Key Points
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There are many variations in the genetic code, both in nuclear and mitochondrial genomes, but all are relatively recent modifications of the 'canonical' code found in the last common ancestor.
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The recent evolution of the genetic code relies on changes in components of the translation apparatus. In particular, many changes are due to base modifications that occur after transcription.
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Three theories have attempted to explain the range of changes to the genetic code:
1. Codon capture: biased mutations can eliminate certain codons from the genome, which are reassigned by neutral processes (that is, in the absence of selection).
2. Genome minimization: the code evolves to minimize the number of tRNAs required for translation.
3. Codon ambiguity: evolution of the genetic code is adaptive and occurs through an intermediate stage in which a codon can be translated into more than one amino acid.
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We find statistical support for the last two of these theories.
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Changes in the genetic code that are revealed by future studies will be used to test the specific predictions of each of these theories. Future work will also further clarify the roles of mutation and selection in producing new genetic codes.
Abstract
The genetic code evolved in two distinct phases. First, the 'canonical' code emerged before the last universal ancestor; subsequently, this code diverged in numerous nuclear and organelle lineages. Here, we examine the distribution and causes of these secondary deviations from the canonical genetic code. The majority of non-standard codes arise from alterations in the tRNA, with most occurring by post-transcriptional modifications, such as base modification or RNA editing, rather than by substitutions within tRNA anticodons.
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References
Crick, F. H. C. The origin of the genetic code. J. Mol. Biol. 38, 367–379 (1968).Seminal introduction to the origin and evolution of the genetic code, best known for its exposition of the 'frozen accident' theory (that the code became fixed at a suboptimal state, because to change it would be deleterious).
Knight, R. D., Freeland, S. J. & Landweber, L. F. Selection, history and chemistry: the three faces of the genetic code. Trends Biochem. Sci. 24, 241–247 (1999).
Szathmáry, E. The origin of the genetic code: amino acids as cofactors in an RNA world. Trends Genet. 15, 223–229 (1999).
Barrell, B. G., Bankier, A. T. & Drouin, J. A different genetic code in human mitochondria. Nature 282, 189–194 ( 1979).
Osawa, S. Evolution of the Genetic Code (Oxford Univ. Press, Oxford, 1995).Exposition of the 'codon capture' hypothesis, which proposes a neutral mechanism for codon reassignment through a stage in which the codon disappears from the genome entirely.
Schultz, D. W. & Yarus, M. On malleability in the genetic code . J. Mol. Evol. 42, 597– 601 (1996).Exposition of the 'ambiguous intermediate' hypothesis, which suggests that the genetic code changes through a state in which some codons have more than one meaning.
Santos, M. A., Cheesman, C., Costa, V., Moradas-Ferreira, P. & Tuite, M. F. Selective advantages created by codon ambiguity allowed for the evolution of an alternative genetic code in Candida spp. Mol. Microbiol. 31, 937–947 (1999).Provides experimental support for the idea that ambiguous decoding can be advantageous in some circumstances.
Wagner, G. P. & Altenberg, L. Complex adaptations and the evolution of evolvability. Evolution 50, 967– 976 (1996).
Andersson, S. G. & Kurland, C. G. Genomic evolution drives the evolution of the translation system. Biochem. Cell Biol. 73, 775–787 ( 1995).Most complete exposition of the 'genome reduction' hypothesis, which suggests that pressure to minimize mitochondrial genomes leads to the reassignment of specific codons.
Sugita, T. & Nakase, T. Non-universal usage of the leucine CUG codon and the molecular phylogeny of the genus Candida. Syst. Appl. Microbiol. 22, 79–86 (1999).
Tourancheau, A. B., Tsao, N., Klobutcher, L. A., Pearlman, R. E. & Adoutte, A. Genetic code deviations in the ciliates: evidence for multiple and independent events. EMBO J. 14, 3262–3267 (1995).
Ehara, M., Inagaki, Y., Watanabe, K. I. & Ohama, T. Phylogenetic analysis of diatom coxI genes and implications of a fluctuating GC content on mitochondrial genetic code evolution. Curr. Genet. 37, 29–33 ( 2000).
