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dc.contributor.authorFarhat, Maha R.
dc.contributor.authorFreschi, Luca
dc.contributor.authorCalderon, Roger
dc.contributor.authorIoerger, Thomas
dc.contributor.authorSnyder, Matthew
dc.contributor.authorMeehan, Conor J.
dc.contributor.authorde Jong, Bouke
dc.contributor.authorRigouts, Leen
dc.contributor.authorSloutsky, Alexander
dc.contributor.authorKaur, Devinder
dc.contributor.authorSunyaev, Shamil
dc.contributor.authorvan Soolingen, Dick
dc.contributor.authorShendure, Jay
dc.contributor.authorSacchettini, Jim
dc.contributor.authorMurray, Megan
dc.date2022-08-11T08:09:53.000
dc.date.accessioned2022-08-23T16:47:22Z
dc.date.available2022-08-23T16:47:22Z
dc.date.issued2019-05-13
dc.date.submitted2019-07-08
dc.identifier.citation<p>Nat Commun. 2019 May 13;10(1):2128. doi: 10.1038/s41467-019-10110-6. <a href="https://doi.org/10.1038/s41467-019-10110-6">Link to article on publisher's site</a></p>
dc.identifier.issn2041-1723 (Linking)
dc.identifier.doi10.1038/s41467-019-10110-6
dc.identifier.pmid31086182
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41066
dc.description.abstractDrug 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 associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31086182&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectGenome-wide association studies
dc.subjectAntimicrobial resistance
dc.subjectBacterial genetics
dc.subjectTuberculosis
dc.subjectBacteria
dc.subjectBacterial Infections and Mycoses
dc.subjectGenetic Phenomena
dc.subjectImmunology and Infectious Disease
dc.subjectMicrobiology
dc.titleGWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions
dc.typeArticle
dc.source.journaltitleNature communications
dc.source.volume10
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4872&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3857
dc.identifier.contextkey14880261
refterms.dateFOA2022-08-23T16:47:22Z
html.description.abstract<p>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 associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.</p>
dc.identifier.submissionpathoapubs/3857
dc.contributor.departmentDepartment of Medicine
dc.contributor.departmentNew England Newborn Screening Program
dc.contributor.departmentMassachusetts Supranational TB Reference Laboratory
dc.source.pages2128


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Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.