Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis

被引：305

作者：

Farhat, Maha R. ^{[1
]}

Shapiro, B. Jesse ^{[2
,3
,4
,5
]}

Kieser, Karen J. ^{[6
]}

Sultana, Razvan ^{[7
]}

Jacobson, Karen R. ^{[8
,9
]}

Victor, Thomas C. ^{[9
]}

Warren, Robin M. ^{[9
]}

Streicher, Elizabeth M. ^{[9
]}

Calver, Alistair ^{[10
]}

Sloutsky, Alex ^{[11
]}

Kaur, Devinder ^{[11
]}

Posey, Jamie E. ^{[12
]}

Plikaytis, Bonnie ^{[12
]}

Oggioni, Marco R. ^{[13
]}

Gardy, Jennifer L. ^{[14
]}

Johnston, James C. ^{[15
]}

Rodrigues, Mabel ^{[16
]}

Tang, Patrick K. C. ^{[16
]}

Kato-Maeda, Midori ^{[17
]}

Borowsky, Mark L.

Muddukrishna, Bhavana ^{[18
,19
]}

Kreiswirth, Barry N. ^{[20
]}

Kurepina, Natalia ^{[20
]}

Galagan, James ^{[2
,21
,22
,23
]}

Gagneux, Sebastien ^{[24
,25
]}

Birren, Bruce ^{[2
]}

Rubin, Eric J. ^{[6
]}

Lander, Eric S. ^{[2
]}

Sabeti, Pardis C. ^{[2
,3
,4
,6
]}

Murray, Megan ^{[26
,27
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pulm & Crit Care, Boston, MA 02114 USA

[2] Eli & Edythe L Broad Inst, Cambridge, MA USA

[3] Harvard Univ, Fac Arts & Sci, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA

[4] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA

[5] Univ Montreal, Dept Sci Biol, Montreal, PQ H3C 3J7, Canada

[6] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Dept Bioinformat & Computat Biol, Boston, MA 02115 USA

[8] Boston Univ, Sch Med, Infect Dis Sect, Boston, MA 02118 USA

[9] Univ Stellenbosch, Fac Med & Hlth Sci, Ctr Mol & Cellular Biol,Dept Sci & Technol,Div Mo, MRC,Natl Res Fdn Ctr Excellence Biomed IB Res, ZA-7505 Tygerberg, South Africa

[10] Anglogold Ashanti Hlth West Vaal Hosp, Orkney, South Africa

[11] Univ Massachusetts, Sch Med, Massachusetts Supranat TB Reference Lab, Boston, MA 02125 USA

[12] Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA USA

[13] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[14] British Columbia Ctr Dis Control, Communicable Dis Prevent & Control Serv, Vancouver, BC, Canada

[15] British Columbia Ctr Dis Control, Clin Prevent Serv, Vancouver, BC, Canada

[16] British Columbia Ctr Dis Control, Prov Hlth Serv Author Labs, Publ Hlth Microbiol & Reference Lab, Mycobacteriol TB Lab, Vancouver, BC, Canada

[17] Univ Calif San Francisco, Div Pulm & Crit Care, San Francisco, CA 94143 USA

[18] Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA 02114 USA

[19] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[20] State Univ New Jersey, Rutgers, Publ Hlth Res Inst TB Ctr, Newark, NJ USA

[21] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA

[22] Boston Univ, Dept Microbiol, Boston, MA 02215 USA

[23] Boston Univ, Bioinformat Program, Boston, MA 02215 USA

[24] Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[25] Univ Basel, Basel, Switzerland

[26] Harvard Univ, Dept Global Hlth & Social Med, Boston, MA 02115 USA

[27] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 10期

基金：

瑞士国家科学基金会;

关键词：

INTRINSIC MULTIDRUG-RESISTANCE; COMPENSATORY MUTATIONS; 2-COMPONENT SYSTEM; RIFAMPIN-RESISTANT; ESCHERICHIA-COLI; FITNESS; GENES; SUSCEPTIBILITY; ANTIBIOTICS; EXPRESSION;

D O I：

10.1038/ng.2747

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis whole genomes, we identified genome-wide signatures of positive selection specific to the 47 drug-resistant strains. By searching for convergent evolution-the independent fixation of mutations in the same nucleotide position or gene-we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode components in cell wall biosynthesis, transcriptional regulation and DNA repair pathways. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin.

引用

页码：1183 / U320

页数：9

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