Biological context of evolutionary constraint in PTM regions.

<p><b>(A)</b> Negative selection of PTM regions is apparent across human tissues and ubiquitously expressed genes, as 90% of tissue-specific groups of proteins have significantly more rare substitutions in PTM regions. Tissues are ranked by proportion of rare substitutions in PTM sites, and expected proportions in the entire protein group are shown in red boxplots. <b>(B)</b> Pathway analysis visualised as an enrichment map reveals 400 biological processes and pathways with significant PTM-specific selection (FDR <i>p</i><0.05). Most processes (90%) show negative selection in PTM regions and ∼75% of processes are also over-represented in PTM-associated disease genes. Nodes indicate processes and pathways and edges show overlaps in annotated genes. Selection in the two population datasets is indicated by node and edge colors (light blue and orange for pathways with negative and positive PTM selection, respectively; dark blue and red for PTM-selected pathways with disease association). <b>(C)</b> An example of PTM-associated disease substitutions enriched in significantly selected pathways. The Gene Ontology process of protein modifications (GO:0031401) is enriched in PTM-specific mutations of a wide range of diseases. Word size corresponds to disease annotation frequency.