Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis. Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resist...

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Autores principales:	Tatum D. Mortimer, Alexandra M. Weber, Caitlin S. Pepperell
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Mycobacterium tuberculosis antibiotic resistance evolution genomics positive selection Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4b85698be3954282b6b71fb330d54639
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spelling	oai:doaj.org-article:4b85698be3954282b6b71fb330d546392021-12-02T18:15:43ZSignatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mSystems.00108-172379-5077https://doaj.org/article/4b85698be3954282b6b71fb330d546392018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00108-17https://doaj.org/toc/2379-5077ABSTRACT Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis. Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resistant M. tuberculosis arises solely by de novo chromosomal mutation. Using whole-genome sequencing data from two natural populations of M. tuberculosis, we characterized the population genetics of known drug resistance loci using measures of diversity, population differentiation, and convergent evolution. We found resistant subpopulations to be less diverse than susceptible subpopulations, consistent with ongoing transmission of resistant M. tuberculosis. A subset of resistance genes (“sloppy targets”) were characterized by high diversity and multiple rare variants; we posit that a large genetic target for resistance and relaxation of purifying selection contribute to high diversity at these loci. For “tight targets” of selection, the path to resistance appeared narrower, evidenced by single favored mutations that arose numerous times in the phylogeny and segregated at markedly different frequencies in resistant and susceptible subpopulations. These results suggest that diverse genetic architectures underlie drug resistance in M. tuberculosis and that combined approaches are needed to identify causal mutations. Extrapolating from patterns observed for well-characterized genes, we identified novel candidate variants involved in resistance. The approach outlined here can be extended to identify resistance variants for new drugs, to investigate the genetic architecture of resistance, and when phenotypic data are available, to find candidate genetic loci underlying other positively selected traits in clonal bacteria. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tuberculosis populations. Identifying the mutations that cause drug resistance in M. tuberculosis is important for guiding TB treatment and halting the spread of drug resistance. Whole-genome sequencing (WGS) of M. tuberculosis isolates can be used to identify novel mutations mediating drug resistance and to predict resistance patterns faster than traditional methods of drug susceptibility testing. We have used WGS from natural populations of drug-resistant M. tuberculosis to characterize effects of selection for advantageous mutations on patterns of diversity at genes involved in drug resistance. The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in M. tuberculosis and other clonal pathogens.Tatum D. MortimerAlexandra M. WeberCaitlin S. PepperellAmerican Society for MicrobiologyarticleMycobacterium tuberculosisantibiotic resistanceevolutiongenomicspositive selectionMicrobiologyQR1-502ENmSystems, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis antibiotic resistance evolution genomics positive selection Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis antibiotic resistance evolution genomics positive selection Microbiology QR1-502 Tatum D. Mortimer Alexandra M. Weber Caitlin S. Pepperell Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis. Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resistant M. tuberculosis arises solely by de novo chromosomal mutation. Using whole-genome sequencing data from two natural populations of M. tuberculosis, we characterized the population genetics of known drug resistance loci using measures of diversity, population differentiation, and convergent evolution. We found resistant subpopulations to be less diverse than susceptible subpopulations, consistent with ongoing transmission of resistant M. tuberculosis. A subset of resistance genes (“sloppy targets”) were characterized by high diversity and multiple rare variants; we posit that a large genetic target for resistance and relaxation of purifying selection contribute to high diversity at these loci. For “tight targets” of selection, the path to resistance appeared narrower, evidenced by single favored mutations that arose numerous times in the phylogeny and segregated at markedly different frequencies in resistant and susceptible subpopulations. These results suggest that diverse genetic architectures underlie drug resistance in M. tuberculosis and that combined approaches are needed to identify causal mutations. Extrapolating from patterns observed for well-characterized genes, we identified novel candidate variants involved in resistance. The approach outlined here can be extended to identify resistance variants for new drugs, to investigate the genetic architecture of resistance, and when phenotypic data are available, to find candidate genetic loci underlying other positively selected traits in clonal bacteria. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tuberculosis populations. Identifying the mutations that cause drug resistance in M. tuberculosis is important for guiding TB treatment and halting the spread of drug resistance. Whole-genome sequencing (WGS) of M. tuberculosis isolates can be used to identify novel mutations mediating drug resistance and to predict resistance patterns faster than traditional methods of drug susceptibility testing. We have used WGS from natural populations of drug-resistant M. tuberculosis to characterize effects of selection for advantageous mutations on patterns of diversity at genes involved in drug resistance. The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in M. tuberculosis and other clonal pathogens.
format	article
author	Tatum D. Mortimer Alexandra M. Weber Caitlin S. Pepperell
author_facet	Tatum D. Mortimer Alexandra M. Weber Caitlin S. Pepperell
author_sort	Tatum D. Mortimer
title	Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	signatures of selection at drug resistance loci in <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/4b85698be3954282b6b71fb330d54639
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Signatures of Selection at Drug Resistance Loci in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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