Large-scale genomic analysis shows association between homoplastic genetic variation in Mycobacterium tuberculosis genes and meningeal or pulmonary tuberculosis

Ruesen, Carolien; Chaidir, Lidya; Laarhoven, Arjan van; Dian, Sofiati; Ganiem, Ahmad Rizal; Nebenzahl-Guimaraes, Hanna; Huynen, Martijn; Alisjahbana, Bachti; Dutilh, Bas E.; Crevel, Reinout van

doi:10.1186/s12864-018-4498-z

Cited by 20 publications

(34 citation statements)

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“…The use of genomic data to detect homoplasy events is not an uncommon scientific technique [52][53][54]. In Mycobacterium tuberculosis, it is a well-known method to identify advantageous mutations, as they are likely to be associated with phenotypes such as drug resistance, heightened transmissibility, or host adaptation [12][13][14][15]. A similar approach was taken recently by Benjak et al to screen for highly polymorphic genes and genomic regions of Mycobacterium leprae [55].…”

Section: Discussionmentioning

confidence: 99%

“…A similar approach was taken recently by Benjak et al to screen for highly polymorphic genes and genomic regions of Mycobacterium leprae [55]. Homoplasy-based association analysis limits phylogenetic bias by correcting for genetic relatedness of strains with the same phenotype, thereby increasing statistical power to find true associations [14]. Taking this into account, the use of homoplasybased association analysis seems viable to relate polymorphic sites to phenotypic traits in bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…One can use the Consistency Index to recognize genomic locations subjected to homoplasy, and relate the single-nucleotide polymorphism (SNP) positions that are inconsistent with the phylogeny to antibiotic resistance, as has e.g. been done in multiple studies on Mycobacteria spp [12][13][14][15].…”

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confidence: 99%

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Genome-wide analysis in Escherichia coli unravels an unprecedented level of genetic homoplasy associated with cefotaxime resistance

Coolen¹,

Drijver

Verweij

et al. 2020

Preprint

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ABSTRACTCefotaxime (CTX) is a commonly used third-generation cephalosporin (3GC) to treat infections caused by Escherichia coli. Two genetic mechanisms have been associated with 3GC resistance in E. coli. The first is the conjugative transfer of a plasmid harboring antibiotic resistance genes. The second is the introduction of mutations in the promoter region of the ampC β-lactamase gene that cause chromosomal-encoded β-lactamase hyperproduction. A wide variety of promoter mutations related to AmpC hyperproduction have been described. However, their link to a specific 3GC such as CTX resistance has not been reported. Here, we measured CTX MICs in 172 cefoxitin resistant E. coli isolates and performed genome-wide analysis of homoplastic mutations associated with CTX resistance by comparing Illumina whole-genome sequencing data of all isolates to a PacBio tailored-made reference chromosome. We mapped the mutations on the reference chromosome and determined their occurrence in the phylogeny, revealing extreme homoplasy at the −42 position of the ampC promoter. The 24 occurrences of a “T” at the −42 position rather than the wild type “C”, resulted from 18 independent C>T mutations in 5 phylogroups. The −42 C>T mutation was only observed in E. coli lacking a plasmid-encoded ampC gene. The association of the −42 C>T mutation with CTX resistance was confirmed to be significant (FDR < 0.05). To conclude, genome-wide analysis of homoplasy in combination with CTX resistance identifies the −42 C>T mutation of the ampC promotor as significantly associated with CTX resistance and underline the role of recurrent mutations in the spread of antibiotics resistance.Impact StatementIn the past decades, the worldwide spread of extended spectrum beta-lactamases (ESBLs) has led to a substantial increase in the prevalence of resistant common pathogens, thereby restricting available treatment options. Although acquired resistance genes, e.g. ESBLs, get most attention, chromosome-encoded resistance mechanisms may play an important role as well. In E. coli chromosome-encoded β-lactam resistance can be caused by alterations in the promoter region of the ampC gene. To improve our understanding of how frequently these alterations occur, a comprehensive interpretation of the evolution of these mutations is essential. This study is the first to apply genome-wide homoplasy analysis to better perceive adaptation of the E. coli genome to antibiotics. Thereby, this study grants insights into how chromosomal-encoded antibiotic resistance evolves and, by combining genome-wide association studies with homoplasy analyses, provides potential strategies for future association studies into the causes of antibiotics resistance.Data summaryAll data is available under BioProject: PRJNA592140. Raw Illumina sequencing data and metadata of all 171 E. coli isolates used in this study is available from the Sequence Read Archive database under accession no. SAMN15052485 to SAMN15052655. Full reference chromosome of ampC_0069 is available via GenBank accession no. CP046396.1 and NCBI Reference Sequence: NZ_CP046396.1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genome-wide analysis in Escherichia coli unravels an unprecedented level of genetic homoplasy associated with cefotaxime resistance

Coolen¹,

Drijver

Verweij

et al. 2020

Preprint

Self Cite

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“…The majority of the tuberculosis burden and deaths are concentrated in middle-income countries. There are few studies making attempts to relate extrapulmonary forms of the disease to a specific genetic variant of M. tuberculosis on a genome-wide scale ( 2 – 4 ). In order to continue efforts to identify a genetic variant that could impact disease severity and tissue tropism, more genome sequences of extrapulmonary strains from different geographic regions need to be analyzed.…”

Section: Genome Announcementmentioning

confidence: 99%

“…In order to continue efforts to identify a genetic variant that could impact disease severity and tissue tropism, more genome sequences of extrapulmonary strains from different geographic regions need to be analyzed. However, no meningeal isolates of M. tuberculosis from Latin America were represented in databases or bioinformatics analyses ( 4 ). M. tuberculosis strain MYC004 was isolated by the Laboratorio Estatal de Salud Pública, from the cerebrospinal fluid of a male patient diagnosed in 2012 with tuberculous meningitis in Michoacán, Mexico.…”

Section: Genome Announcementmentioning

confidence: 99%