Hayashi-Ishimaru, Y., Ohama, T., Kawatsu, Y., Nakamura, K. & Osawa, S. UAG is a sense codon in several chlorophycean mitochondria . Curr. Genet. 30, 29–33 (1996).
Hayashi-Ishimaru, Y., Ehara, M., Inagaki, Y. & Ohama, T. A deviant mitochondrial genetic code in prymnesiophytes (yellow-algae): UGA codon for tryptophan. Curr. Genet. 32, 296–299 (1997).
Castresana, J., Feldmaier-Fuchs, G. & Pääbo, S. Codon reassignment and amino acid composition in hemichordate mitochondria. Proc. Natl Acad. Sci. USA 95, 3703–3707 (1998).
Osawa, S., Jukes, T. H., Watanabe, K. & Muto, A. Recent evidence for evolution of the genetic code. Microbiol. Rev. 56, 229–264 (1992).
Lagerkvist, U. Unorthodox codon reading and the evolution of the genetic code. Cell 23, 305–306 ( 1981).
Knight, R. D. & Landweber, L. F. Guilt by association: the arginine case revisited. RNA 6, 499– 510 (2000).
Ito, K., Uno, M. & Nakamura, Y. A tripeptide 'anticodon' deciphers stop codons in messenger RNA. Nature 403, 680–684 (2000).Experimental demonstration that bacterial release factors use only a few amino acids to recognize the specific mRNA stop codons.
Perret, V. et al. Relaxation of a transfer RNA specificity by removal of modified nucleotides. Nature 344, 787– 789 (1990).
Muramatsu, T. et al. Codon and amino-acid specificities of a transfer RNA are both converted by a single post-transcriptional modification. Nature 336, 179–181 ( 1988).
Cermakian, N. & Cedegren, R. C. in Modification and Editing of RNA (eds Grosjean, H. & Benne, R.) 535– 541 (American Society for Microbiology, Washington, 1998).Reviews the distribution of modified bases throughout the three domains of life, and argues that many of the modifications pre-date the last common ancestor of extant life.
Unrau, P. J. & Bartel, D. P. RNA-catalysed nucleotide synthesis . Nature 395, 260–263 (1998).
Levy, M. & Miller, S. L. The prebiotic synthesis of modified purines and their potential role in the RNA world. J. Mol. Evol. 48, 631–637 ( 1999).
Edmonds, C. G. et al. Posttranscriptional modification of tRNA in thermophilic archaea (Archaebacteria). J. Bacteriol. 173, 3138 –3148 (1991).
Giege, R., Sissler, M. & Florentz, C. Universal rules and idiosyncratic features in tRNA identity . Nucleic Acids Res. 26, 5017– 5035 (1998).Excellent review of tRNA identity.
Murgola, E. J. tRNA, suppression, and the code. Annu. Rev. Genet. 19, 57–80 (1985).
Arnez, J. G. & Moras, D. Structural and functional considerations of the aminoacylation reaction. Trends Biochem. Sci. 22, 211–216 (1997).
Matsuyama, S., Ueda, T., Crain, P. F., McCloskey, J. A. & Watanabe, K. A novel wobble rule found in starfish mitochondria. Presence of 7-methylguanosine at the anticodon wobble position expands decoding capability of tRNA. J. Biol. Chem. 273, 3363–3368 (1998). This is one of a series of papers from Watanabe's lab, and shows the role of specific base modifications in changing the genetic code in mitochondria.
Tomita, K., Ueda, T. & Watanabe, K. 7-Methylguanosine at the anticodon wobble position of squid mitochondrial tRNA(Ser)GCU: molecular basis for assignment of AGA/AGG codons as serine in invertebrate mitochondria. Biochim. Biophys. Acta 1399, 78–82 ( 1998).
Alfonzo, J. D., Blanc, V., Estevez, A. M., Rubio, M. A. & Simpson, L. C to U editing of the anticodon of imported mitochondrial tRNA(Trp) allows decoding of the UGA stop codon in Leishmania tarentolae. EMBO J. 18, 7056–7062 (1999).
