Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis

dc.contributorAalto Universityen
dc.contributor.authorSkwark, Marcin J.
dc.contributor.authorCroucher, Nicholas J.
dc.contributor.authorPuranen, Santeri
dc.contributor.authorChewapreecha, Claire
dc.contributor.authorPesonen, Maiju
dc.contributor.authorXu, Yingying
dc.contributor.authorTurner, Paul
dc.contributor.authorHarris, Simon R.
dc.contributor.authorBeres, Stephen B.
dc.contributor.authorMusser, James M.
dc.contributor.authorParkhill, Julian
dc.contributor.authorBentley, Stephen D.
dc.contributor.authorAurell, Erik
dc.contributor.authorCorander, Jukka
dc.contributor.departmentVanderbilt University
dc.contributor.departmentImperial College London
dc.contributor.departmentDepartment of Computer Science
dc.contributor.departmentUniversity of Cambridge
dc.contributor.departmentUniversity of Oxford
dc.contributor.departmentWellcome Trust Sanger Institute
dc.contributor.departmentHouston Methodist Hospital
dc.contributor.departmentCornell University
dc.contributor.departmentDepartment of Applied Physics
dc.description.abstractRecent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. We apply genomeDCA to two large population data sets representing the major human pathogens Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A Streptococcus). For pneumococcus we identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within the pbp2x, pbp1a and pbp2b genes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these antibiotic resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. The group A Streptococcus (GAS) data set population represents a clonal population with relatively little genetic variation and a high level of linkage disequilibrium across the genome. Despite this, we were able to pinpoint two RNA pseudouridine synthases, which were each strongly linked to a separate set of loci across the chromosome, representing biologically plausible targets of co-selection. The population genomic analysis method applied here identifies statistically significantly co-evolving locus pairs, potentially arising from fitness selection interdependence reflecting underlying protein-protein interactions, or genes whose product activities contribute to the same phenotype. This discovery approach greatly enhances the future potential of epistasis analysis forsystems biology, and can complement genome-wide association studies as a means of formulating hypotheses for targeted experimental work.en
dc.description.versionPeer revieweden
dc.identifier.citationSkwark , M J , Croucher , N J , Puranen , S , Chewapreecha , C , Pesonen , M , Xu , Y , Turner , P , Harris , S R , Beres , S B , Musser , J M , Parkhill , J , Bentley , S D , Aurell , E & Corander , J 2017 , ' Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis ' , PLoS Genetics , vol. 13 , no. 2 , e1006508 .
dc.identifier.otherPURE UUID: ffb5ea08-466b-42c4-b985-b81c90a985d4
dc.identifier.otherPURE ITEMURL:
dc.identifier.otherPURE LINK:
dc.identifier.otherPURE FILEURL:
dc.relation.ispartofseriesPLOS GENETICSen
dc.relation.ispartofseriesVolume 13, issue 2en
dc.titleInteracting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysisen
dc.typeA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessäfi