Evolutionary Constraint and Disease Associations of Post-Translational Modification Sites in Human Genomes
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{"title"=>"Evolutionary Constraint and Disease Associations of Post-Translational Modification Sites in Human Genomes", "type"=>"journal", "authors"=>[{"first_name"=>"Jüri", "last_name"=>"Reimand", "scopus_author_id"=>"18134791400"}, {"first_name"=>"Omar", "last_name"=>"Wagih", "scopus_author_id"=>"36642915300"}, {"first_name"=>"Gary D.", "last_name"=>"Bader", "scopus_author_id"=>"7102726136"}], "year"=>2015, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537404", "scopus"=>"2-s2.0-84924402531", "sgr"=>"84924402531", "pui"=>"602891007", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"25611800", "doi"=>"10.1371/journal.pgen.1004919"}, "id"=>"8e1fbad7-524e-3a9a-a7be-d89ac0f668a2", "abstract"=>"Interpreting the impact of human genome variation on phenotype is challenging. The functional effect of protein-coding variants is often predicted using sequence conservation and population frequency data, however other factors are likely relevant. We hypothesized that variants in protein post-translational modification (PTM) sites contribute to phenotype variation and disease. We analyzed fraction of rare variants and non-synonymous to synonymous variant ratio (Ka/Ks) in 7,500 human genomes and found a significant negative selection signal in PTM regions independent of six factors, including conservation, codon usage, and GC-content, that is widely distributed across tissue-specific genes and function classes. PTM regions are also enriched in known disease mutations, suggesting that PTM variation is more likely deleterious. PTM constraint also affects flanking sequence around modified residues and increases around clustered sites, indicating presence of functionally important short linear motifs. Using target site motifs of 124 kinases, we predict that at least ∼180,000 motif-breaker amino acid residues that disrupt PTM sites when substituted, and highlight kinase motifs that show specific negative selection and enrichment of disease mutations. We provide this dataset with corresponding hypothesized mechanisms as a community resource. As an example of our integrative approach, we propose that PTPN11 variants in Noonan syndrome aberrantly activate the protein by disrupting an uncharacterized cluster of phosphorylation sites. Further, as PTMs are molecular switches that are modulated by drugs, we study mutated binding sites of PTM enzymes in disease genes and define a drug-disease network containing 413 novel predicted disease-gene links.", "link"=>"http://www.mendeley.com/research/evolutionary-constraint-disease-associations-posttranslational-modification-sites-human-genomes", "reader_count"=>63, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>24, "Student > Ph. D. Student"=>23, "Student > Master"=>6, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>3, "Student > Doctoral Student"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>24, "Student > Ph. D. Student"=>23, "Student > Master"=>6, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>3, "Student > Doctoral Student"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>13, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>36, "Chemistry"=>1, "Computer Science"=>6}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>36}, "Computer Science"=>{"Computer Science"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>13}}, "reader_count_by_country"=>{"Canada"=>1, "Argentina"=>1, "United States"=>2, "Japan"=>1, "Luxembourg"=>1, "Brazil"=>1, "United Kingdom"=>1, "Malaysia"=>1, "Spain"=>2}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1870758"], "description"=>"<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.</p>", "links"=>[], "tags"=>["Human Genomes Interpreting", "PTPN 11 variants", "population frequency data", "PTM regions", "target site motifs", "variation", "disease mutations"], "article_id"=>1293222, "categories"=>["Biological Sciences"], "users"=>["Jüri Reimand", "Omar Wagih", "Gary D. Bader"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004919.g002", "stats"=>{"downloads"=>2, "page_views"=>42, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biological_context_of_evolutionary_constraint_in_PTM_regions_/1293222", "title"=>"Biological context of evolutionary constraint in PTM regions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-01-22 02:44:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1870765"], "description"=>"<p><b>(A)</b> Negative selection of PTM regions is apparent in different modification types, in central residues modified by PTMs (left) and in flanking regions. <b>(B)</b> PTM regions often contain multiple types of modifications. <b>(C)</b> Negative selection is stronger in regions with clustered PTMs. <b>(D)</b> Variation analysis of kinase binding motifs reveals 24 kinases whose motif-breaker sites are negatively selected in the population (14 kinases), enriched in PTM-specific disease mutations (19 kinases) or both (9 kinases, shown in boldface). Motif-breaker sites are protein residues that disrupt kinase binding motifs when substituted. <b>(E)</b> Network of kinase-substrate interactions mediated by motif-breaker sites of the 24 kinases. Disease gene interactions are shown in red and black dots represent kinases with significant motif-breaker sites. Boxplot shows that disease genes have more interactions with motif-breaker sites than other proteins. <b>(F)</b> Protein residues highlighted as motif-breaker sites of the 24 kinases, shown relative to PTM site. Motif-breaker sites accumulate within 3 residues and are enriched in R,K,Q,E amino acids. Expected values from amino acid weighted permutations are shown with error bars indicating ±1 s.d.