Evolution of the Genetic

Code

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Article Contents
. Introduction

Shin-ichi Yokobori, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
Takuya Ueda, University of Tokyo, Kashiwa, Japan
Kimitsuna Watanabe, National Institute of Advanced Industrial Science and Technology,

. Deviations from the Universal Genetic Code

Tokyo, Japan

. Concluding Remarks

. Evolutionary Implications
. Origins of the Genetic Code
. Mechanisms for the Evolution of the Genetic Code

Online posting date: 19th April 2010

From the present situation of genetic code so far elucidated for various species of extant organisms, it is speculated that the genetic code system had started from a
limited number of amino acids and evolved to the universal genetic code which is being used by most extant
organisms. During evolution, the genetic code is changeable by some factors such as directional mutational pressure on genomes, genome economization and evolution
of tRNA (and its cognate aminoacyl transfer ribonucleic
acid synthetase). The metazoan (multicellular animal)
mitochondrial genetic code is interesting issue as the
model case of evolution of genetic code, since the metazoan mitochondrial genetic code is greatly deviated from
the universal genetic code, and varied among lineages.
The present situation on the genetic code is discussed.

Introduction
The variation in the genetic code was rst found by Sangers group in 1979 (Barrell et al., 1979), who showed that in
HeLa cell mitochondria the triplet UGA was used for the
Trp codon instead of termination. Since then, a number of
variations have been reported, not only in mitochondria
from various sources but also in eubacterial and nuclear
systems. The present interpretation of such variations is
that although the genetic code was once xed when the
universal code was established before appearance of last
common ancestor of all extant organisms (or progenote/
commonote), it has subsequently evolved along with the

ELS subject area: Biochemistry

How to cite:
Yokobori, Shin-ichi; Ueda, Takuya; and Watanabe, Kimitsuna (April
2010) Evolution of the Genetic Code. In: Encyclopedia of Life Sciences
(ELS). John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0000548.pub2

evolution of the present three main diversied groups

of Bacteria (Eubacteria), Archaea (Archaebacteria) and
Eukarya (Eukaryota). See also: Genes: Denition and
Structure; Sanger, Frederick
What is the driving force of changes in the genetic code
has been widely discussed. Among extant organisms, vertebrate mitochondria have the simplest nonuniversal genetic code.

Deviations from the Universal Genetic

Code
Figure 1a and b summarizes variations in mitochondrial
and in eubacterial and eukaryotic nuclear genetic codes,
respectively. Although changes from both nonsense (stop)
and sense codons to other sense codons often occur in
variations in the mitochondrial genetic code as discussed
later, in the eukaryotic nuclear genetic code only one
instance has been observed in which a sense codon has
changed to another sense codon (the CUG codon is
changed from Leu to Ser in some Candida spp.). See also:
Genetic Code: Introduction

Mitochondrial genetic code

Twelve codons have so far been determined to be involved
in variations in the genetic code in mitochondria. Two of
these, UAG and UGA, are termination codons changed to
Leu/Ala and Trp, respectively. In addition, UAA codon
specifying Tyr was recently reported from nematode,
Radopholus similis, mitochondria of which genome (mitochondrial genome) was completely sequenced (Jacob et al.,
2009). UAA termination codon was once assumed to be
used as Tyr codon in planarian mitochondria (Bessho et al.,
1992), but no data for other platyhelminth mitochondria
are available in the literature to conrm this (Telford et al.,
2000). The remaining nine are CUN (N=U, C, A or G)
(Leu to Thr) (Li and Tzagolo, 1979; Hardy and ClarkWalker, 1990), AUA (Ile to Met) (Anderson et al., 1981),
UCA (Ser to stop) (Nedelcu et al., 2000), AAA (Lys to Asn)

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Evolution of the Genetic Code

Mitochondria

Ala
Some green algae (i.e. Hydrodictyon reticulatum)
Leu
Some green algae (i.e. Scenedesmus spp.)

Stop
Scenedesmus obliquus

Thr
Bubbling yeasts

Met
Most metazoans
Bubbling yeasts

Tyr
Nematode (Radopholus similis)

UUU
UUC
UUA
UUG

Phe
Phe
Leu
Leu

UCU
UCC
UCA
UCG

Ser
Ser
Ser
Ser

UAU
UAC
UAA
UAG

Tyr
Tyr
Stop
Stop

UGU
UGC
UGA
UGG

Cys
Cys
Stop
Trp

CUU
CUC
CUA
CUG

Leu
Leu
Leu
Leu

CCU
CCC
CCA
CCG

Pro
Pro
Pro
Pro

CAU
CAC
CAA
CAG

His
His
Gln
Gln

CGU
CGC
CGA
CGG

Arg
Arg
Arg
Arg

AUU
AUC
AUA
AUG

IIe
IIe
IIe
Met

ACU
ACC
ACA
ACG

Thr
Thr
Thr
Thr

AAU
AAC
AAA
AAG

Asn
Asn
Lys
Lys

AGU
AGC
AGA
AGA

Ser
Ser
Arg
Arg

GUU
GUC
GUA
GUG

Val
Val
Val
Val

GCU
GCC
GCA
GCG

Ala
Ala
Ala
Ala

GAU
GAC
GAA
GAG

Asp
Asp
Glu
Glu

GGU
GGC
GGA
GGG

Gly
Gly
Gly
Gly

Trp
Except
Viridiplantae (green plants)
Stramenopiles
Cryptophyta
Mycetozoa

Ser
Most invertebrates
Gly
Tunicates
Stop
Vertebrates

Lys
Some arthropods
Asn
Platyhelminthes
Echinoderms

(a)

Gln
Ciliates
Acetabularia spp.

