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Current Genomics

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ISSN (Print): 1389-2029
ISSN (Online): 1875-5488

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Review Article

Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics

Author(s): Mauno Vihinen*

Volume 24, Issue 1, 2023

Published on: 27 April, 2023

Page: [18 - 23] Pages: 6

DOI: 10.2174/1389202924666230417101020

Price: $65

Abstract

Synonymous (also known as silent) variations are by definition not considered to change the coded protein. Still many variations in this category affect either protein abundance or properties. As this situation is confusing, we have recently introduced systematics for synonymous variations and those that may on the surface look like synonymous, but these may affect the coded protein in various ways. A new category, unsense variation, was introduced to describe variants that do not introduce a stop codon into the variation site, but which lead to different types of changes in the coded protein. Many of these variations lead to mRNA degradation and missing protein. Here, consequences of the systematics are discussed from the perspectives of variation annotation and interpretation, evolutionary calculations, nonsynonymous-to-synonymous substitution rates, phylogenetics and other evolutionary inferences that are based on the principle of (nearly) neutral synonymous variations. It may be necessary to reassess published results. Further, databases for synonymous variations and prediction methods for such variations should consider unsense variations. Thus, there is a need to evaluate and reflect principles of numerous aspects in genetics, ranging from variation naming and classification to evolutionary calculations.

Keywords: Synonymous variation, silent variation, unsense variation, phylogenetics, distribution of fitness effects, nonsynonymous- to-synonymous substitution ratio.

