Insertion and deletion evolution reflects antibiotics selection pressure in a Mycobacterium tuberculosis outbreak
In genome evolution, genetic variants are the source of diversity, which natural selection acts upon. Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB...
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| description | In genome evolution, genetic variants are the source of diversity, which natural selection acts upon. Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. This suggests that epistatic interactions between indels and substitutions affect antibiotic resistance and compensatory evolution in MTB. |
| doi_str_mv | 10.1371/journal.ppat.1008357 |
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Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. This suggests that epistatic interactions between indels and substitutions affect antibiotic resistance and compensatory evolution in MTB.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1008357</identifier><identifier>PMID: 32997707</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anti-Bacterial Agents - pharmacology ; Antibiotic resistance ; Antibiotics ; Antitubercular Agents - pharmacology ; Biology and Life Sciences ; Causes of ; Computer and Information Sciences ; Disease Outbreaks - prevention & control ; Drug resistance ; Epidemics ; Epistasis ; Evolution ; Evolution, Molecular ; Genes ; Genetic aspects ; Genetic diversity ; Genetic engineering ; Genetic variance ; Genetic variation ; Genome - genetics ; Genomes ; Genomics ; Germany ; Health aspects ; Humans ; Infections ; Insertion ; Medicine and Health Sciences ; Microbial drug resistance ; Multidrug resistance ; Mutation ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - genetics ; Mycobacterium tuberculosis - pathogenicity ; Natural selection ; Outbreaks ; RNA polymerase ; Selection, Genetic ; Tuberculosis ; Tuberculosis - genetics</subject><ispartof>PLoS pathogens, 2020-09, Vol.16 (9), p.e1008357</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Godfroid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. Inherited indels may co-occur with substitutions in genes along related biological pathways; examples are iron storage and resistance to second-line antibiotics. 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Treatment of human tuberculosis (TB) induces a strong selection pressure for the emergence of antibiotic resistance-conferring variants in the infecting Mycobacterium tuberculosis (MTB) strains. MTB evolution in response to treatment has been intensively studied and mainly attributed to point substitutions. However, the frequency and contribution of insertions and deletions (indels) to MTB genome evolution remains poorly understood. Here, we analyzed a multi-drug resistant MTB outbreak for the presence of high-quality indels and substitutions. We find that indels are significantly enriched in genes conferring antibiotic resistance. Furthermore, we show that indels are inherited during the outbreak and follow a molecular clock with an evolutionary rate of 5.37e-9 indels/site/year, which is 23 times lower than the substitution rate. 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| subjects | Anti-Bacterial Agents - pharmacology Antibiotic resistance Antibiotics Antitubercular Agents - pharmacology Biology and Life Sciences Causes of Computer and Information Sciences Disease Outbreaks - prevention & control Drug resistance Epidemics Epistasis Evolution Evolution, Molecular Genes Genetic aspects Genetic diversity Genetic engineering Genetic variance Genetic variation Genome - genetics Genomes Genomics Germany Health aspects Humans Infections Insertion Medicine and Health Sciences Microbial drug resistance Multidrug resistance Mutation Mycobacterium tuberculosis Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - pathogenicity Natural selection Outbreaks RNA polymerase Selection, Genetic Tuberculosis Tuberculosis - genetics |
| title | Insertion and deletion evolution reflects antibiotics selection pressure in a Mycobacterium tuberculosis outbreak |
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