Organisms

Ser
Candida spp.

(b)
Figure 1

UUU
UUC
UUA
UUG

Phe
Phe
Leu
Leu

UCU
UCC
UCA
UCG

Ser
Ser
Ser
Ser

UAU
UAC
UAA
UAG

Tyr
Tyr
Term.
Term.

UGU
UGC
UGA
UGG

Cys
Cys
Term.
Trp

CUU
CUC
CUA
CUG

Leu
Leu
Leu
Leu

CCU
CCC
CCA
CCG

Pro
Pro
Pro
Pro

CAU
CAC
CAA
CAG

His
His
Gln
Gln

CGU
CGC
CGA
CGG

Arg
Arg
Arg
Arg

AUU
AUC
AUA
AUG

IIe
IIe
IIe
Met

ACU
ACC
ACA
ACG

Thr
Thr
Thr
Thr

AAU
AAC
AAA
AAG

Asn
Asn
Lys
Lys

AGU
AGC
AGA
AGG

Ser
Ser
Arg
Arg

GUU
GUC
GUA
GUG

Val
Val
Val
Val

GCU
GCC
GCA
GCG

Ala
Ala
Ala
Ala

GAU
GAC
GAA
GAG

Asp
Asp
Glu
Glu

GGU
GGC
GGA
GGG

Gly
Gly
Gly
Gly

Cys
Euplotes sp.
Try
Mycoplasma spp.
Spiroplasma spp.

Distribution of nonuniversal codons in (a) mitochondria and (b) organisms. Modified from Osawa et al. (1990).

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Evolution of the Genetic Code

(Himeno et al., 1987) and AGR (R=A and G) (Arg to

either Ser, Gly or stop) (Barrell et al., 1979; Clary and
Wolstenholme, 1985; Yokobori et al., 1993). In addition,
AGG codon was suggested to specify Lys in certain
arthropod mitochondria (Abascal et al., 2006). The UGA
codon is changed from stop to Trp in all mitochondria
studied except for those of Viridiplantae (green plants),
Stramenopiles, Cryptophyta and Mycetozoa, whereas the
change of CUN from Leu to Thr occurs only in mitochondria of bubbling yeast (Saccharomyces cerevisiae) and
its relatives. In a green alga Scenedesmus obliquus mitochondria, UCA codon seems to be stop besides UAG seems
to be Leu (Nedelcu et al., 2000). Codon changes have been
found to occur preferentially in animal mitochondria
except in the cases of AUA and UGA, which are also seen
in yeast and fungal mitochondria (Figure 1a). Table 1 shows
how these codon changes spread over mitochondria from
various species.
Systematic analysis of mitochondrial tRNAs (transfer
ribonucleic acids) involved in decoding these diversied
(or nonuniversal) codons has led to the tentative conclusion that almost all the genetic code variations arise
mainly from alterations in their anticodon nucleotides
(especially at the rst nucleotide (position 34, or the
wobble position) of the anticodon), although a few additional factors may also need to be taken into consideration. The codonanticodon pairing relationships in the
mitochondrial systems can be classied into three categories (Table 2). The rst category is that a single species
of tRNA can read all four codons (four-way wobble). It is
well known that tRNAs possessing an unmodied U at
the wobble position can read all four codons in a codon
box (Andachi et al., 1989; Inagaki et al., 1995), and the
same holds for tRNAs with an unmodied A or 7-methyl
G (m7G) at the wobble position (Inagaki et al., 1995). The
second category of pairing relationships is one in which
the codon box is divided at the ratio 3:1. Within a box, a
codon ending with G is read by a tRNA possessing an
unmodied C at the wobble position, whereas the
remaining three codons ending with U, C and A are read
by a tRNA possessing an unmodied G and I (inosine) at
the wobble position (three-way wobble). Such cases are
observed in the codon boxes of starsh AAN and Drosophila AGN (in this case no tRNA corresponding to
AGG exists, so AGG is an unassigned codon; see later).
In the third category, the codon box is divided as 2:2. In
this case, two codons ending with U and C are read by a
tRNA possessing an unmodied G and Q (queosine)
at the wobble position, whereas the remaining two
codons ending with A and G are read by a tRNA possessing either modied uridine such as 5-carboxymethylaminomethyl U (cmnm5U) or 5-formyl C (f5 C) at
the wobble position (two-way wobble) (Takemoto et al.,
2009). This situation is observed in the codon boxes UGN
of all organisms (except higher plants), AUN of vertebrates, Drosophila and nematodes, AAN of vertebrates,
Drosophila and nematodes, and AGN of vertebrates (in
this case AGR codons are termination codons) and

