ArticleGenome research2018
Exonic splice regulation imposes strong selection at synonymous sites.
Article in Genome research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Chromatin Accessibility Reveals Adaptive Regulatory Variation in a Keystone Freshwater Fish.Molecular ecology · 2026Article
- The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals.PLoS biology · 2026Article
- Positive selection on brain cis-regulatory elements in the human lineage drives changes in gene expression and susceptibility to neuropsychiatric disorders.HGG advances · 2026Article
- Synonymous and non-synonymous variants at splice junctions can disrupt splicing and are frequently linked to disease associated loss of function genes.BMC genomics · 2025Article
- Bacterial gene 5' ends have unusual mutation rates that can mislead tests of selection.PLoS biology · 2025Article
- Functional synonymous mutations and their evolutionary consequences.Nature reviews. Genetics · 2025Review
- Interpreting mammalian synonymous site conservation in light of the unwanted transcript hypothesis.Nature communications · 2025Article
- Complete sequencing of the mitochondrial genome of tea plantFrontiers in plant science · 2025Article
- Genome-wide impact of codon usage bias on translation optimization in Drosophila melanogaster.Nature communications · 2024Article
- Selection on synonymous sites: the unwanted transcript hypothesis.Nature reviews. Genetics · 2024Review
- Population-specific variations inAntimicrobial agents and chemotherapy · 2024Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.Genome biology · 2023Article
- Developmental Selection and the Perception of Mutation Bias.Molecular biology and evolution · 2023Article
- In silico methods for predicting functional synonymous variants.Genome biology · 2023Review
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.bioRxiv : the preprint server for biology · 2023Article
- A minimal role for synonymous variation in human disease.American journal of human genetics · 2022Article
- Exonic splicing code and protein binding sites for calcium.Nucleic acids research · 2022Article
- Compositional biases in RNA viruses: Causes, consequences and applications.Wiley interdisciplinary reviews. RNA · 2022Review
- Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing ofInternational journal of molecular sciences · 2022Article
- Characterizing the mutational landscape of MM and its precursor MGUS.American journal of cancer research · 2022Article
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2 authors.
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Abstract
What proportion of coding sequence nucleotides have roles in splicing, and how strong is the selection that maintains them? Despite a large body of research into exonic splice regulatory signals, these questions have not been answered. This is because, to our knowledge, previous investigations have not explicitly disentangled the frequency of splice regulatory elements from the strength of the evolutionary constraint under which they evolve. Current data are consistent both with a scenario of weak and diffuse constraint, enveloping large swaths of sequence, as well as with well-defined pockets of strong purifying selection. In the former case, natural selection on exonic splice enhancers (ESEs) might primarily act as a slight modifier of codon usage bias. In the latter, mutations that disrupt ESEs are likely to have large fitness and, potentially, clinical effects. To distinguish between these scenarios, we used several different methods to determine the distribution of selection coefficients for new mutations within ESEs. The analyses converged to suggest that ∼15%-20% of fourfold degenerate sites are part of functional ESEs. Most of these sites are under strong evolutionary constraint. Therefore, exonic splice regulation does not simply impose a weak bias that gently nudges coding sequence evolution in a particular direction. Rather, the selection to preserve these motifs is a strong force that severely constrains the evolution of a substantial proportion of coding nucleotides. Thus synonymous mutations that disrupt ESEs should be considered as a potentially common cause of single-locus genetic disorders.
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