BIOINFORMATICS ANALYSIS OF RARE AMINO ACID SUBSTITUTIONS IN THE DISC1 INTERACTOME IMPLICATED IN SCHIZOPHRENIA

Background Disrupted In Schizophrenia 1 (DISC1) gene is a well-researched target for developing psychiatric disorders including schizophrenia, bipolar disorder and major depression. DISC1 protein directly interacts with a large set of proteins, so-called DISC1 Interactome, that are involved in brain development and neuronal signaling. Recent exome sequencing projects showed that coding variants with low allele frequency have large effects on the risk for developing schizophrenia, which indicates that rare mutations account for much of the missing heritability in the development of schizophrenia. Methods In the presented study, we applied bioinformatics approaches to analyse the effects of rare amino acid substitutions in the DISC1 Interactome on protein structure and function from public databases. We applied sequence-based machine learning methods to predict the effects of the rare disease-causing mutations on protein function, protein stability and post translational modification. In addition, we carried out structure-based modelling methods to analyse the effects of rare mutations on protein stability and protein-protein interaction. Results We collected 6,254 non-synonymous coding mutations reported in the 1000 Genomes Project located in 104 DISC1 Interactome genes from dbNSFP. Of the 6,254 variants, 5,929 coding mutations (95%) are rare amino acid substitutions with a minor allele frequency less than 1%. We observed that the distributions of damaging mutations are found to be higher in rare mutations than those in common mutations in the DISC1 Interactome. Some amino acid substitutions may be involved in post translational modifications such as phosphorylation and sumoylation. We showed that the rare missense mutations could significantly affect the protein structures, which result in the changes on protein stability and protein-protein interaction. Discussion The bioinformatics analysis improves our understanding of the roles of rare amino acid substitutions in the DISC1 interactome genes in susceptibility to schizophrenia. The findings can provide useful information to estimate the functional effects of rare DISC1 Interactome mutations on protein function and structure, which offer the targets for developing more precise treatments and medications for schizophrenia patients.