LOGOS: A MODULAR BAYESIAN MODEL FOR DE NOVO MOTIF DETECTION

Abstract

The complexity of the global organization and internal structure of motifs in higher eukaryotic organisms raises significant challenges for motif detection techniques. To achieve successful de novo motif detection, it is necessary to model the complex dependencies within and among motifs and to incorporate biological prior knowledge. In this paper, we present LOGOS, an integrated LOcal and GlObal motif Sequence model for biopolymer sequences, which provides a principled framework for developing, modularizing, extending and computing expressive motif models for complex biopolymer sequence analysis. LOGOS consists of two interacting submodels: HMDM, a local alignment model capturing biological prior knowledge and positional dependency within the motif local structure; and HMM, a global motif distribution model modeling frequencies and dependencies of motif occurrences. Model parameters can be fit using training motifs within an empirical Bayesian framework. A variational EM algorithm is developed for de novo motif detection. LOGOS improves over existing models that ignore biological priors and dependencies in motif structures and motif occurrences, and demonstrates superior performance on both semi-realistic test data and cis-regulatory sequences from yeast and Drosophila genomes with regard to sensitivity, specificity, flexibility and extensibility.