Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis
Title | Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Skwark, MJ, Croucher, NJ, Puranen, S, Chewapreecha, C, Pesonen, M, Xu, YY, Turner, P, Harris, SR, Beres, SB, Musser, JM, Parkhill, J, Bentley, SD, Aurell, E, Corander, J |
Journal | PLoS Genet |
Volume | 13 |
Issue | 2 |
Pagination | e1006508 |
Date Published | Feb |
ISBN Number | 1553-7404 (Electronic)1553-7390 (Linking) |
Abstract | Recent 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 for systems biology, and can complement genome-wide association studies as a means of formulating hypotheses for targeted experimental work. |
URL | http://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006508&type=printable |