Fast and memory-efficient mapping of short bisulfite sequencing reads using a two-letter alphabet

DNA cytosine methylation is an important epigenomic mark with a wide range of functions in many organisms. Whole genome bisulfite sequencing is the gold standard to interrogate cytosine methylation genome-wide. Algorithms used to map bisulfite-converted reads often encode the four-base DNA alphabet with three letters by reducing two bases to a common letter. This encoding substantially reduces the entropy of nucleotide frequencies in the resulting reference genome. Within the paradigm of read mapping by first filtering possible candidate alignments, reduced entropy in the sequence space can increase the required computing effort. We introduce another bisulfite mapping algorithm (abismal), based on the idea of encoding a four-letter DNA sequence as only two letters, one for purines and one for pyrimidines. We show that this encoding can lead to greater specificity compared to existing encodings used to map bisulfite sequencing reads. Through the two-letter encoding, the abismal software tool maps reads in less time and using less memory than most bisulfite sequencing read mapping software tools, while attaining similar accuracy. This allows in silico methylation analysis to be performed in a wider range of computing machines with limited hardware settings.