ArticleGigaScience2021
Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.
Article in GigaScience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids.Molecules and cells · 2026Article
- Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.Biochimica et biophysica acta. Molecular cell research · 2026Review
- Association of the Dedicator of Cytokinesis 2 (DOCK2) Gene Polymorphisms with COVID-19 and Plasma LDH, AST, ALT, and Ferritin Levels.Biomolecules · 2026Article
- A naturally synonymous mutation modulates an ERK-centered regulatory network to mediate thermotolerance divergence in Crassostrea oysters.Communications biology · 2026Article
- SyMetrics: an integrated machine learning model for evaluating the pathogenicity of synonymous variants in the human genome.NAR genomics and bioinformatics · 2026Article
- Synonymous Variants of Potential Significance Identified by a 52-Gene Clinical Sequencing Panel in Non-Small Cell Lung Cancer.Genes, chromosomes & cancer · 2026Article
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- Pathogenic CDKN2A germline variants are rare in a cohort of unselected pancreatic cancer patients from Pakistan.Familial cancer · 2025Article
- Functional synonymous mutations and their evolutionary consequences.Nature reviews. Genetics · 2025Review
- Quantifying the Evolution of SNPs That Affect RNA Secondary Structure in Arabidopsis thaliana Genes.Molecular biology and evolution · 2025Article
- VariantFoldRNA: a flexible, containerized, and scalable pipeline for genome-wide riboSNitch prediction.NAR genomics and bioinformatics · 2025Article
- A Disintegrin and Metalloprotease with Thrombospondin Motif, Member 13, and Von Willebrand Factor in Relation to the Duality of Preeclampsia and HIV Infection.International journal of molecular sciences · 2025Review
- Synthetic rational design of live-attenuated Zika viruses based on a computational model.Nucleic acids research · 2025Article
- RNA encodes physical information.bioRxiv : the preprint server for biology · 2024Article
- An alcohol dehydrogenase 7 gene polymorphism associates with both acute and chronic pain in sickle cell disease.Pharmacogenomics · 2023Article
- Cannabis Pharmacogenomics: A Path to Personalized Medicine.Current issues in molecular biology · 2023Review
- Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores.Molecular genetics & genomic medicine · 2023Article
- IndelsRNAmute: predicting deleterious multiple point substitutions and indels mutations.BMC bioinformatics · 2022Article
- Disease-associated human genetic variation through the lens of precursor and mature RNA structure.Human genetics · 2022Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe role of synonymous single-nucleotide variants in human health and disease is poorly understood, yet evidence suggests that this class of "silent" genetic variation plays multiple regulatory roles in both transcription and translation. One mechanism by which synonymous codons direct and modulate the translational process is through alteration of the elaborate structure formed by single-stranded mRNA molecules. While tools to computationally predict the effect of non-synonymous variants on protein structure are plentiful, analogous tools to systematically assess how synonymous variants might disrupt mRNA structure are lacking.
resultsWe developed novel software using a parallel processing framework for large-scale generation of secondary RNA structures and folding statistics for the transcriptome of any species. Focusing our analysis on the human transcriptome, we calculated 5 billion RNA-folding statistics for 469 million single-nucleotide variants in 45,800 transcripts. By considering the impact of all possible synonymous variants globally, we discover that synonymous variants predicted to disrupt mRNA structure have significantly lower rates of incidence in the human population.
conclusionsThese findings support the hypothesis that synonymous variants may play a role in genetic disorders due to their effects on mRNA structure. To evaluate the potential pathogenic impact of synonymous variants, we provide RNA stability, edge distance, and diversity metrics for every nucleotide in the human transcriptome and introduce a "Structural Predictivity Index" (SPI) to quantify structural constraint operating on any synonymous variant. Because no single RNA-folding metric can capture the diversity of mechanisms by which a variant could alter secondary mRNA structure, we generated a SUmmarized RNA Folding (SURF) metric to provide a single measurement to predict the impact of secondary structure altering variants in human genetic studies.
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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.