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

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          Abstract

          Cefotaxime (CTX) is a third-generation cephalosporin (3GC) commonly used 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 harbouring antibiotic-resistance genes. The second is the introduction of mutations in the promoter region of the ampC β-lactamase gene that cause chromosome-encoded β-lactamase hyperproduction. A wide variety of promoter mutations related to AmpC hyperproduction have been described. However, their link to CTX resistance has not been reported. We recultured 172 cefoxitin-resistant E. coli isolates with known CTX minimum inhibitory concentrations 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 sequenced 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 five 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 (false discovery rate <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 underlines the role of recurrent mutations in the spread of antibiotic resistance.

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            The Sequence Alignment/Map format and SAMtools

            Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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              Basic local alignment search tool.

              A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score. Recent mathematical results on the stochastic properties of MSP scores allow an analysis of the performance of this method as well as the statistical significance of alignments it generates. The basic algorithm is simple and robust; it can be implemented in a number of ways and applied in a variety of contexts including straightforward DNA and protein sequence database searches, motif searches, gene identification searches, and in the analysis of multiple regions of similarity in long DNA sequences. In addition to its flexibility and tractability to mathematical analysis, BLAST is an order of magnitude faster than existing sequence comparison tools of comparable sensitivity.
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                Author and article information

                Journal
                Microb Genom
                Microb Genom
                mgen
                mgen
                Microbial Genomics
                Microbiology Society
                2057-5858
                2021
                12 April 2021
                12 April 2021
                : 7
                : 4
                : 000556
                Affiliations
                [ 1] Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboud University Medical Center , Nijmegen, The Netherlands
                [ 2] departmentDepartment of Infection Control , Amphia Ziekenhuis , Breda, The Netherlands
                [ 3] Laboratory for Medical Microbiology and Immunology, Elisabeth-Tweesteden Hospital , Tilburg, The Netherlands
                [ 4] Department of Human Genetics, Radboud University Medical Center , Nijmegen, The Netherlands
                [ 5] departmentLaboratory for Microbiology , Microvida , Breda, The Netherlands
                [ 6] Julius Center for Health Sciences and Primary Care, UMCU , Utrecht, The Netherlands
                [ 7] Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center , Nijmegen, The Netherlands
                Author notes
                *Correspondence: Jordy P. M. Coolen, jordy.coolen@ 123456radboudumc.nl
                [†]

                These authors share senior authorship.

                [‡]

                These authors also contributed equally to this work

                Author information
                https://orcid.org/0000-0003-0443-6250
                https://orcid.org/0000-0002-6092-5983
                https://orcid.org/0000-0002-7236-8934
                https://orcid.org/0000-0002-5446-2230
                https://orcid.org/0000-0003-2665-6844
                https://orcid.org/0000-0001-6189-5491
                Article
                000556
                10.1099/mgen.0.000556
                8208684
                33843573
                dbce8025-b457-4c93-b344-256d6ab00ff3
                © 2021 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.

                History
                : 08 July 2020
                : 11 March 2021
                Categories
                Research Articles
                Evolution and Responses to Interventions
                Custom metadata
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                ampc,bioinformatics,escherichia coli,genomics,whole-genome sequencing

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