urochordates. See also: Transfer RNA in Decoding and

the Wobble Hypothesis; Universal Genetic Code and its
Natural Variations
Based on the experimental evidence outlined earlier, the
following rule seems to hold for mitochondrial decoding
systems. A tRNA possessing an unmodied G at the
wobble position is generally able to read all three codons
ending with U, C and A, and the remaining codon ending
with G is read by a tRNA possessing an unmodied C at the
wobble position, which means the relevant codon box is
divided as 3:1. However, if a tRNA is present possessing
either a modied U or a modied C at the wobble position,
or if there is a release factor in the system, each of these
molecules will function as a competitor against the tRNA
possessing an unmodied G in decoding a codon ending
with A; in this case, the relevant codon box is divided as 2:2.
The unmodied G at the anticodon rst position may
decode A-ending codon as suggested by the RNA sequence
analysis of D. melanogaster tRNASerGCU (Tomita et al.,
1999), since no competing tRNA decoding AGA codon
exists in the mitochondria. However, urochordate Halocynthia roretzi mitochondrial tRNASerGCU, which is
thought to decode only AGY codons, has unmodied G at
the anticodon rst position (Kondow et al., 1999). The H.
roretzi mitochondria have tRNAGlyUCU that may
decode AGR codons. Existence of tRNAGlyUCU may
restrict the decoding capacity of tRNASerGCU to only
AGY codons in urochordate mitochondria (Kondow et al.,
1999). The composition of tRNA species and their anticodon repertries determine the codon table (see Yokobori
et al., 2001). Existence of competitor tRNA and its amount
have been shown to be an important factor for the rate of
incorporation of certain amino acid by certain tRNA to the
codon which is the target of competition (Kramer and
Farabaugh, 2007). The possibilities that nucleotides other
than the wobble nucleotide (such as those located at position 33, 35 or 37) and the tertiary structure of tRNA are
also responsible for decoding the nonuniversal genetic code
remain to be claried. In certain arthropod mitochondria,
AGG has been suggested to specify Lys instead of Arg/Ser/
Gly (Abascal et al., 2006). In this case, tRNALys of which
anticodon is CUU was suggested to be responsible to
decode this codon, so that wobble pairing between second
positions of anticodon and codon (U:G) was suggested.
Their mitochondrial genomes encode tRNASerGCU gene.
If anticodon rst position of its transcript were not modied from G to m7G, the tRNASer could not decode AGG
codon (Tomita et al., 1999). At the moment, there is no
direct evidence that the tRNALysCUU can decode AGG
codon in these arthropod mitochondria. As seen earlier,
wobble rule at the anticodon third position is expanded in
mitochondria. It can be related to how mitochondrial
tRNA enter and stably exist at the A site of mitochondrial
ribosome. If even second positions of codon and anticodon
can be permitted to form wobble base pair, it may also be
related to the relaxed situation of tRNA in the A site of
mitochondrial ribosome. Further studies are needed to
clarify these issues.

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4
Evolution of the Genetic Code

Table 1 Variations in the mitochondrial genetic code

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Organism

CUN
Leu

AUA Ile

UCA
Ser

UAA
stop

UAG
stop

AAA
Lys

UGA
stop

AGR Arg

Examples

Vertebrates
Tunicates (Urochordates)
Cephalochordates
Echinoderms
Arthropods

Met
Met
Met

Met

Asn

Trp
Trp
Trp
Trp
Trp

Stop
Gly
Ser
Ser
Ser,

A nematode
Most invertebrate phyla (i.e.
Mollusks, most Nematodes)

Met
Met

Tyr

Trp
Trp

Ser
Ser

Platyhelminths,
Cnidarians, Placozoans,
Porifers
Bubbling yeasts

Asn

Trp
Trp

Ser

Thr

Met

Trp

Green algae

Ala

Green algae

Stop

Leu

Viridiplantae (green plants),

Stramenopiles, Cryptophyta
and Mycetozoa

Human, bovine, frog

Halocynthia roretzi
Branchiostoma oridae
Starsh, sea urchin
Drosophila spp., mosquito,
honeybee
Radopholus similis
Squid, Mytilus edulis,
Caenorhabditis elegans, Ascaris
suum
Fasciola hepatica, planaria
Hydra, Metridium senile,
Trichoplax adhaerens
Saccharomyces cerevisiae,
Torulopsis glabrata
Hydrodictyon reticulatum,
Pediastrum boryanum,
Tetraedron bitridens
Coelastrum microporum,
Scenedesmus spp.
Aeabidopsis, Dictyostelium
discoideum

Notes: , Same as the universal code; , in Drosophila spp. AGA only; , in certain arthropod mt (such as silk moth Bombix mori mt), AGG specifying Lys was proposed; , only rhabditophoran
mt has been using these genetic codes. Other platyhelminth mt are reported to use codon table used in most invertebrate mt (such as molluscan mt). , in planaria (Dugesia japonica) mt, UAA is
reported to specify Tyr.