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[1]
Kurosaki, T.; Popp, M.W.; Maquat, L.E. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat. Rev. Mol. Cell Biol., 2019, 20(7), 406-420.
[http://dx.doi.org/10.1038/s41580-019-0126-2] [PMID: 30992545]
[2]
Lindeboom, R.G.H.; Vermeulen, M.; Lehner, B.; Supek, F. The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat. Genet., 2019, 51(11), 1645-1651.
[http://dx.doi.org/10.1038/s41588-019-0517-5] [PMID: 31659324]
[3]
Vihinen, M. Systematics for types and effects of RNA variations. RNA Biol., 2021, 18(4), 481-498.
[http://dx.doi.org/10.1080/15476286.2020.1817266] [PMID: 32951567]
[4]
Vihinen, M. Muddled genetic terms miss and mess the message. Trends Genet., 2015, 31(8), 423-425.
[http://dx.doi.org/10.1016/j.tig.2015.05.008] [PMID: 26091961]
[5]
Sauna, Z.E.; Kimchi-Sarfaty, C. Understanding the contribution of synonymous mutations to human disease. Nat. Rev. Genet., 2011, 12(10), 683-691.
[http://dx.doi.org/10.1038/nrg3051] [PMID: 21878961]
[6]
Shabalina, S.A.; Spiridonov, N.A.; Kashina, A. Sounds of silence: Synonymous nucleotides as a key to biological regulation and complexity. Nucleic Acids Res., 2013, 41(4), 2073-2094.
[http://dx.doi.org/10.1093/nar/gks1205] [PMID: 23293005]
[7]
Vihinen, M. When a synonymous variant is nonsynomous. Genes, 2022, 13(8), 1485.
[http://dx.doi.org/10.3390/genes13081485] [PMID: 36011397]
[8]
Mueller, W.F.; Larsen, L.S.Z.; Garibaldi, A.; Hatfield, G.W.; Hertel, K.J. The silent sway of splicing by synonymous substitutions. J. Biol. Chem., 2015, 290(46), 27700-27711.
[http://dx.doi.org/10.1074/jbc.M115.684035] [PMID: 26424794]
[9]
Bailey, S.F.; Alonso Morales, L.A.; Kassen, R. Effects of synonymous mutations beyond codon bias: The evidence for adaptive synonymous substitutions from microbial evolution experiments. Genome Biol. Evol., 2021, 13(9)evab141
[http://dx.doi.org/10.1093/gbe/evab141] [PMID: 34132772]
[10]
Vihinen, M. Variation Ontology for annotation of variation effects and mechanisms. Genome Res., 2014, 24(2), 356-364.
[http://dx.doi.org/10.1101/gr.157495.113] [PMID: 24162187]
[11]
Vihinen, M. Systematic errors in annotations of truncations, loss-of-function and synonymous variants. Front. Genet., 2023, 141015017
[http://dx.doi.org/10.3389/fgene.2023.1015017] [PMID: 36713076]
[12]
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. A minimal role for synonymous variation in human disease. Am. J. Hum. Genet., 2022, 109(12), 2105-2109.
[http://dx.doi.org/10.1016/j.ajhg.2022.10.016] [PMID: 36459978]
[13]
Rhine, C.L.; Neil, C.; Wang, J.; Maguire, S.; Buerer, L.; Salomon, M.; Meremikwu, I.C.; Kim, J.; Strande, N.T.; Fairbrother, W.G. Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes. PLoS Genet., 2022, 18(1)e1009884
[http://dx.doi.org/10.1371/journal.pgen.1009884] [PMID: 35051175]
[14]
Shen, X.; Song, S.; Li, C.; Zhang, J. Synonymous mutations in representative yeast genes are mostly strongly non-neutral. Nature, 2022, 606(7915), 725-731.
[http://dx.doi.org/10.1038/s41586-022-04823-w] [PMID: 35676473]
[15]
Zeng, Z.; Bromberg, Y. Predicting functional effects of synonymous variants: A systematic review and perspectives. Front. Genet., 2019, 10, 914.
[http://dx.doi.org/10.3389/fgene.2019.00914] [PMID: 31649718]
[16]
Zeng, Z.; Aptekmann, A.A.; Bromberg, Y. Decoding the effects of synonymous variants. Nucleic Acids Res., 2021, 49(22), 12673-12691.
[http://dx.doi.org/10.1093/nar/gkab1159] [PMID: 34850938]
[17]
Miao, X.; Li, X.; Wang, L.; Zheng, C.; Cai, J. DSMNC: A database of somatic mutations in normal cells. Nucleic Acids Res., 2019, 47(D1), D971-D975.
[http://dx.doi.org/10.1093/nar/gky1045] [PMID: 30380071]
[18]
