作者
Maha R Farhat, Luca Freschi, Roger Calderon, Thomas Ioerger, Matthew Snyder, Conor J Meehan, Bouke de Jong, Leen Rigouts, Alex Sloutsky, Devinder Kaur, Shamil Sunyaev, Dick van Soolingen, Jay Shendure, Jim Sacchettini, Megan Murray
发表日期
2019/5/13
期刊
Nature communications
卷号
10
期号
1
页码范围
2128
出版商
Nature Publishing Group UK
简介
Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms …
引用总数
20192020202120222023202462137332513