Skip to main content
SpringerLink
Log in

Selection Shapes Synonymous Stop Codon Use in Mammals

  • Original Article
  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

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

Consent for Publication

Not applicable.

References

  • Aken BL, Achuthan P, Akanni W, Amode MR, Bernsdorff F, Bhai J, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Gil L, Giron CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Juettemann T, Keenan S, Laird MR, Lavidas I, Maurel T, McLaren W, Moore B, Murphy DN, Nag R, Newman V, Nuhn M, Ong CK, Parker A, Patricio M, Riat HS, Sheppard D, Sparrow H, Taylor K, Thormann A, Vullo A, Walts B, Wilder SP, Zadissa A, Kostadima M, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Cunningham F, Yates A, Zerbino DR, Flicek P (2017) Ensembl 2017. Nucleic Acids Res 45(D1):D635–D642

    CAS  PubMed  Google Scholar 

  • Anisimova M, Kosiol C (2009) Investigating protein-coding sequence evolution with probabilistic codon substitution models. Mol Biol Evol 26(2):255–271

    CAS  PubMed  Google Scholar 

  • Arribere JA, Cenik ES, Jain N, Hess GT, Lee CH, Bassik MC, Fire AZ (2016) Translation readthrough mitigation. Nature 534(7609):719–723

    CAS  PubMed  PubMed Central  Google Scholar 

  • Atkins JF, Loughran G, Bhatt PR, Firth AE, Baranov PV (2016) Ribosomal frameshifting and transcriptional slippage: from genetic steganography and cryptography to adventitious use. Nucleic Acids Res 44(15):7007–7078