Wen, P.; Xiao, P.; Xia, J. dbDSM: A manually curated database for deleterious synonymous mutations. Bioinformatics, 2016, 32(12), 1914-1916.
[http://dx.doi.org/10.1093/bioinformatics/btw086] [PMID: 27153700]
[19]
Bali, V.; Bebok, Z. Decoding mechanisms by which silent codon changes influence protein biogenesis and function. Int. J. Biochem. Cell Biol., 2015, 64, 58-74.
[http://dx.doi.org/10.1016/j.biocel.2015.03.011] [PMID: 25817479]
[20]
Vihinen, M. Individual genetic heterogeneity. Genes, 2022, 13(9), 1626.
[http://dx.doi.org/10.3390/genes13091626] [PMID: 36140794]
[21]
Kim, Y.J.; Kang, J.; Seymen, F.; Koruyucu, M.; Zhang, H.; Kasimoglu, Y.; Bayram, M.; Tuna-Ince, E.B.; Bayrak, S.; Tuloglu, N.; Hu, J.C.C.; Simmer, J.P.; Kim, J.W. Alteration of exon definition causes amelogenesis imperfecta. J. Dent. Res., 2020, 99(4), 410-418.
[http://dx.doi.org/10.1177/0022034520901708] [PMID: 31999931]
[22]
Nielsen, K.B.; Sørensen, S.; Cartegni, L.; Corydon, T.J.; Doktor, T.K.; Schroeder, L.D.; Reinert, L.S.; Elpeleg, O.; Krainer, A.R.; Gregersen, N.; Kjems, J.; Andresen, B.S. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: A synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am. J. Hum. Genet., 2007, 80(3), 416-432.
[http://dx.doi.org/10.1086/511992] [PMID: 17273963]
[23]
Tonin, R.; Catarzi, S.; Caciotti, A.; Procopio, E.; Marini, C.; Guerrini, R.; Morrone, A. Progressive myoclonus epilepsy in Gaucher disease due to a new Gly–Gly mutation causing loss of an exonic splicing enhancer. J. Neurol., 2019, 266(1), 92-101.
[http://dx.doi.org/10.1007/s00415-018-9084-4] [PMID: 30382391]
[24]
Liu, C.; Rennie, W.A.; Carmack, C.S.; Kanoria, S.; Cheng, J.; Lu, J.; Ding, Y. Effects of genetic variations on microRNA: target interactions. Nucleic Acids Res., 2014, 42(15), 9543-9552.
[http://dx.doi.org/10.1093/nar/gku675] [PMID: 25081214]
[25]
Brest, P.; Lapaquette, P.; Souidi, M.; Lebrigand, K.; Cesaro, A.; Vouret-Craviari, V.; Mari, B.; Barbry, P.; Mosnier, J.F.; Hébuterne, X.; Harel-Bellan, A.; Mograbi, B.; Darfeuille-Michaud, A.; Hofman, P. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat. Genet., 2011, 43(3), 242-245.
[http://dx.doi.org/10.1038/ng.762] [PMID: 21278745]
[26]
Tay, Y.; Zhang, J.; Thomson, A.M.; Lim, B.; Rigoutsos, I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 2008, 455(7216), 1124-1128.
[http://dx.doi.org/10.1038/nature07299] [PMID: 18806776]
[27]
Bhagavatula, G.; Rich, M.S.; Young, D.L.; Marin, M.; Fields, S. A massively parallel fluorescence assay to characterize the effects of synonymous mutations on TP53 expression. Mol. Cancer Res., 2017, 15(10), 1301-1307.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0245] [PMID: 28652265]
[28]
Wang, K.; Li, M.; Hakonarson, H. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res., 2010, 38(16)e164
[http://dx.doi.org/10.1093/nar/gkq603] [PMID: 20601685]
[29]
Cingolani, P.; Platts, A.; Wang, L.L.; Coon, M.; Nguyen, T.; Wang, L.; Land, S.J.; Lu, X.; Ruden, D.M. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff. Fly, 2012, 6(2), 80-92.
[http://dx.doi.org/10.4161/fly.19695] [PMID: 22728672]
[30]
McLaren, W.; Gil, L.; Hunt, S.E.; Riat, H.S.; Ritchie, G.R.S.; Thormann, A.; Flicek, P.; Cunningham, F. The ensembl variant effect predictor. Genome Biol., 2016, 17(1), 122.
[http://dx.doi.org/10.1186/s13059-016-0974-4] [PMID: 27268795]
[31]
Sharp, N. Mutations matter even if proteins stay the same. Nature, 2022, 606(7915), 657-659.
[http://dx.doi.org/10.1038/d41586-022-01091-6] [PMID: 35676345]
[32]
Goldman, N.; Yang, Z. A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol. Biol. Evol., 1994, 11(5), 725-736.
[PMID: 7968486]
[33]
Arenas, M. Trends in substitution models of molecular evolution. Front. Genet., 2015, 6, 319.
