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Bioinformatics. 2017 Oct 1;33(19):3003-3010. doi: 10.1093/bioinformatics/btx336.

DNA sequence+shape kernel enables alignment-free modeling of transcription factor binding.

Author information

1
Department of Statistics, University of California Riverside, Riverside, CA 92521, USA.
2
Molecular and Computational Biology Program, Departments of Biological Sciences, Chemistry, Physics, and Computer Science, University of Southern California, Los Angeles, CA 90089, USA.
3
Department of Genome Sciences, Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA.

Abstract

Motivation:

Transcription factors (TFs) bind to specific DNA sequence motifs. Several lines of evidence suggest that TF-DNA binding is mediated in part by properties of the local DNA shape: the width of the minor groove, the relative orientations of adjacent base pairs, etc. Several methods have been developed to jointly account for DNA sequence and shape properties in predicting TF binding affinity. However, a limitation of these methods is that they typically require a training set of aligned TF binding sites.

Results:

We describe a sequence + shape kernel that leverages DNA sequence and shape information to better understand protein-DNA binding preference and affinity. This kernel extends an existing class of k-mer based sequence kernels, based on the recently described di-mismatch kernel. Using three in vitro benchmark datasets, derived from universal protein binding microarrays (uPBMs), genomic context PBMs (gcPBMs) and SELEX-seq data, we demonstrate that incorporating DNA shape information improves our ability to predict protein-DNA binding affinity. In particular, we observe that (i) the k-spectrum + shape model performs better than the classical k-spectrum kernel, particularly for small k values; (ii) the di-mismatch kernel performs better than the k-mer kernel, for larger k; and (iii) the di-mismatch + shape kernel performs better than the di-mismatch kernel for intermediate k values.

Availability and implementation:

The software is available at https://bitbucket.org/wenxiu/sequence-shape.git.

Contact:

rohs@usc.edu or william-noble@uw.edu.

Supplementary information:

Supplementary data are available at Bioinformatics online.

PMID:
28541376
PMCID:
PMC5870879
DOI:
10.1093/bioinformatics/btx336
[Indexed for MEDLINE]
Free PMC Article

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