Evolution of the Genetic Code

Table 2 Proposed rules for pairing between the wobble nucleotide (anticodon rst nucleotide: A) and the codon third (B) in
mitochondria
Category I

Category II

Category III

(L)

U*

F5C

7G

Note: U, cmnm5U or unknown U derivative.

In nonmatazoan mitochondria, L (lysidine) often decodes A at codon third nucleotide. In Category II, A at the codon third position is decoded by
L, I or G.

Candida code with a sense codon changed to

another sense codon
In nine species of the asporogenic yeast Candida, CUG is
changed from a Leu to a Ser codon (Yokogawa et al.,
1992). This is the only known case of a nuclear genetic
code variation involving a change from one sense codon
to another. The tRNA responsible for its decoding
(tRNASerCAG) is a chimaeric tRNA possessing both the
tRNALeu anticodon (CAG) complementary to the CUG
codon and tRNASer identity. Furthermore, tRNASerCAG
from all these Candida species except Candida cylindrasea
possesses Ser-accepting activity with about 3% Leuaccepting activity, which originates from the presence of
G33 and m1G37 instead of U33 and A37 in usual tRNASer.
This CUG codon has thus been named a polysemous
codon since it can be translated simultaneously as both Ser
and Leu, even in an in vivo system (Suzuki et al., 1997).

Variations in other eubacterial and nuclear

genetic codes
Table 3 shows variations in eubacterial and eukaryotic

nuclear genetic codes. Except for CUG, all the changes are
from stop codons (UGA and UAR) to other sense codons,
and they can be explained by alterations in the anticodons
of the tRNAs corresponding to the diversied (nonuniversal) codons and release factor mutations. In the case
of Tetrahymena spp., UAR codons were captured by
tRNAGlns of which anticodon are UmUA and CUA
(Hanyu et al., 1986). Since ordinal tRNAGlns may have
anticodon UUG or CUG, the tRNAGln specifying UAR
codons could be created from ordinal tRNAGln with single
mutational process. The tRNAGlns for UAR codons might
have played a role as suppressor tRNAs. The eukaryotic
release factor 1 (eRF1) recognizes all three termination
codons (UGA and UAR) (Nakamura and Ito, 2003). By
eliminating the recognition ability of eRF1 for UAR
codons in ciliate ancestor, UAR codons could become Gln
codons. The codonanticodon interactions conform to the
conventional wobble rule that has been expanded from
Cricks (1966) original proposal. Recent study suggested
that the elimination of UAR-recognition ability of eRF1
occurred in dierent changes on the eRF1s in Paramecium

sp. and Stylonicia sp. Therefore, establishment of situation

where only UGA is the termination codon found in ciliates
occurred at least twice independently (Lekomtsev et al.,
2007). See also: Protein Synthesis Termination; Watson
Crick Base Pairs

Evolutionary Implications
Most genetic code changes are thought to have been
brought about by directional mutational pressure on genomes, as well as by genome economization, during the
evolution of organisms (see Osawa and Jukes, 1989; Osawa
et al., 1990; Osawa, 1995). The notion of mutational pressure is derived from the observation that the G+C contents of genomic DNAs (deoxyribonucleic acids) from
various organisms dier from one to another, depending
on the chromosomes or chromosomal regions in eukaryotes, and on the phylogeny in eubacteria. Dierences in
G+C contents are thought to have originated from directional evolutionary pressure (constraint), probably due
to GC- or AT-bias during replication of the genome. Such
biases are also observed in mitochondrial genomes, especially in those of animals, whose sizes are very much
reduced (or economized) (  16 kbp). Metazoan mitochondrial system is indeed so simple if compared with
nuclear systems. First, number of their genes that transcripts are subjects for translation is much smaller than that
of nuclear genes. Second, genes of all tRNA species
working in metazoan mitochondria are encoded by mitochondrial genomes, and thus it is easy to know complete
tRNA species set working in mitochondria, although there
are few exceptions (Cnidarian mitochondrial genome lacks
most of tRNA genes (Pont-Kingdon et al., 1994), and
marsupial mitochondrial genomes seem not to encode
functional tRNA gene for Lys (Dorner et al., 2001)). Most
nonmetazoan mitochondrial genomes do not encode
complete set of tRNA genes sucient for decoding all
codons (Tarassov et al., 2007; Alfonzo and Soll, 2009).
Third, each codon is decoded by the single tRNA species
with few possible exceptions (Mytilus spp. (Mollusca,
Gastropoda)) and urochordate mitochondrial genomes
encode two tRNAMet genes (Homann et al., 1992;

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Evolution of the Genetic Code

Table 3 Variations in eubacterial and nuclear genetic codes

tRNA anticodon for
altered code

Organism

UGA stop

UAR stop

CUG Leu

Mollicutes
(Eubacteria)
Mycoplasma 7
spp.
Spiroplasma 1 sp.

Trp

Trp

N: unknown

Hemiascomycetes
(yeasts)
Candida 9 spp.

Ser

CAG

Gln

Gln

UmUA for codons

UAA and UAG;
CUA for codon UAG
N

Cys

Gln
Gln

N
N
N

Gln

Holotrichous ciliates
Tetrahymena 2
spp.
Paramecium 2 spp.
Hypotrichous ciliates
Stylonicia 1 sp.
Oxytricha 2 spp.
Euplotes 1 sp.
Unicellular green
algae
Acetabularia 2
spp.

