylation of targeted adenine bases.<ref name=":12" /> This occurs as intracellular stochastic methylation, where a some targeted adenine bases on a given DNA molecule are methylated while others remain unmethylated.<ref name=":12" /><ref>{{cite journal | vauthors = Beaulaurier J, Zhang XS, Zhu S, Sebra R, Rosenbluh C, Deikus G, Shen N, Munera D, Waldor MK, Chess A, Blaser MJ, Schadt EE, Fang G | title = Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes | journal = Nature Communications | volume = 6 | issue = 1 | pages = 7438 | date = June 2015 | pmid = 26074426 | pmc = 4490391 | doi = 10.1038/ncomms8438 | bibcode = 2015NatCo...6.7438B}}</ref> MamA mutations causing intercellular mosaic methylation are most common in the globally successful Beijing sublineage of ''M. tuberculosis.<ref name=":12" />'' Due to the influence of methylation on gene expression at some locations in the genome,<ref name=":11" /> it has been hypothesized that IMM may give rise to phenotypic diversity, and partially responsible for the global success of Beijing sublineage.<ref name=":12" />