A minimal role for synonymous variation in human disease
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Abstract
Synonymous mutations change the DNA sequence of a gene without affecting the amino acid sequence of the encoded protein. Although some synonymous mutations can affect RNA splicing, translational efficiency, and mRNA stability, studies in human genetics, mutagenesis screens, and other experiments and evolutionary analyses have repeatedly shown that most synonymous variants are neutral or only weakly deleterious, with some notable exceptions. Based on a recent study in yeast, there have been claims that synonymous mutations could be as important as nonsynonymous mutations in causing disease, assuming the yeast findings hold up and translate to humans. Here, we argue that there is insufficient evidence to overturn the large, coherent body of knowledge establishing the predominant neutrality of synonymous variants in the human genome.
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There were only three significant gene-level cis-CDS pQTLs in the synonymous collapsing model.
“Moreover, there were only three significant gene-level cis-CDS pQTLs in the synonymous (syn) collapsing model19,20 (full definitions of collapsing models can be found in Extended Data Table 1).”
From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [20]
The Methods section describes a synonymous-variant gene-based collapsing model, supporting the model cited in the sentence. But the reported results concern UK Biobank clinical phenotypes, not cis-CDS pQTLs; the paper does not support the count of three significant pQTLs. (LLM, conf=0.82)
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Cites
Codon optimality, bias and usage in translation and mRNA decay
Hanson, G., & Coller, J. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.91 · Cited by 825 · see citing works
The sequences of 150,119 genomes in the UK Biobank
Halldorsson, B. V., Eggertsson, H. P., Moore, K. H. S., Hauswedell, H., Eiriksson, O., Ulfarsson, M. O., Palsson, G., Hardarson, M. T., Oddsson, A., Jensson, B. O., et al. (2022) · Nature · doi:10.1038/s41586-022-04965-x · Cited by 448 · see citing works
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Research works printed but not linked: 1
- [2]2. Shen, X., Song, S., Li, C. & Zhang, J. Synonymous mutations in representative yeast genes are mostly strongly non-neutral. Nature 1–7 (2022) doi:10.1038/s41586-022-04823-w. · DOI · Paper page
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Rare variant associations with plasma protein levels in the UK Biobank
Dhindsa, R. S., Burren, O. S., Sun, B. B., Prins, B. P., Matelska, D., Wheeler, E., Mitchell, J., Oerton, E., Hristova, V. A., Smith, K. R., et al. (2023) · Nature · doi:10.1038/s41586-023-06547-x · Cited by 193 · see citing works
Self-citation
- Authors
- Dhindsa, R. S., Wang, Q., Vitsios, D., Burren, O. S., Hu, F., DiCarlo, J. E., Kruglyak, L., MacArthur, D. G., Hurles, M. E., & Petrovski, S.
- Affiliations
- Baylor College of Medicine (US)
- AstraZeneca (United States) (US)
- AstraZeneca (United Kingdom) (GB)
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Broad Institute (US)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Dhindsa, Ryan S.
- Petrovski, Slavé
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 109
- Issue
- 12
- Pages
- 2105-2109
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC9808499
- OpenAlex
- W4310783369
- Cited by
- 38
- References
- 2
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 10 · 2023: 9 · 2022: 3
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (F32 NS127854)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- synonymous mutations, human disease, deleterious mutations, RNA splicing, translation efficiency, mRNA stability, non-synonymous mutations
- MeSH terms
- Amino Acid Sequence, Biological Evolution, Humans, Mutation, Saccharomyces cerevisiae, Genome, Human
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