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Selection Shapes Synonymous Stop Codon Use in Mammals

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Abstract

Phylogenetic models of the evolution of protein-coding sequences can provide insights into the selection pressures that have shaped them. In the application of these models synonymous nucleotide substitutions, which do not alter the encoded amino acid, are often assumed to have limited functional consequences and used as a proxy for the neutral rate of evolution. The ratio of nonsynonymous to synonymous substitution rates is then used to categorize the selective regime that applies to the protein (e.g., purifying selection, neutral evolution, diversifying selection). Here, we extend the Muse and Gaut model of codon evolution to explore the extent of purifying selection acting on substitutions between synonymous stop codons. Using a large collection of coding sequence alignments, we estimate that a high proportion (approximately 57%) of mammalian genes are affected by selection acting on stop codon preference. This proportion varies substantially by codon, with UGA stop codons far more likely to be conserved. Genes with evidence of selection acting on synonymous stop codons have distinctive characteristics, compared to unconserved genes with the same stop codon, including longer \(3^{\prime }\) untranslated regions (UTRs) and shorter mRNA half-life. The coding regions of these genes are also much more likely to be under strong purifying selection pressure. Our results suggest that the preference for UGA stop codons found in many multicellular eukaryotes is selective rather than mutational in origin.

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Data Availability

Code and data to reproduce our results are available from https://github.com/cseoighe/StopEvol.

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Acknowledgements

We are grateful to Estienne Swart and Gary Loughran for comments on the manuscript.

Funding

C.S. is supported by Science Foundation Ireland, Award Number 16/IA/4612. P.V.B. is supported by SFI-HRB-Wellcome Trust Biomedical Research Partnership (210692/Z/18/Z). S.J.K. wishes to acknowledge personal support from the Irish Research Council.

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CS initiated the project, developed the model, wrote the code, performed analysis and drafted the manuscript. PVB, HY and SK suggested and performed further analyses. AP developed and maintains the software repository.

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Correspondence to Cathal Seoighe.

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Seoighe, C., Kiniry, S.J., Peters, A. et al. Selection Shapes Synonymous Stop Codon Use in Mammals. J Mol Evol 88, 549–561 (2020). https://doi.org/10.1007/s00239-020-09957-x

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