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

## TL;DR

This paper introduces SEER, a new method to identify genetic elements linked to bacterial traits using genome data.

## Contribution

SEER is a novel scalable method for identifying sequence elements enriched in bacterial phenotypes, accounting for clonal structure.

## Key findings

- SEER identifies known resistance determinants in Streptococcus pneumoniae using large genome collections.
- The method is computationally scalable and corrects for bacterial clonal population structure.

## 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 even 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 characterised 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.