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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/33000
Title: Comprehensive Identification of Single Nucleotide Polymorphisms Associated with Beta-lactam Resistance within Pneumococcal Mosaic Genes
Authors: Claire Chewapreecha
Pekka Marttinen
Nicholas J. Croucher
Susannah J. Salter
Simon R. Harris
Alison E. Mather
William P. Hanage
David Goldblatt
Francois H. Nosten
Claudia Turner
Paul Turner
Stephen D. Bentley
Julian Parkhill
Wellcome Trust Sanger Institute
Harvard School of Public Health
Aalto University
Imperial College London
UCL Institute of Child Health
Mahidol University
Nuffield Department of Clinical Medicine
Angkor Hospital for Children
University of Cambridge
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 7-Aug-2014
Citation: PLoS Genetics. Vol.10, No.8 (2014)
Abstract: © 2014 Chewapreecha et al. Traditional genetic association studies are very difficult in bacteria, as the generally limited recombination leads to large linked haplotype blocks, confounding the identification of causative variants. Beta-lactam antibiotic resistance in Streptococcus pneumoniae arises readily as the bacteria can quickly incorporate DNA fragments encompassing variants that make the transformed strains resistant. However, the causative mutations themselves are embedded within larger recombined blocks, and previous studies have only analysed a limited number of isolates, leading to the description of “mosaic genes” as being responsible for resistance. By comparing a large number of genomes of beta-lactam susceptible and non-susceptible strains, the high frequency of recombination should break up these haplotype blocks and allow the use of genetic association approaches to identify individual causative variants. Here, we performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) and indels that could confer beta-lactam non-susceptibility using 3,085 Thai and 616 USA pneumococcal isolates as independent datasets for the variant discovery. The large sample sizes allowed us to narrow the source of beta-lactam non-susceptibility from long recombinant fragments down to much smaller loci comprised of discrete or linked SNPs. While some loci appear to be universal resistance determinants, contributing equally to non-susceptibility for at least two classes of beta-lactam antibiotics, some play a larger role in resistance to particular antibiotics. All of the identified loci have a highly non-uniform distribution in the populations. They are enriched not only in vaccine-targeted, but also non-vaccine-targeted lineages, which may raise clinical concerns. Identification of single nucleotide polymorphisms underlying resistance will be essential for future use of genome sequencing to predict antibiotic sensitivity in clinical microbiology.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84908135412&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/33000
ISSN: 15537404
15537390
Appears in Collections:Scopus 2011-2015

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