dinucleotide weight matrices for predicting transcription factor binding sites generalizing the position weight matrix二核苷酸权重矩阵预测转录因子结合位点推广位置权重矩阵.pdfVIP

Dinucleotide Weight Matrices for Predicting Transcription Factor Binding Sites: Generalizing the Position Weight Matrix Rahul Siddharthan* The Institute of Mathematical Sciences, Chennai, Tamil Nadu, India Abstract Background: Identifying transcription factor binding sites (TFBS) in silico is key in understanding gene regulation. TFBS are string patterns that exhibit some variability, commonly modelled as ‘‘position weight matrices’’ (PWMs). Though convenient, the PWM has significant limitations, in particular the assumed independence of positions within the binding motif; and predictions based on PWMs are usually not very specific to known functional sites. Analysis here on binding sites in yeast suggests that correlation of dinucleotides is not limited to near-neighbours, but can extend over considerable gaps. Methodology/Principal Findings: I describe a straightforward generalization of the PWM model, that considers frequencies of dinucleotides instead of individual nucleotides. Unlike previous efforts, this method considers all dinucleotides within an extended binding region, and does not make an attempt to determine a priori the significance of particular dinucleotide correlations. I describe how to use a ‘‘dinucleotide weight matrix’’ (DWM) to predict binding sites, dealing in particular with the complication that its entries are not independent probabilities. Benchmarks show, for many factors, a dramatic improvement over PWMs in precision of predicting known targets. In most cases, significant further improvement arises by extending the commonly defined ‘‘core motifs’’ by about 10bp on either side. Though this flanking sequence shows no strong motif at the nucleotide level, the predictive power of the dinucleotide model suggests that the ‘‘signature’’ in DNA sequence of protein-binding affinity extends beyond the core p