    PubMed  PubMed Central  Google Scholar 

  • Battle A, Brown CD, Engelhardt BE, Montgomery SB, Aguet F, Ardlie KG, Cummings BB, Gelfand ET, Getz G, Hadley K, Handsaker RE, Huang KH, Kashin S, Karczewski KJ, Lek M, Li X, MacArthur DG, Nedzel JL, Nguyen DT, Noble MS, Segre AV, Trowbridge CA, Tukiainen T, Abell NS, Balliu B, Barshir R, Basha O, Battle A, Bogu GK, Brown A, Brown CD, Castel SE, Chen LS, Chiang C, Conrad DF, Cox NJ, Damani FN, Davis JR, Delaneau O, Dermitzakis ET, Engelhardt BE, Eskin E, Ferreira PG, Fresard L, Gamazon ER, Garrido-Martin D, Gewirtz ADH, Gliner G, Gloudemans MJ, Guigo R, Hall IM, Han B, He Y, Hormozdiari F, Howald C, Kyung Im H, Jo B, Yong Kang E, Kim Y, Kim-Hellmuth S, Lappalainen T, Li G, Li X, Liu B, Mangul S, McCarthy MI, McDowell IC, Mohammadi P, Monlong J, Montgomery SB, Munoz-Aguirre M, Ndungu AW, Nicolae DL, Nobel AB, Oliva M, Ongen H, Palowitch JJ, Panousis N, Papasaikas P, Park Y, Parsana P, Payne AJ, Peterson CB, Quan J, Reverter F, Sabatti C, Saha A, Sammeth M, Scott AJ, Shabalin AA, Sodaei R, Stephens M, Stranger BE, Strober BJ, Sul JH, Tsang EK, Urbut S, van de Bunt M, Wang G, Wen X, Wright FA, Xi HS, Yeger-Lotem E, Zappala Z, Zaugg JB, Zhou YH, Akey JM, Bates D, Chan J, Chen LS, Claussnitzer M, Demanelis K, Diegel M, Doherty JA, Feinberg AP, Fernando MS, Halow J, Hansen KD, Haugen E, Hickey PF, Hou L, Jasmine F, Jian R, Jiang L, Johnson A, Kaul R, Kellis M, Kibriya MG, Lee K, Billy Li J, Li Q, Li X, Lin J, Lin S, Linder S, Linke C, Liu Y, Maurano MT, Molinie B, Montgomery SB, Nelson J, Neri FJ, Oliva M, Park Y, Pierce BL, Rinaldi NJ, Rizzardi LF, Sandstrom R, Skol A, Smith KS, Snyder MP, Stamatoyannopoulos J, Stranger BE, Tang H, Tsang EK, Wang L, Wang M, Van Wittenberghe N, Wu F, Zhang R, Nierras CR, Branton PA, Carithers LJ, Guan P, Moore HM, Rao A, Vaught JB, Gould SE, Lockart NC, Martin C, Struewing JP, Volpi S, Addington AM, Koester SE, Little AR, Brigham LE, Hasz R, Hunter M, Johns C, Johnson M, Kopen G, Leinweber WF, Lonsdale JT, McDonald A, Mestichelli B, Myer K, Roe B, Salvatore M, Shad S, Thomas JA, Walters G, Washington M, Wheeler J, Bridge J, Foster BA, Gillard BM, Karasik E, Kumar R, Miklos M, Moser MT, Jewell SD, Montroy RG, Rohrer DC, Valley DR, Davis DA, Mash DC, Undale AH, Smith AM, Tabor DE, Roche NV, McLean JA, Vatanian N, Robinson KL, Sobin L, Barcus ME, Valentino KM, Qi L, Hunter S, Hariharan P, Singh S, Um KS, Matose T, Tomaszewski MM, Barker LK, Mosavel M, Siminoff LA, Traino HM, Flicek P, Juettemann T, Ruffier M, Sheppard D, Taylor K, Trevanion SJ, Zerbino DR, Craft B, Goldman M, Haeussler M, Kent WJ, Lee CM, Paten B, Rosenbloom KR, Vivian J, Zhu J, Craft B, Goldman M, Haeussler M, Kent WJ, Lee CM, Paten B, Rosenbloom KR, Vivian J, Zhu J, Aguet F, Brown AA, Castel SE, Davis JR, He Y, Jo B, Mohammadi P, Park Y, Parsana P, Segre AV, Strober BJ, Zappala Z, Cummings BB, Gelfand ET, Hadley K, Huang KH, Lek M, Li X, Nedzel JL, Nguyen DY, Noble MS, Sullivan TJ, Tukiainen T, MacArthur DG, Getz G, Addington A, Guan P, Koester S, Little AR, Lockhart NC, Moore HM, Rao A, Struewing JP, Volpi S, Brigham LE, Hasz R, Hunter M, Johns C, Johnson M, Kopen G, Leinweber WF, Lonsdale JT, McDonald A, Mestichelli B, Myer K, Roe B, Salvatore M, Shad S, Thomas JA, Walters G, Washington M, Wheeler J, Bridge J, Foster BA, Gillard BM, Karasik E, Kumar R, Miklos M, Moser MT, Jewell SD, Montroy RG, Rohrer DC, Valley D, Mash DC, Davis DA, Sobin L, Barcus ME, Branton PA, Abell NS, Balliu B, Delaneau O, Fresard L, Gamazon ER, Garrido-Martin D, Gewirtz ADH, Gliner G, Gloudemans MJ, Han B, He AZ, Hormozdiari F, Li X, Liu B, Kang EY, McDowell IC, Ongen H, Palowitch JJ, Peterson CB, Quon G, Ripke S, Saha A, Shabalin AA, Shimko TC, Sul JH, Teran NA, Tsang EK, Zhang H, Zhou YH, Bustamante CD, Cox NJ, Guigo R, Kellis M, McCarthy MI, Conrad DF, Eskin E, Li G, Nobel AB, Sabatti C, Stranger BE, Wen X, Wright FA, Ardlie KG, Dermitzakis ET, Lappalainen T (2017) Genetic effects on gene expression across human tissues. Nature 550(7675):204–213

    PubMed  Google Scholar 

  • Belinky F, Babenko VN, Rogozin IB, Koonin EV (2018) Purifying and positive selection in the evolution of stop codons. Sci Rep 8(1):9260

    PubMed  PubMed Central  Google Scholar 

  • Brown A, Shao S, Murray J, Hegde RS, Ramakrishnan V (2015) Structural basis for stop codon recognition in eukaryotes. Nature 524(7566):493–496

    CAS  PubMed  PubMed Central  Google Scholar 

  • Caceres EF, Hurst LD (2013) The evolution, impact and properties of exonic splice enhancers. Genome Biol 14(12):R143

    PubMed  PubMed Central  Google Scholar 

  • Carlini DB, Genut JE (2006) Synonymous SNPs provide evidence for selective constraint on human exonic splicing enhancers. J Mol Evol 62(1):89–98

    CAS  PubMed  Google Scholar 

  • Chamary JV, Hurst LD (2005) Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals. Genome Biol 6(9):R75

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cridge AG, Crowe-McAuliffe C, Mathew SF, Tate WP (2018) Eukaryotic translational termination efficiency is influenced by the 3\(^{\prime }\) nucleotides within the ribosomal mRNA channel. Nucleic Acids Res 46(4):1927–1944

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dabrowski M, Bukowy-Bieryllo Z, Zietkiewicz E (2015) Translational readthrough potential of natural termination codons in eukaryotes–the impact of RNA sequence. RNA Biol 12(9):950–958