</p>", "links"=>[], "tags"=>["Human Genomes Interpreting", "PTPN 11 variants", "population frequency data", "PTM regions", "target site motifs", "variation", "disease mutations"], "article_id"=>1293229, "categories"=>["Biological Sciences"], "users"=>["Jüri Reimand", "Omar Wagih", "Gary D. Bader"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004919.g003", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biochemical_consequences_PTM_variation_/1293229", "title"=>"Biochemical consequences PTM variation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-01-22 02:44:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1870774"], "description"=>"<p><b>(A)</b> Wordcloud summarizing 152 disease genes with significant enrichment of PTM SNVs from ActiveDriver analysis (PAD list, FDR <i>p</i><0.05). Letter size shows number of PTM mutations in disease. <b>(B)</b> An example of a disease gene from ActiveDriver analysis. The <i>PTPN11</i> gene encoding the protein phosphatase SHP2 includes a Noonan syndrome-associated mutation hotspot in the SH2 domain of the protein. ActiveDriver shows that the 23 mutations significantly coincide with a cluster of poorly characterised phosphorylation sites (red circles), predicting a disease mechanism of aberrant protein activation. <b>(C)</b> Drug-protein-disease network shows PAD genes with PTM mutations whose upstream enzymes are known and druggable with approved pharmaceuticals, highlighting candidates for drug repurposing screens. Only experimentally predicted enzymes bound to significantly disease-mutated PTM sites are shown.</p>", "links"=>[], "tags"=>["Human Genomes Interpreting", "PTPN 11 variants", "population frequency data", "PTM regions", "target site motifs", "variation", "disease mutations"], "article_id"=>1293238, "categories"=>["Biological Sciences"], "users"=>["Jüri Reimand", "Omar Wagih", "Gary D. Bader"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004919.g004", "stats"=>{"downloads"=>3, "page_views"=>46, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enriched_disease_mutations_and_drug_interactions_of_PTM_regions_/1293238", "title"=>"Enriched disease mutations and drug interactions of PTM regions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-01-22 02:44:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1870751"], "description"=>"<p><b>(A)</b> ∼130,000 experimental PTM sites of four types were merged into ∼55,000 PTM regions. <b>(B-C)</b> Specific negative selection in PTM regions is apparent in relatively higher frequency of rare substitutions and lower ratio of non-synonymous variants to synonymous variants (K<sub>a</sub>/K<sub>s</sub>). Boxplots represent comparisons of PTM and non-PTM sequence in 100 bins of proteins with matched tolerance to variation. <b>(D)</b> Negative selection of PTM regions is a distinct evolutionary trend not confounded by other genomic factors. PTM-associated predictors are shown in red with the variable corresponding to PTM regions ranked third after conservation and codon bias. <b>(E)</b> Known disease mutations from the HGMD database are enriched in PTM regions. While central PTM sites appear at an expected mutation rate in this global analysis, amino acid weighted sampling reveals an enrichment of PTM sites (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004919#pgen.1004919.s017\" target=\"_blank\">S15 Fig.</a>). <b>(F)</b> Disease-associated substitutions in PTM regions are often predicted to be benign by mutation function predictors. Total number of variants scored by each method is shown on each bar.</p>", "links"=>[], "tags"=>["Human Genomes Interpreting", "PTPN 11 variants", "population frequency data", "PTM regions", "target site motifs", "variation", "disease mutations"], "article_id"=>1293215, "categories"=>["Biological Sciences"], "users"=>["Jüri Reimand", "Omar Wagih", "Gary D. Bader"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004919.g001", "stats"=>{"downloads"=>2, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Negative_selection_of_post_translational_modification_PTM_regions_in_human_genomes_and_importance_in_disease_/1293215", "title"=>"Negative selection of post-translational modification (PTM) regions in human genomes and importance in disease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-01-22 02:44:41"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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