Small, I., Wintz, H., Akashi, K. & Mireau, H. Two birds with one stone: genes that encode products targeted to two or more compartments . Plant Mol. Biol. 38, 265– 277 (1998).
Mazauric, M. H., Roy, H. & Kern, D. tRNA glycylation system from Thermus thermophilus. tRNAGly identity and functional interrelation with the glycylation systems from other phylae. Biochemistry 38, 13094– 13105 (1999).
Crick, F. H. C. The recent excitement in the coding problem. Prog. Nucleic Acids 1, 163–217 ( 1963).
Crick, F. H. Codon–anticodon pairing: the wobble hypothesis. J. Mol. Biol. 19, 548–555 ( 1966).
Osawa, S. & Jukes, T. H. Codon reassignment (codon capture) in evolution. J. Mol. Evol. 28, 271– 278 (1989).
Schultz, D. W. & Yarus, M. Transfer RNA mutation and the malleability of the genetic code. J. Mol. Biol. 235, 1377–1380 (1994).
Andersson, S. G. & Kurland, C. G. Reductive evolution of resident genomes. Trends Microbiol. 6, 263–268 (1998).
Takai, K., Takaku, H. & Yokoyama, S. In vitro codon-reading specificities of unmodified tRNA molecules with different anticodons on the sequence background of Escherichia coli tRNASer. Biochem. Biophys. Res. Commun. 257, 662–667 (1999).
Szathmáry, E. Codon swapping as a possible evolutionary mechanism. J. Mol. Evol. 32, 178–182 ( 1991).
Lagerkvist, U. 'Two out of three': An alternative method for codon reading. Proc. Natl Acad. Sci. USA 75, 1759–1762 (1978).
Saks, M. E., Sampson, J. R. & Abelson, J. Evolution of a transfer RNA gene through a point mutation in the anticodon. Science 279, 1665– 1670 (1998).Demonstration that a single-base change at the anticodon of a tRNA can change both its decoding and aminoacylation specificities. This paper has important implications for the use of tRNA phylogeny to track the evolution of the genetic code.
Pallanck, K., Pak, M. & Schulman, L. H. in tRNA: Structure, Biosynthesis, and Function (eds Söll, D. & RajBhandary, U.) 371–394 (American Society for Microbiology, Washington, 1995).
Murgola, E. J. in tRNA: Structure, Biosynthesis and Function (eds Söll, D. & RajBhandary, U.) 491–509 (American Society for Microbiology, Washington, 1995).
Jukes, T. H. Genetic code 1990. Outlook. Experientia 46, 1149–1157 (1990).
Tomita, K. et al. Codon reading patterns in Drosophila melanogaster mitochondria based on their tRNA sequences: a unique wobble rule in animal mitochondria . Nucleic Acids Res. 27, 4291– 4297 (1999).
Schimmel, P., Giege, R., Moras, D. & Yokoyama, S. An operational genetic code for amino acids and possible relationship to genetic code. Proc. Natl Acad. Sci. USA 90, 8763– 8768 (1993).
Wright, E. V. Gadsby: a story of over 50,000 words without using the letter 'E' (Wetzel, Los Angeles, 1939).
Jukes, T. H. Neutral changes and modifications of the genetic code. Theor. Popul. Biol. 49, 143–145 ( 1996).
Keeling, P. J. & Doolittle, W. F. Widespread and ancient distribution of a noncanonical genetic Code in diplomonads. Mol. Biol. Evol. 14, 895–901 (1997).
Freeland, S. J. & Hurst, L. D. The genetic code is one in a million. J. Mol. Evol. 47, 238 –248 (1998).A statistical argument to show that the actual genetic code minimizes the effects of error far better than would be expected by chance.
Freeland, S. J., Knight, R. D., Landweber, L. F. & Hurst, L. D. Early fixation of an optimal genetic code. Mol. Biol. Evol. 17, 511–518 (2000).