    PubMed  PubMed Central  Google Scholar 

  • Delport W, Scheffler K, Seoighe C (2009) Models of coding sequence evolution. Brief Bioinform 10(1):97–109

    CAS  PubMed  Google Scholar 

  • Doherty A, McInerney JO (2013) Translational selection frequently overcomes genetic drift in shaping synonymous codon usage patterns in vertebrates. Mol Biol Evol 30(10):2263–2267

    CAS  PubMed  Google Scholar 

  • Doma MK, Parker R (2006) Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature 440(7083):561–564

    CAS  PubMed  PubMed Central  Google Scholar 

  • Douzery EJ, Scornavacca C, Romiguier J, Belkhir K, Galtier N, Delsuc F, Ranwez V (2014) OrthoMaM v8: a database of orthologous exons and coding sequences for comparative genomics in mammals. Mol Biol Evol. 1(7):1923–1928

    Google Scholar 

  • Firth AE, Brierley I (2012) Non-canonical translation in RNA viruses. J Gen Virol 93(Pt 7):1385–1409

    CAS  PubMed  PubMed Central  Google Scholar 

  • Galtier N, Roux C, Rousselle M, Romiguier J, Figuet E, Glemin S, Bierne N, Duret L (2018) Codon usage bias in animals: disentangling the effects of natural selection, effective population size, and GC-biased gene conversion. Mol Biol Evol 35(5):1092–1103

    CAS  PubMed  Google Scholar 

  • Gil M, Zanetti MS, Zoller S, Anisimova M (2013) CodonPhyML: fast maximum likelihood phylogeny estimation under codon substitution models. Mol Biol Evol 30(6):1270–1280

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goldman N, Yang Z (1994) A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol 11(5):725–736

    CAS  PubMed  Google Scholar 

  • Gouy M, Gautier C (1982) Codon usage in bacteria: correlation with gene expressivity. Nucleic Acids Res 10(22):7055–7074

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O (2010) New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 59(3):307–321

    CAS  PubMed  Google Scholar 

  • Hasegawa M, Kishino H, Yano T (1985) Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22(2):160–174

    CAS  PubMed  Google Scholar 

  • Hellen CUT (2018) Translation termination and ribosome recycling in eukaryotes. Cold Spring Harb Perspect Biol 10(10):a032656

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herrero J, Muffato M, Beal K, Fitzgerald S, Gordon L, Pignatelli M, Vilella AJ, Searle SM, Amode R, Brent S, Spooner W, Kulesha E, Yates A, Flicek P (2016) Ensembl comparative genomics resources. Database (Oxf) 2016:bav096

    Google Scholar 

  • Huang DW, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37(1):1–13

    Google Scholar 

  • Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57

    CAS  Google Scholar 

  • Jungreis I, Chan CS, Waterhouse RM, Fields G, Lin MF, Kellis M (2016) Evolutionary dynamics of abundant stop codon readthrough. Mol Biol Evol 33(12):3108–3132

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jungreis I, Lin MF, Spokony R, Chan CS, Negre N, Victorsen A, White KP, Kellis M (2011) Evidence of abundant stop codon readthrough in Drosophila and other metazoa. Genome Res 21(12):2096–2113

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kenigsberg E, Yehuda Y, Marjavaara L, Keszthelyi A, Chabes A, Tanay A, Simon I (2016) The mutation spectrum in genomic late replication domains shapes mammalian GC content. Nucleic Acids Res 44(9):4222–4232

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kinsella RJ, Kahari A, Haider S, Zamora J, Proctor G, Spudich G, Almeida-King J, Staines D, Derwent P, Kerhornou A, Kersey P, Flicek P (2011) Ensembl BioMarts: a hub for data retrieval across taxonomic space. Database (Oxf) 2011:bar030

    Google Scholar 

  • Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, Gladyshev VN (2003) Characterization of mammalian selenoproteomes. Science 300(5624):1439–1443

    CAS  PubMed  Google Scholar 

  • Li C, Zhang J (2019) Stop-codon read-through arises largely from molecular errors and is generally nonadaptive. PLoS Genet 15(5):e1008141

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liebhaber SA, Kan YW (1981) Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics. J Clin Investig 68(2):439–446

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lindsay H, Yap VB, Ying H, Huttley GA (2008) Pitfalls of the most commonly used models of context dependent substitution. Biol Direct 3:52

    PubMed  PubMed Central  Google Scholar 

  • Loughran G, Chou MY, Ivanov IP, Jungreis I, Kellis M, Kiran AM, Baranov PV, Atkins JF (2014) Evidence of efficient stop codon readthrough in four mammalian genes. Nucleic Acids Res 42(14):8928–8938

