Set cover-based methods for motif selection.

Motivation: De novo motif discovery algorithms find statistically over-represented sequence motifs that may function as transcription factor binding sites. Current methods often report large numbers of motifs, making it difficult to perform further analyses and experimental validation. The motif selection problem seeks to identify a minimal set of putative regulatory motifs that characterize sequences of interest (e.g. ChIP-Seq binding regions).

Results: In this study, the motif selection problem is mapped to variants of the set cover problem that are solved via tabu search and by relaxed integer linear programing (RILP). The algorithms are employed to analyze 349 ChIP-Seq experiments from the ENCODE project, yielding a small number of high-quality motifs that represent putative binding sites of primary factors and cofactors. Specifically, when compared with the motifs reported by Kheradpour and Kellis, the set cover-based algorithms produced motif sets covering 35% more peaks for 11 TFs and identified 4 more putative cofactors for 6 TFs. Moreover, a systematic evaluation using nested cross-validation revealed that the RILP algorithm selected fewer motifs and was able to cover 6% more peaks and 3% fewer background regions, which reduced the error rate by 7%.

Availability And Implementation: The source code of the algorithms and all the datasets are available at https://github.com/YichaoOU/Set_cover_tools.

Supplementary Information: Supplementary data are available at Bioinformatics online.