ArticlePLoS genetics2015
Evolutionary constraint and disease associations of post-translational modification sites in human genomes.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 73 citations in OpenAlex.
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- Pan-microalgal dark proteome mapping via interpretable deep learning and synthetic chimeras.Patterns (New York, N.Y.) · 2025Article
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- Targeting N-Myristoylation Through NMT2 Prevents Cardiac Hypertrophy and Heart Failure.JACC. Basic to translational science · 2023Article
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- Human phospho-signaling networks of SARS-CoV-2 infection are rewired by population genetic variants.Molecular systems biology · 2022Article
- Computational and experimental methods for classifying variants of unknown clinical significance.Cold Spring Harbor molecular case studies · 2022Article
- Review
- Post-translational Modifications in Brain Diseases: A Future for Biomarkers.Advances in experimental medicine and biology · 2022Article
- Enhancing the Discovery of Functional Post-Translational Modification Sites with Machine Learning Models - Development, Validation, and Interpretation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Evolutionary and functional lessons from human-specific amino acid substitution matrices.NAR genomics and bioinformatics · 2021Article
- A global map of associations between types of protein posttranslational modifications and human genetic diseases.iScience · 2021Article
- The Burden of Post-Translational Modification (PTM)-Disrupting Mutations in the Tumor Matrisome.Cancers · 2021Article
- ActiveDriverDB: Interpreting Genetic Variation in Human and Cancer Genomes Using Post-translational Modification Sites and Signaling Networks (2021 Update).Frontiers in cell and developmental biology · 2021Article
- Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Post-translational Modification Crosstalk and Hotspots in Sirtuin Interactors Implicated in Cardiovascular Diseases.Frontiers in genetics · 2020Article
- Parallel selection on ecologically relevant gene functions in the transcriptomes of highly diversifying salmonids.BMC genomics · 2019Article
- Improved measures for evolutionary conservation that exploit taxonomy distances.Nature communications · 2019Article
- A resource of variant effect predictions of single nucleotide variants in model organisms.Molecular systems biology · 2018Article
- A Methodological Assessment and Characterization of Genetically-Driven Variation in Three Human Phosphoproteomes.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.