ShapeGTB: the role of local DNA shape in prioritization of functional variants in human promoters with machine learning

PeerJ

article

Maja Malkowska¹  Julian Zubek²  Dariusz Plewczynski²  Lucjan S. Wyrwicz¹ 

[1] Laboratory of Bioinformatics and Biostatistics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology;Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw;Faculty of Mathematics and Information Science, Warsaw University of Technology

关键词: Single-nucleotide polymorphism;    DNA shape;    DNA sequence variation;    Promoter;    Variant prioritization;    Machine learning;   

DOI  :  10.7717/peerj.5742

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Motivation The identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes. Results We demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional single nucleotide polymorphisms within promoter regions—ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (average precision 0.93 vs. 0.47–0.55). On the external validation set based on ClinVar database it displayed worse performance but was still competitive with other methods (average precision 0.47 vs. 0.23–0.42). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future.

【 授权许可】

CC BY