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Synonymous mutations in representative yeast genes are mostly strongly non-neutral

Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral 1 – 5 . Here, to experimentally verify this presumption, we constructed 8,341 yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in on...

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Bibliographic Details
Published in:Nature (London) 2022-06, Vol.606 (7915), p.725-731
Main Authors: Shen, Xukang, Song, Siliang, Li, Chuan, Zhang, Jianzhi
Format: Article
Language:English
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Summary:Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral 1 – 5 . Here, to experimentally verify this presumption, we constructed 8,341 yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 endogenous genes with diverse functions and expression levels and measured their fitness relative to the wild type in a rich medium. Three-quarters of synonymous mutations resulted in a significant reduction in fitness, and the distribution of fitness effects was overall similar—albeit nonidentical—between synonymous and nonsynonymous mutations. Both synonymous and nonsynonymous mutations frequently disturbed the level of mRNA expression of the mutated gene, and the extent of the disturbance partially predicted the fitness effect. Investigations in additional environments revealed greater across-environment fitness variations for nonsynonymous mutants than for synonymous mutants despite their similar fitness distributions in each environment, suggesting that a smaller proportion of nonsynonymous mutants than synonymous mutants are always non-deleterious in a changing environment to permit fixation, potentially explaining the common observation of substantially lower nonsynonymous than synonymous substitution rates. The strong non-neutrality of most synonymous mutations, if it holds true for other genes and in other organisms, would require re-examination of numerous biological conclusions about mutation, selection, effective population size, divergence time and disease mechanisms that rely on the assumption that synoymous mutations are neutral. A survey of 8,341 mutations in 21 yeast genes shows that synonymous mutations are nearly as harmful as nonsynonymous mutations, in part because they both affect the mRNA level of the gene mutated.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-022-04823-w