Prioritization of pathogenic mutations in the protein kinase superfamily.

Abstract

Most of the many mutations described in human protein kinases are tolerated without significant disruption of the corresponding structures or molecular functions, while some of them have been associated to a variety of human diseases, including cancer. In the last decade, a plethora of computational methods to predict the effect of missense single-nucleotide variants (SNVs) have been developed. Still, current high-throughput sequencing efforts and the concomitant need for massive interpretation of protein sequence variants will demand for more efficient and/or accurate computational methods in the forthcoming years. We present KinMut, a support vector machine (SVM) approach, to identify pathogenic mutations in the protein kinase superfamily. KinMut relays on a combination of sequence-derived features that describe mutations at different levels: (1) Gene level: membership to a specific group in Kinbase and the annotation with GO terms; (2) Domain level: annotated PFAM domains; and (3) Residue level: physicochemical features of amino acids, specificity determining positions, and functional annotations from SwissProt and FireDB. The system has been trained with the set of 3492 human kinase mutations in UniProt for which experimental validation of their pathogenic or neutral character exists. In addition, we discuss the relative importance of these independent properties and their combination for the development of a kinase-specific predictor. Finally, we compare KinMut with other state-of-the-art prediction methods. Family-specific features appear among the most discriminative information sources, which allow us to produce accurate results in a reliable and very simple way with minimal supervision. Our study aims to broaden the knowledge on the mechanisms by which mutations in the human kinome contribute to disease with a particular focus in cancer. The classifier as well as further documentation is available at http://kinmut.bioinfo.cnio.es/.