Yarus, M. & Schultz, D. W. Response: Further comments on codon reassignment. J. Mol. Evol. 45, 1– 8 (1997).
Curran, J. F. Decoding with the A:I wobble pair is inefficient. Nucleic Acids Res. 23, 683–688 ( 1995).
Andersson, G. E. & Kurland, C. G. An extreme codon preference strategy: codon reassignment. Mol. Biol. Evol. 8, 530–544 ( 1991).
Yarus, M. RNA-ligand chemistry: a testable source for the genetic code. RNA 6, 475–484 ( 2000).
Schneider, S. U. & de Groot, E. J. Sequences of two rbcS cDNA clones of Batophora oerstedii: structural and evolutionary considerations. Curr. Genet. 20, 173– 175 (1991).
Lozupone, C. A., Knight, R. D. & Landweber, L. F. The molecular basis of nuclear genetic code change in ciliates. Curr. Biol. (in the press).
Oba, T., Andachi, Y., Muto, A. & Osawa, S. CGG: an unassigned or nonsense codon in Mycoplasma capricolum. Proc. Natl Acad. Sci. USA 88, 921–925 ( 1991).
Kuck, U., Jekosch, K. & Holzamer, P. DNA sequence analysis of the complete mitochondrial genome of the green alga Scenedesmus obliquus: evidence for UAG being a leucine and UCA being a non-sense codon. Gene 253 , 13–18 (2000).
Kano, A., Ohama, T., Abe, R. & Osawa, S. Unassigned or nonsense codons in Micrococcus luteus. J. Mol. Biol. 230, 51–56 (1993).
Cavalier-Smith, T. Kingdom protozoa and its 18 phyla. Microbiol. Rev. 57, 953–994 (1993).
Telford, M. J., Herniou, E. A., Russell, R. B. & Littlewood, D. T. Changes in mitochondrial genetic codes as phylogenetic characters: two examples from the flatworms. Proc. Natl Acad. Sci. USA 97, 11359–11364 (2000).
Inagaki, Y., Ehara, M., Watanabe, K. I., Hayashi-Ishimaru, Y. & Ohama, T. Directionally evolving genetic code: the UGA codon from stop to tryptophan in mitochondria. J. Mol. Evol. 47, 378–384 (1998).
Clark-Walker, G. D. & Weiller, G. F. The structure of the small mitochondrial DNA of Kluyveromyces thermotolerans is likely to reflect the ancestral gene order in fungi. J. Mol. Evol. 38, 593–601 (1994).
Laforest, M. J., Roewer, I. & Lang, B. F. Mitochondrial tRNAs in the lower fungus Spizellomyces punctatus: tRNA editing and UAG 'stop' codons recognized as leucine. Nucleic Acids Res. 25, 626–632 (1997).
Wilson, R. J. & Williamson, D. H. Extrachromosomal DNA in the Apicomplexa. Microbiol. Mol. Biol. Rev. 61, 1–16 (1997).
Yasuhira, S. & Simpson, L. Phylogenetic affinity of mitochondria of Euglena gracilis and kinetoplastids using cytochrome oxidase I and hsp60. J. Mol. Evol. 44, 341– 347 (1997).
Lovett, P. S. et al. UGA can be decoded as tryptophan at low efficiency in Bacillus subtilis. J. Bacteriol. 173, 1810–1812 (1991).
Tomita, K., Ueda, T. & Watanabe, K. The presence of pseudouridine in the anticodon alters the genetic code: a possible mechanism for assignment of the AAA lysine codon as asparagine in echinoderm mitochondria. Nucleic Acids Res. 27, 1683–1689 (1999).
Horie, N. et al. Modified nucleosides in the first positions of the anticodons of tRNA(Leu)4 and tRNA(Leu)5 from Escherichia coli. Biochemistry 38, 207–217 ( 1999).
Tomita, K., Ueda, T. & Watanabe, K. 5-formylcytidine (f5C) found at the wobble position of the anticodon of squid mitochondrial tRNA(Met)CAU. Nucleic Acids Symp. Ser. 37, 197–198 ( 1997).