    CAS  PubMed  PubMed Central  Google Scholar 

  • Loughran G, Howard MT, Firth AE, Atkins JF (2017) Avoidance of reporter assay distortions from fused dual reporters. RNA 23(8):1285–1289

    CAS  PubMed  PubMed Central  Google Scholar 

  • McCaughan KK, Brown CM, Dalphin ME, Berry MJ, Tate WP (1995) Translational termination efficiency in mammals is influenced by the base following the stop codon. Proc Natl Acad Sci USA 92(12):5431–5435

    CAS  PubMed  PubMed Central  Google Scholar 

  • Muse SV, Gaut BS (1994) A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. Mol Biol Evol 11(5):715–724

    CAS  PubMed  Google Scholar 

  • Nelder JA, Mead R (1965) A simplex method for function minimization. Comput J 7:308–313

    Google Scholar 

  • Ngandu NK, Scheffler K, Moore P, Woodman Z, Martin D, Seoighe C (2008) Extensive purifying selection acting on synonymous sites in HIV-1 Group M sequences. Virol J 5:160

    PubMed  PubMed Central  Google Scholar 

  • Pesole G, Mignone F, Gissi C, Grillo G, Licciulli F, Liuni S (2001) Structural and functional features of eukaryotic mRNA untranslated regions. Gene 276(1–2):73–81

    CAS  PubMed  Google Scholar 

  • Pond SK, Muse SV (2005) Site-to-site variation of synonymous substitution rates. Mol Biol Evol 22(12):2375–2385

    CAS  PubMed  Google Scholar 

  • Pouyet F, Mouchiroud D, Duret L, Semon M (2017) Recombination, meiotic expression and human codon usage. eLife 6:e27344

    PubMed  PubMed Central  Google Scholar 

  • R Core Team (2017) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. https://www.R-project.org/

  • Rubinstein ND, Doron-Faigenboim A, Mayrose I, Pupko T (2011) Evolutionary models accounting for layers of selection in protein-coding genes and their impact on the inference of positive selection. Mol Biol Evol 28(12):3297–3308

    CAS  PubMed  Google Scholar 

  • Sauna ZE, Kimchi-Sarfaty C (2011) Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet 12(10):683–691

    CAS  PubMed  Google Scholar 

  • Schueren F, Thoms S (2016) Functional translational readthrough: a systems biology perspective. PLoS Genet 12(8):e1006196

    PubMed  PubMed Central  Google Scholar 

  • Sun J, Chen M, Xu J, Luo J (2005) Relationships among stop codon usage bias, its context, isochores, and gene expression level in various eukaryotes. J Mol Evol 61(4):437–444

    CAS  PubMed  Google Scholar 

  • Tani H, Mizutani R, Salam KA, Tano K, Ijiri K, Wakamatsu A, Isogai T, Suzuki Y, Akimitsu N (2012) Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals. Genome Res 22(5):947–956

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tate WP, Poole ES, Horsfield JA, Mannering SA, Brown CM, Moffat JG, Dalphin ME, McCaughan KK, Major LL, Wilson DN (1995) Translational termination efficiency in both bacteria and mammals is regulated by the base following the stop codon. Biochem Cell Biol 73(11–12):1095–1103

    CAS  PubMed  Google Scholar 

  • Tavaré S (1986) Some probabilistic and statistical problems in the analysis of DNA sequences. Lectures on mathematics in the life sciences, vol 17(2). American Mathematical Society, Providence, pp 57–86

  • Trotta E (2016) Selective forces and mutational biases drive stop codon usage in the human genome: a comparison with sense codon usage. BMC Genomics 17:366

    PubMed  PubMed Central  Google Scholar 

  • Yanagitani K, Kimata Y, Kadokura H, Kohno K (2011) Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science 331(6017):586–589

    CAS  PubMed  Google Scholar 

  • Yordanova MM, Loughran G, Zhdanov AV, Mariotti M, Kiniry SJ, O’Connor PBF, Andreev DE, Tzani I, Saffert P, Michel AM, Gladyshev VN, Papkovsky DB, Atkins JF, Baranov PV (2018) AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation. Nature 553(7688):356–360

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Ireland

    Cathal Seoighe, Andrew Peters & Haixuan Yang

  2. School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

    Stephen J. Kiniry & Pavel V. Baranov

Authors
  1. Cathal Seoighe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen J. Kiniry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pavel V. Baranov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haixuan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Cathal Seoighe.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical Approval

Not applicable.

Additional information

Handling editor: David Liberles.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(PDF 1651 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-020-09957-x

Keywords

Search

Navigation