UCA

Notes: , Same as the universal code, or not determined and U, cmnm5Um.
Source: Modied from Osawa (1995).

Yokobori et al., 2005); one has anticodon CAU and the

other has anticodon UAU. AUG codons on these mitochondrial genes might be decoded by these tRNAMet species. Thus, mitochondrial system, in particular metazoan
mitochondrial system, is a good example to learn how
genetic code has evolved. See also: Evolution of Genome
Organization; Functional Constraint and Molecular Evolution; Mutations and the Genetic Code
One of the most plausible theories attempting to explain
the origin of genetic code changes is the codon capture
theory proposed by Osawa and Jukes (1989), which
postulates that directional mutational pressure (e.g.
GC-pressure) has caused a certain codon (e.g. AAA, see
Figure 2) to become unassigned by changing itself to the
other synonymous codon (AAG). At the same time,
tRNALysUUU, capable of recognizing both AAA and
AAG codons, would have disappeared from the genome,
although tRNALysCUU, recognizing the AAG codon,
remained. An unassigned codon means a codon recognized
by neither a tRNA nor a release factor, which should have
disappeared from the open reading frame (ORF) of the
genome. Once a tRNA corresponding to the unassigned
codon (in our example, AAA) appeared in the system as a
result of a mutation of another tRNA (e.g. tRNAAsn
GUU), which could be induced by new AT-pressure on the
6

genome as aforementioned, the codon (AAA) would have

reappeared in the ORF owing to the mutation of another
codon (AAU or AAC), which would have been captured by
the tRNA and reassigned as another amino acid (Asn)
(Figure 2). tRNAAsnGUU may be able to recognize not only
AAU and AAC codons but also the AAA codon without
mutation if no competitor tRNALysUUU exists (see Table
2), so that tRNAAsnGUU may have been ready to read the
AAA codon just after tRNALysUUU disappeared from the
genome (Castresana et al., 1998). Thus, the original AAA
Lys codon has become an AAA Asn codon. Important
evidence in support of the codon capture theory is the
presence of unassigned codons, which have been found in
organisms whose genomes are extremely AT- or GC-rich,
such as Mycoplasma capricolum (CGG), Micrococcus
luteus (AGA and AUA) and mitochondria of Balanoglossus carnosus (a hemichordate) (AAA; the case
aforementioned) (Castresana et al., 1998), Torulopsis
glabrata (a yeast) (CGN) (Hardy and Clark-Walker, 1990),
Prototheca wickerhamii (a green alga) (CGG and UGA or
UAG) (Wol et al., 1993) and Drosophila (AGG) (Clary
and Wolstenholme, 1985). Another piece of supportive
evidence is that some codons postulated by the theory as
candidates for variation have been proved actually to be
varied in extant organisms: for example, AGR Gly in

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Evolution of the Genetic Code

AAA = Lys (most animals)

GC-pressure
AAA changes to AAG

tRNA Lys UUU

AAA = unassigned

AT-pressure?

tRNA Asn GUU

tRNA Asn*GUU
AAA restored

AAA = Asn (platyhelminths, echinoderms)

Figure 2 Possible evolutional consequences of AAA codon changing from
Lys to Asn in animal mitochondria depending on the codon capture
hypothesis. tRNAAsnGUU is tRNAAsnGUU that possibly received structural
modifications so as to read not only the AAU and AAC codons but also the
AAA codon (or in this case such modification may not be necessary; see
text). A similar process has been presented by Castresana et al. (1998).

ascidian mitochondria (Yokobori et al., 1993, 1999) and

UGA Cys in Euplotes (Meyer et al., 1991).
An alternative hypothesis aiming to explain the origin of
nonuniversal codons is the ambiguous intermediate theory proposed by Schultz and Yarus (1994), which postulates that genetic code change is a relatively fast process
driven by selection and reassignment of codons, facilitated
by a translationally ambiguous intermediate where the
transitional codon is read simultaneously as two dierent
amino acids by two tRNAs, one cognate and the other
near-cognate. The latter tRNA would be derived from the
cognate tRNA by mutation, for example, at the base pair
2743. Schultz and Yarus emphasize that such a mutated
tRNA would facilitate normally forbidden near-cognate
pairings between codon and anticodon at the tRNA
binding sites on ribosome, thereby enabling simultaneous
reading of the transitional codon with two meanings. This
would cause the genetic code to change rather quickly so
that the cells would be able to adapt to the sudden environmental change (Santos et al., 1996). There has been little
experimental evidence in support of the presence of these

