ArticleNature2015
Identification of cis-suppression of human disease mutations by comparative genomics.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
64 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum.Diagnostics (Basel, Switzerland) · 2024Guideline
- Meta-analysis of dispensable essential genes and their interactions with bypass suppressors.Life science alliance · 2024Pooled it
- Article
- Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2.Protein science : a publication of the Protein Society · 2025Article
- Identification of coevolving positions by ancestral reconstruction.Communications biology · 2025Article
- WGCCRR: a web-based tool for genome-wide screening of convergent indels and substitutions of amino acids.Bioinformatics advances · 2024Article
- Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- The landscape of tolerated genetic variation in humans and primates.Science (New York, N.Y.) · 2023Article
- The landscape of tolerated genetic variation in humans and primates.bioRxiv : the preprint server for biology · 2023Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1.Antibiotics (Basel, Switzerland) · 2022Article
- Phylogenetic inference of changes in amino acid propensities with single-position resolution.PLoS computational biology · 2022Article
- Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts.Frontiers in genetics · 2022Review
- Structural bioinformatics enhances the interpretation of somatic mutations in KDM6A found in human cancers.Computational and structural biotechnology journal · 2022Article
- Complex response to physiological and drug-induced hepatic heme demand in monoallelicMolecular genetics and metabolism reports · 2021Article
- Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes.Nature medicine · 2021Article
- Compensatory epistasis explored by molecular dynamics simulations.Human genetics · 2021Article
- Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.Human mutation · 2021Article
- Article
- MitImpact 3: modeling the residue interaction network of the Respiratory Chain subunits.Nucleic acids research · 2021Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors.
Funding
Abstract
Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.
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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.