Genome‐wide analysis of single nucleotide variants on phosphorylation motifs

Abstract

In order to conveniently characterize enormous phosphorylation sites, we attempted to summarize them as phosphorylation motifs, extracting the motif structure from the features of the surrounding amino acid sequence of the phosphorylation sites. Approximately 100,000 known phosphorylation sites registered in PhosphoSitePlus (http://www.phosphosite.org) were clustered with the features of amino acids and were organized into about 200 phosphorylation motifs based on the distribution of amino acids in each cluster. The determined motifs were analyzed by signal transduction pathway analysis, GeneOntrogy analysis and comparative evolutionary analysis to determine gene function, signal pathway and physiological importance parameters (Yoshizaki H et al. BMC genomics 2014). In addition, a database was created in which the phosphorylation motifs, motif structures for approximately one million of serine, threonine and tyrosine residues on the human genome, and kinase‐substrate information for kinase prediction were stored (Yoshizaki H Gigascience 2015). Using these data, we investigated associations between cancer‐specific mutations and phosphorylation motifs. Of more than 16 million cancer specific mutations registered in the International Cancer Genome Consortium (ICGC) (https://icgc.org/), about 100,000 mutations were found on the phosphorylation motif sequences with amino acid substitutions. Distributions with these mutations and cancer tissues for these mutations and the evolutionary conservation of each phosphorylation motif were investigated. As a result, it was revealed that the frequency of cancer specific mutagenesis on the phosphorylation motif has a positive correlation with the evolutionary conservation of the motif. In addition, this correlation was not confirmed by healthy subject SNP data. This means that in cancer tissues, mutations tend to accumulate in physiologically important phosphorylation motifs, mutations on the phosphorylation motif in the cancer tissue are not random mutations due to genomic instability, suggesting spontaneously selective mutations. Furthermore, in cancer specific mutations, the position and frequency of mutations in the motif were biased due to the type of phosphorylation motif, and biases in the motif sequence change by amino acid substitution were also observed. Our results suggest that mutations on the phosphorylation motif affect not only the destruction of the motif structure but also the signal disruption due to the appearance of a new motif by amino acid substitution. This study combining tissue specific gene mutation information with our own phosphorylation motif data is expected to lead to predict the effect on canceration by gene mutation, to functionally unknown phosphorylation sites.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.