tRNAs that decode a single codon as two dierent amino

acids.
However, codon ambiguity has recently come to reality
as aforementioned, the polysemous codon and its
decoding chimaeric tRNASerCAG have been found in
several Candida spp. (Suzuki et al., 1997). This nding may
be helpful for interpreting the codon reassignment in these
Candida spp., because they usually possess intrachromosomal and interchromosomal mosaic distribution pattern
of G+C content, which may make it dicult to eliminate
specic codons for unassigned codons from the genomes by
AT- or GC-pressure alone (Santos et al., 1977). It should be
noted that the original ambiguous intermediate theory is
based on the ambiguous decoding in which a single codon is
read simultaneously as two dierent amino acids by two
tRNAs, whereas the polysemous codon is strictly decoded
by a single tRNA, but is charged simultaneously with two
dierent amino acids.
Recent simulation study on codon reassignment
(Sengupta et al., 2007) suggested that, depending on the
initial conditions such as genome size and number of codon
interested, the favoured pathway of codon reassignment is
dierent (either codon capture or ambiguous codon). In
this study, codon capture is preferred when termination
codon is involved in codon reassignment. However,
ambiguous codon pathway is preferred when codon
reassignment occurs on sense codon. It is still unclear
whether simulation results of this study can be directly used
for explanation of codon reassignment, since characteristics of tRNA and aminoacyl tRNA synthetases (ARS),
which are less mentioned in the simulation, may aect
actual codon reassignment process. A unied solution for
this problem may be given by further study. See also:
Codon Usage in Molecular Evolution
Recognition mechanism of tRNA by cognate ARS, in
other word, tRNA identity, is also an important factor
when evolutionary process of genetic code is considered.
Certain tRNA must be recognized by cognate ARS and
must be charged with cognate amino acid. Identity elements of tRNA are region/sequence recognized by cognate
ARS as positive determinants and recognized by noncognate ARS as negative determinants. Anticodon
sequences of tRNAs are often important identity elements.
For example, three nucleotides of anticodon of tRNAMet
and tRNATrp are known to be strong identity elements
(Muramatsu et al., 1988; Nakanishi et al., 2005). However,
some tRNAs are known that their anticodon sequences are
not important identity elements. For example, AlaRS does
not recognize anticodon region, but recognizes G3:U70
pair in acceptor stem of cognate tRNA (Park et al., 1989;
Hou et al., 1989). It is also known that the anticodon
sequence of tRNALeu (class II) is not important for the
recognition by the cognate LeuRS (Asahara et al., 1993).
To expand codon specicity of tRNATrp to UGA codon
in addition to UGG codon, the CCA anticodon of
tRNATrp is needed to change to UCA. Since anticodon
sequence of this tRNA is an important recognition region
by TrpRS (Himeno et al., 1991), recognition property of

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Evolution of the Genetic Code

TrpRS for tRNATrp might change before reassignment of

UGA codon from termination to Trp or in cooperation
with the reassignment. Similar situation can be presumed
for recognition of tRNAGly for AGR codon in ascidian
mitochondria.
In contrast, since anticodon of tRNAAla is not recognized by AlaRS, anticodon sequence of tRNAAla can easily
change (Park et al., 1989; Hou et al., 1989). For example,
green algae Hydorodictyon reticulatum mitochondria was
reported to use UAG as Ala codon (Hayashi-Ishimaru
et al., 1996). In this case, the anticodon CUA of tRNAAla
might be acceptable for AlaRS. This situation is same for
other green algae of which mitochondria use UAG codon
as Leu codon (Hayashi-Ishimaru et al., 1996). The anticodon CUA can have been originated from CAA which is a
normal anticodon seqence of tRNALeu.

Origins of the Genetic Code

It is widely accepted that the original living organism was
generated by chance from simple materials, including
amino acids and nucleic acid components, which were
produced spontaneously on the primitive earth. It was
shown by Urey and Miller in 1953 that amino acids can be
produced by electronic discharge in a mixture of inorganic
compounds such as methane(CH4), hydrazoic acid (HN3),
water and hydrogen (Miller, 1953). These compounds
form a strongly reducing environment, which mimics the
primitive atmosphere of the earth. Since the experiment by
Urey and Miller in 1953, a number of similar experiments
under dierent conditions (not only reduced environment
but also oxidized environment) have been performed, and
syntheses of amino acids have been observed. Amino acids
produced by electronic discharge (or by another energy
such as radiation), such as Gly, Ala, Val, Leu, Ile, Pro, Asp,
Glu and Ser, are very similar to those found in meteorites.
Thus, it is reasonable to assume that there would have been
a considerable number of amino acids in existence on the
primitive earth, which were produced abiotically without
biosynthetic pathways and which could have been
incorporated directly into the primitive coding system.
However, syntheses of nucleic bases in such experiments
have been known to be quite dicult. Nucleic bases have
been merely found in the resultant compounds of Millers
experiments. How to create nucleic acid compounds and
oligo/poly nucleotides is still a quite important issue when
we think about the origin of life, although there being
various pathways for nucleotide (and its component) synthesis in prebiotic era (Powner et al., 2009). It is possible to
speculate that the genetic code might have started with
fewer amino acids than 20 amino acids in the universal
genetic code. As aforementioned, easiness of prebiotic
synthesis of each amino acid is dierent. See also: Origin of
Life
How specic correlation between certain nucleotide
sequence and certain amino acid in prebiotic era was
established the next issue for the origin of genetic code.
8