Watanabe, Y. et al. Primary sequence of mitochondrial tRNA(Arg) of a nematode Ascaris suum: occurrence of unmodified adenosine at the first position of the anticodon. Biochim. Biophys. Acta 1350, 119–122 (1997).
Boren, T. et al. Undiscriminating codon reading with adenosine in the wobble position . J. Mol. Biol. 230, 739– 749 (1993).
Grimm, M., Brunen-Nieweler, C., Junker, V., Heckmann, K. & Beier, H. The hypotrichous ciliate Euplotes octocarinatus has only one type of tRNACys with GCA anticodon encoded on a single macronuclear DNA molecule. Nucleic Acids Res. 26, 4557–4565 ( 1998).
Watanabe, K. & Osawa, S. in tRNA: Structure, Biosynthesis, and Function (eds Söll, D. & RajBhandary, U.) 225– 250 (American Society for Microbiology, Washington, 1995).
Yokoyama, S. & Nishimura, S. in tRNA: Structure, Biosynthesis, and Function (eds. Söll, D. & RajBhandary, U.) 207– 223 (American Society for Microbiology, Washington 1995).
Björk, G. R. in Modification and Editing of RNA (eds Grosjean, H. & Benne, R.) 577–581 (American Society for Microbiology, Washington, 1998).
Curran, J. F. in Modification and Editing of RNA (eds Grosjean, H. & Benne, R.) 493–516 (American Society for Microbiology, Washington, 1998).Excellent review of the base-pairing roles of normal and modified bases at the wobble position in the tRNA anticodon.
Motorin, Y. & Grosjean, H. in Modification and Editing of RNA (eds Grosjean, H. & Benne, R.) 543–549 (American Society for Microbiology, Washington, 1998 ).
Acknowledgements
S.J.F. is supported by a Human Frontier Science Program fellowship.
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ENCYCLOPEDIA OF LIFE SCIENCES
Glossary
- DIPLOMONADS
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Among the earliest-diverging eukaryotes, these unicellular organisms have two nuclei, but lack mitochondria. The gastrointestinal parasite Giardia is a diplomonad.
- RELEASE FACTORS
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Proteins involved in translation termination that specifically recognize stop codons and catalyse the disassembly of the translation complex.
- AMINOACYL-tRNA SYNTHETASE
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The enzyme that attaches an amino acid to its cognate tRNA(s).
- WOBBLE RULES
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An extension to Watson–Crick base pairing, these rules indicate that, in the context of the first anticodon position of the tRNA (complementary to the third codon position), more flexibility allows non-standard base pairs (such as G with U rather than with C).
- RIBOZYME
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RNA that can perform a catalytic task, such as the self-splicing Group I intron in the ciliate Tetrahymena.
- THIOL
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A thiol (or sulphydryl) group is a chemical group that contains sulphur and hydrogen.
- SUPPRESSOR MUTATION
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A mutation that counteracts the effects of another mutation. A suppressor mutation maps at a different site to that of the mutation that it counteracts, either within the gene or at a more distant locus. Mutations in tRNAs often act as suppressors, because they can change the meaning of the mutated codon back to the original (albeit usually at a low level, because efficient suppressors are often lethal).
- RNA EDITING
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Changes in the RNA sequence after transcription is completed. Examples include modification of C to U or of A to I by deamination, or insertion and/or deletion of particular bases.
- FAMILY BOX
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A set of four codons that are identical at the first two positions, differ only at the third position and code for the same amino acid. For instance, GUU, GUC, GUA and GUG comprise a family box for valine in all known codes.
- BINOMIAL TEST
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If an observation has only two possible outcomes and there are multiple observations, the binomial distribution gives the probability that x or more outcomes of a given type would occur by chance.
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Knight, R., Freeland, S. & Landweber, L. Rewiring the keyboard: evolvability of the genetic code. Nat Rev Genet 2, 49–58 (2001). https://doi.org/10.1038/35047500
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DOI: https://doi.org/10.1038/35047500
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