A global map of the impact of deletion of Post-Translational Modification sites in genetic diseases

BackgroundThere are >200 protein post-translational modification (PTMs) types described in eukaryotes, having diverse species conservation levels, proteome coverage, number of high-throughput experiments and functional roles. From a clinical perspective, a number of diseases have been associated to deregulated PTM sites and missense rare variants are globally enriched in PTMs. We hypothesize that some genetic diseases may be caused by the deregulation of particular functions produced by the removal of a specific PTM type by genomic variants. ResultsWe collected >320,000 human PTMs of 59 types and cross them with >4M missense DNA variants annotated with pathogenic predictions and disease associations. We report >1.74M PTM-variant concurrences in >16,500 proteins that an enrichment analysis distributed in 217 pairwise significant associations between 18 PTM types and 150 genetic diseases. Around 23% of these associations are already described in the literature, 34% have partial evidences based on single variants, related diseases or regulatory evidences, and 43% are novel. Removal of acetylation presents the highest effect, still low studied PTM types like S-glutathionylation or S-nitrosylation show relevance. A network of PTM types and phenotypes associations is also discussed. Using pathogenicity predictions we identified potential PTM sites to produce particular diseases if genomic variants remove them. ConclusionsOur results show an important impact of PTM removal producing genetic diseases and phenotypes that is PTM type specific. We describe for the first time a general scenario of PTM types and genetic diseases direct associations, many of them novel, that provides new capacities to understand and diagnose these disorders.