Specic relationship between an amino acid and RNA

sequence has been thought to be determined by chemical
and stereochemical or physiochemical properties (Woese,
1967; Melcher, 1974; Balasubramanian et al., 1980;
Shimizu, 1982) and to be determined accidentally (Crick,
1968). Yarus et al. (2009) summarized that codon/anticodon sequences corresponding to eight amino acids are
found at the amino acid binding region of amino acid
binding RNA molecules in signicant probability.
Dependent on this and other evidences, Yarus et al. (2009)
proposed the direct RNA templating hypothesis. The
hypothesis consists of three steps. In the rst step, some
amino acids or some activated amino acids bind directly to
the RNA template that contains short amino acid binding
sequences (triplets corresponding to the codon, anticodon
or combination of both). Then, concatenation of amino
acid depending on the RNA sequences might occur. At this
time, the RNA plays a role as rRNA (ribosomal RNA),
mRNA (messenger RNA) and tRNA in modern context.
In the second step, amino acid bound RNA containing
anticoodn sequence appeared. The amino acid bound
RNA with anticodon might have interacted codon on the
RNA templating molecule. At this time, primitive tRNA
and RNA molecule acting as rRNA+mRNA become to
be separated. In the third step, primitive tRNA, primitive
mRNA and primitive ribosome (probably without protein
components) were established, by separation of function
and region of mRNA part containing sequence of codons
and region of ribosome part providing environment for
polymerization of amino acids. The amino acids which do
not directly interact with either of codon or anticodon
sequences might have been incorporated into the primitive
translation system via using components synthesized by the
preceding primitive translation system.
Although there have been several dierent postulations
about amino acids that arose early and late in evolution,
the current interpretation is that the coding system arose
with a limited number of amino acids (e.g. Gly, Ala, Ser,
Asp, Glu and Val), and that others (such as Arg, His, Met,
Trp, Asn and Gln), which would have been generated
abiotically or biotically after the biosynthetic pathways
developed, were later added until the total of 20 was
reached, presumably after the development of ribosomes
and proteinaceous ARSs. This would have occurred in a
single progenote (or comonote) that displaced all contemporaries with other codes. The prototype of the universal genetic code would thus have been established.
See also: Transfer RNA

Mechanisms for the Evolution of the

Genetic Code
From a detailed examination of genetic code variations in
extant organisms as described earlier (see Figure 1, Table 1
and Table 3), Osawa and Jukes (1989) have proposed an
outline scheme depicting the evolution of a translation

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Translation system
GNN INN
+ CNN
80S

RNA
ENCYCLOPEDIA OF LIFE SCIENCES & 2010, John Wiley & Sons, Ltd. www.els.net

Protoribosome

Ribosome (RNP)

ARS I
ARS II

ARSs for 20
amino acids
tRNAs for 20
amino acids

tRNA

Eukaryotic
code

70S ribosome
70S

Early code

AUA (Met)
UGA (Trp)

+ GNN
+ CNN
AUA (Ile)
UGA (Trp)

+CNN
Archaebacterial
code

Universal
code

CNN
ICG (Arg)

1 or
a few

More

20

Sec?

Amino acids in the genetic code

Mitochondrial
code

GNN
CNN
AUA (Met)
UGA (Trp)
Endosymbiosis
and genomic
economization

GC-pressure
AT-pressure

Hypothetical codes

Either GC- or AT-pressure

Actual codes

Chloroplast
code

GNN

CNN
GNN
Anticodons above/right of lines
Codons below/left of lines

Evolution of translation apparatus and genetic codes showing periods of GC- and AT-pressure, and the main changes in codon assignments and tRNA anticodons. Modified from Osawa (1995).

Evolution of the Genetic Code

Figure 3

Kingdom'

