Sequence element enrichment analysis to determine the genetic basis of bacterial phenotypes

John A. Lees, Minna Vehkala, Niko Välimäki, Simon R. Harris, Claire Chewapreecha, Nicholas J. Croucher, Pekka Marttinen, Mark R. Davies, Andrew C. Steer, Steven Y C Tong, Antti Honkela, Julian Parkhill, Stephen D. Bentley, Jukka Corander

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    Abstract

    Bacterial genomes vary extensively in terms of both gene content and gene sequence. This plasticity hampers the use of traditional SNP-based methods for identifying all genetic associations with phenotypic variation. Here we introduce a computationally scalable and widely applicable statistical method (SEER) for the identification of sequence elements that are significantly enriched in a phenotype of interest. SEER is applicable to tens of thousands of genomes by counting variable-length k-mers using a distributed string-mining algorithm. Robust options are provided for association analysis that also correct for the clonal population structure of bacteria. Using large collections of genomes of the major human pathogens Streptococcus pneumoniae and Streptococcus pyogenes, SEER identifies relevant previously characterized resistance determinants for several antibiotics and discovers potential novel factors related to the invasiveness of S. pyogenes. We thus demonstrate that our method can answer important biologically and medically relevant questions.

    Original languageEnglish
    Article number12797
    Pages (from-to)1-8
    Number of pages8
    JournalNature Communications
    Volume7
    DOIs
    Publication statusPublished - 16 Sep 2016

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    Lees, J. A., Vehkala, M., Välimäki, N., Harris, S. R., Chewapreecha, C., Croucher, N. J., ... Corander, J. (2016). Sequence element enrichment analysis to determine the genetic basis of bacterial phenotypes. Nature Communications, 7, 1-8. [12797]. https://doi.org/10.1038/ncomms12797