Abstract
BackgroundIt has recently become possible to rapidly and accurately detect epigenetic signatures in bacterial genomes using third generation sequencing data. Monitoring the speed at which a single polymerase inserts a base in the read strand enables one to infer whether a modification is present at that specific site on the template strand. These sites can be challenging to detect in the absence of high coverage and reliable reference genomes.MethodsHere we provide a new method for detecting epigenetic motifs in bacteria on datasets with low-coverage, with incomplete references, and with mixed samples (i.e. metagenomic data). Our approach treats motif inference as a kmer comparison problem. First, genomes (or contigs) are deconstructed into kmers. Then, native genome-wide distributions of interpulse durations (IPDs) for kmers are compared with corresponding whole genome amplified (WGA, modification free) IPD distributions using log likelihood ratios. Finally, kmers are ranked and greedily selected by iteratively correcting for sequences within a particular kmer's neighborhood.ConclusionsOur method can detect multiple types of modifications, even at very low-coverage and in the presence of mixed genomes. Additionally, we are able to predict modified motifs when genomes with "neighbor" modified motifs exist within the sample. Lastly, we show that these motifs can provide an alternative source of information by which to cluster metagenomics contigs and that iterative refinement on these clustered contigs can further improve both sensitivity and specificity of motif detection.Availabilityhttps://github.com/alibashir/EMMCKmer
Highlights
It has recently become possible to rapidly and accurately detect epigenetic signatures in bacterial genomes using third generation sequencing data
They range from directed and controlled modifications to more irregular damage events [6,7]. These modifications can trigger a wide variety of functions, such as origin of replication firing in E. coli [8,9] and gene silencing in humans [10]
DNA methylation has been most commonly seen on cytosine at position 5 (m5C) [10,12]
Summary
It has recently become possible to rapidly and accurately detect epigenetic signatures in bacterial genomes using third generation sequencing data. Monitoring the speed at which a single polymerase inserts a base in the read strand enables one to infer whether a modification is present at that specific site on the template strand. These sites can be challenging to detect in the absence of high coverage and reliable reference genomes. DNA modification can occur in a wide variety of living organisms, from bacteriophages [1,2] to prokaryotes [3,4] and eukaryotes [5] They range from directed and controlled modifications to more irregular damage events [6,7].
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