Eubacterial
code
CNN +CNN

Evolution of the Genetic Code

apparatus and the genetic code (Figure 3) in which they

assume that the main driving force of evolution is directional mutational pressure on the genome and, to a lesser
extent, genome economization. They emphasize that the
number of tRNA species that translate codons is critical for
the evolution of the genetic code. For example, they assume
that in the early genetic code the translation of codons to 20
amino acids was performed more simply than in the present
highly evolved code, using the minimum or near-minimum
number of tRNA species. Based on the present animal
mitochondrial genetic code, they assume that in the early
code AUA was used for Met and UGA for Trp, and that
the number of tRNAs necessary for translation was thus
23. In this case, four codons in a family box were read by a
single tRNA with an unmodied U at the wobble position
(four-way wobble) and both codons in a two-codon set
were read by a single tRNA (two-way wobble); codons
ending with purine were read by a tRNA with a modied U
at the wobble position and those ending with pyrimidine by
a tRNA with an unmodied G at this position. There is a
possibility that some codons in the early code were not used
(unassigned codons), because Leu UUR/CUN, Arg CGN/
AGR and Ser UCN/AGY are redundant, and the removal
of one of them does not aect the number of amino acids
used for protein synthesis. See also: Evolution of Genome
Organization
Directional mutational pressure aects both codons and
tRNA genes. GC-pressure probably acted on the early
genetic code, and this would have resulted in the establishment of the universal genetic code by generating tRNAs
with GNN and CNN anticodons in the genome and forcing
codons ending with A and U to mutate to their synonymous codons ending with G and C. In this process, codon
changes from AUA Met to AUA Ile and from UGA Trp to
stop would have occurred. For example, under GC-pressure, AUA codons would all have been converted to AUG,
which at this stage would have been the sole codon for
Met. The anticodon of tRNAMet (UAU, where U is a
modied U) was changed by mutation to CAU, pairing
with AUG. AUA thus became an unassigned codon. In the
subsequent process, it is assumed that the tRNAMetCAU
gene duplicated (see later) and that, in one of the duplicated
tRNAs, C at the wobble position of the anticodon became
modied to L (lysidine or 2-lysylcytidine in the case of
Escherichia coli tRNA) on the emergence of a certain
modication enzyme. This change would have resulted in
the tRNA accepting Ile instead of Met and pairing with A
instead of G (tRNAIleLAU). AUA codons could now be
produced from AUY Ile codons by mutation and were
captured by the new tRNAIleLAU. The genes for tRNAMet
CAU and tRNAIleLAU are known to be adjacently
located on the chromosomes of Bacillus subtilis, Mycoplasma capricolum and Spiroplasma spp., which may provide evidence for the ancient duplication of the gene for
tRNAMetCAU and the subsequent conversion of one of the
duplicates to tRNAIleLAU. See also: Evolutionary Developmental Biology: Gene Duplication, Divergence and Cooption
10

After the establishment of the universal genetic code in

the progenote (or comonote), diversication into three
main groups eubacteria, archaebacteria and eukaryotes
occurred. The code evolved along with these groups,
resulting in dierent tRNA anticodon compositions. The
evolution of the genetic code has continued within each of
the three groups, quite often under the eect of directional
mutational pressure. For example, in the case of the
eubacterial and archaebacterial codes, evolution has led to
dierences in the contents of CNN anticodons in dierent
bacterial families, and a higher G+C content in DNA
caused by GC-pressure is accompanied by appearance of
larger numbers of CNN anticodons. The mitochondrial
and chloroplast genetic codes are very likely to have
evolved through retroregression from the eubacterial genetic code. There are 31 anticodons in the chloroplast code,
compared to 22 in the vertebrate mitochondrial code
(because in vertebrate mitochondria AGR codons are used
for termination, the anticodon number is less than the
minimal number of anticodons in the early code (23)). Most
of the CNN anticodons in the ancestral eubacterial code
have disappeared during the evolution of the chloroplast
code, presumably under AT-pressure and genomic
economization (Osawa and Jukes, 1989). The four-way
wobble is used in three family boxes (CUN Leu, CCN Pro
and GCN Ala) in the chloroplast code, which has apparently evolved from an ancestral eubacterial code along a
pathway similar to that of the mitochondrial code,
although the evolutionary process has not proceeded as far.
Mitochondrial genetic codes, especially those of metazoan
(multi cellular) animals, have diversied strikingly, probably mainly owing to severe genome economization, in
addition to AT- or GC-pressures. The number of tRNA
genes in mitochondrial genomes has been reduced to 22 in
vertebrate mitochondria, resulting in the simplest genetic
code of extant organisms. See also: Mitochondria: Origin

Concluding Remarks
As seen earlier, genetic code has evolved and still is evolving, as the result of evolution of various components of
translation system tRNA, RFs, ribosomes, mRNAs
(genes) and others. Todays variation of genetic code
among dierent translation systems seems to be promoted
by genome sequence (nucleotide composition in genes,
disappearance and reappearance of certain codon on the
genome, loss and gain of tRNA genes and so on). However,
properties of tRNA, aminoacyl tRNA synthetase, RFs and
other factors seem to give frameworks of plasticity of
genetic code. In particular, recent progress of structural
biological studies of translation-related macromolecules
and complexes such as various aminoacyl tRNA synthetases have given us new insight on how each codon is corresponded to specic amino acid or RF (Nakanishi et al.,
2005; Song et al., 2000). This kind of knowledge would help
us to understand the history of genetic code evolution.

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Evolution of the Genetic Code

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Further Reading
Matsuyama S, Ueda T, Crain PF, McCloskey JA and Watanabe
K (1998) A novel wobble rule found in starsh mitochondria.
Journal of Biological Chemistry 273: 32633268.
Ohama T, Inagaki Y, Bessho Y and Osawa S (2008) Evolving
genetic code. Proceedings of Japan Academy Series B 84: 5874.
Osawa S, Jukes TH, Watanabe K and Muto A (1992) Recent
evidence for evolution of the genetic code. Microbiological
Review 56: 229264.
Sengupta S and Higgs PG (2005) A unied model of codon
reassignment in alternative genetic codes. Genetics 170: 831840.
Watanabe K and Osawa S (1995) tRNA sequences and variations
in the genetic code. In: Soll D and RajBhandary UL (eds)
tRNA: Structure, Biosynthesis, and Functions pp. 225250.
Washington, DC: American Society for Microbiology.
Wolstenholme DR (1992) Animal mitochondrial DNA: structure
and evolution. International Review of Cytology 141: 173216.

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