[http://dx.doi.org/10.3389/fgene.2015.00319] [PMID: 26579193]
[34]
Zhang, Z.; Yu, J. Evaluation of six methods for estimating synonymous and nonsynonymous substitution rates. Genomics Proteomics Bioinform., 2006, 4(3), 173-181.
[http://dx.doi.org/10.1016/S1672-0229(06)60030-2] [PMID: 17127215]
[35]
Wisotsky, S.R.; Kosakovsky Pond, S.L.; Shank, S.D.; Muse, S.V. Synonymous site-to-site substitution rate variation dramatically inflates false positive rates of selection analyses: Ignore at your own peril. Mol. Biol. Evol., 2020, 37(8), 2430-2439.
[http://dx.doi.org/10.1093/molbev/msaa037] [PMID: 32068869]
[36]
Librado, P.; Vieira, F.G.; Sánchez-Gracia, A.; Kolokotronis, S.O.; Rozas, J. Mycobacterial phylogenomics: An enhanced method for gene turnover analysis reveals uneven levels of gene gain and loss among species and gene families. Genome Biol. Evol., 2014, 6(6), 1454-1465.
[http://dx.doi.org/10.1093/gbe/evu117] [PMID: 24904011]
[37]
Sharma, Y.; Miladi, M.; Dukare, S.; Boulay, K.; Caudron-Herger, M.; Groß, M.; Backofen, R.; Diederichs, S. A pan-cancer analysis of synonymous mutations. Nat. Commun., 2019, 10(1), 2569.
[http://dx.doi.org/10.1038/s41467-019-10489-2] [PMID: 31189880]
[38]
Livingstone, M.; Folkman, L.; Yang, Y.; Zhang, P.; Mort, M.; Cooper, D.N.; Liu, Y.; Stantic, B.; Zhou, Y. Investigating DNA-, RNA-, and protein-based features as a means to discriminate pathogenic synonymous variants. Hum. Mutat., 2017, 38(10), 1336-1347.
[http://dx.doi.org/10.1002/humu.23283] [PMID: 28649752]
[39]
Cheng, N.; Wang, H.; Tang, X.; Zhang, T.; Gui, J.; Zheng, C.H.; Xia, J. An ensemble framework for improving the prediction of deleterious synonymous mutation. IEEE Trans. Circ. Syst. Video Tech., 2022, 32(5), 2603-2611.
[http://dx.doi.org/10.1109/TCSVT.2021.3063145]
[40]
Ranganathan, G.S.; Alexov, E. An ensemble approach to predict the pathogenicity of synonymous variants. Genes, 2020, 11(9), 1102.
[http://dx.doi.org/10.3390/genes11091102] [PMID: 32967157]
[41]
Cheng, N.; Li, M.; Zhao, L.; Zhang, B.; Yang, Y.; Zheng, C.H.; Xia, J. Comparison and integration of computational methods for deleterious synonymous mutation prediction. Brief. Bioinform., 2020, 21(3), 970-981.
[http://dx.doi.org/10.1093/bib/bbz047] [PMID: 31157880]
[42]
Buske, O.J.; Manickaraj, A.; Mital, S.; Ray, P.N.; Brudno, M. Identification of deleterious synonymous variants in human genomes. Bioinformatics, 2015, 31(5), 799.
[http://dx.doi.org/10.1093/bioinformatics/btu765] [PMID: 25488928]
[43]
Zhang, T.; Wu, Y.; Lan, Z.; Shi, Q.; Yang, Y.; Guo, J. Syntool: A novel region-based intolerance score to single nucleotide substitution for synonymous mutations predictions based on 123,136 individuals. BioMed Res. Int., 2017, 2017, 1-5.
[http://dx.doi.org/10.1155/2017/5096208] [PMID: 28812016]
[44]
Zhang, X.; Li, M.; Lin, H.; Rao, X.; Feng, W.; Yang, Y.; Mort, M.; Cooper, D.N.; Wang, Y.; Wang, Y.; Wells, C.; Zhou, Y.; Liu, Y. regSNPs-splicing: A tool for prioritizing synonymous single-nucleotide substitution. Hum. Genet., 2017, 136(9), 1279-1289.
[http://dx.doi.org/10.1007/s00439-017-1783-x] [PMID: 28391525]
[45]
Gelfman, S.; Wang, Q.; McSweeney, K.M.; Ren, Z.; La Carpia, F.; Halvorsen, M.; Schoch, K.; Ratzon, F.; Heinzen, E.L.; Boland, M.J.; Petrovski, S.; Goldstein, D.B. Annotating pathogenic non-coding variants in genic regions. Nat. Commun., 2017, 8(1), 236.
[http://dx.doi.org/10.1038/s41467-017-00141-2] [PMID: 28794409]
[46]
Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; Voelkerding, K.; Rehm, H.L. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet. Med., 2015, 17(5), 405-424.
[http://dx.doi.org/10.1038/gim.2015.30] [PMID: 25741868]

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