Detection and analysis of disease-associated single nucleotide polymorphism influencing post-translational modifications

Abstract

Post-translational modification (PTM) is playing key role in the cellular signaling processes and non-synonymous single nucleotide polymorphism (SNP) may affect PTM and signaling pathways. However, only a few kinds of PTMs have been mapped to nsSNPs in the previous studies, without considering disease-association. The functional implication of disease-associated SNPs and the mechanisms of diseases can be explained by analyzing disease-associated SNPs from genome-wide association studies (GWASs) and SNPs influencing PTMs. In this thesis, we defined PTM-SNP as SNPs influencing PTMs and collected PTM-SNPs with disease-association information by integrating information of PTM sites, SNP sites, and GWAS data. From the collected PTM-SNP and phosphorylation network, we detected disease-associated phosphorylation network dynamics to find the disease mechanisms. Firstly, we developed methods and protocols for identifying PTM sites and disease-associated SNPs from mass spectrometry data and GWAS data. Our novel method for PTM identification can identify not only ubiquitin and ubiquitin-like proteins but also all previous known PTMs without any restriction. The protocols for detecting disease-associated SNPs and SNP combination is also developed using GWAS data and random forest classifier. Secondly, on the basis of the information of PTM, SNP, and GWAS, we built comprehensive PTM-SNP database by integrating information of PTMs, SNPs, and disease-associated SNPs. PTM-SNPs are highly associated with diseases, compared with SNPs on other functional sites. PTM sites known to be involved in biological signalling, such as phosphorylation, ubiquitina-tion, and acetylation, have a greater proportion of disease-associated PTM-SNPs than other PTM sites. Final-ly, we detected disease-associated phosphorylation network dynamics using disease-associated phosphoryla-tion-SNPs. The disease-specific phosphorylation signaling dynamics is revealed by predicting all possible kinase-substr...