BioSystems 54 (1999) 39 – 46

www.elsevier.com/locate/biosystems

Evolution of the genetic code: the nonsense, antisense, and

antinonsense codes make no sense
G. Houen *
Department of Protein Chemistry, Statens Serum Institut, Artilleri6ej 5, DK-2300 Copenhagen S, Denmark

Received 16 April 1999; received in revised form 26 May 1999; accepted 6 July 1999

Abstract

According to the molecular recognition theory, the complementarity of the sense and nonsense DNA strands is
reflected in a complementarity of polypeptides and the corresponding nonsense polypeptides. A comparison of the
sense and nonsense code matrices, and of the antisense and antinonsense code matrices, either by visual inspection or
by comparing the corresponding hydrophobicity matrices (e.g. by simply adding them together), revealed no
complementarity of these pairs of matrices in terms of possible attractive physical forces. Instead, it was evident that
the codes divide the amino acids into two major groups: hydrophilic and hydrophobic, a division which is directly
correlated with the folding property of proteins. A simple primordial genetic code distinguishing between these two
types of amino acids would have been capable of generating three-dimensionally folded peptides, which could stabilize
coding RNAs by forming ribonucleoprotein complexes. This evolutionary scheme is reflected in the present
organisation of information processing and storage in essentially all organisms. RNAs are processed and translated
into proteins by ribonucleoproteins, while other steps in information retrieval and processing, such as DNA
replication, transcription, protein folding and posttranslational processing, are catalyzed by proteins. This shows that
the evolution of DNA as an information storage medium was a secondary event, unrelated to the evolution of the
genetic code. From the primordial hydrophilic/hydrophobic (f.ex. Leu/Arg) code, evolution proceeded by introduc-
tion of a catalytic amino acid (Ser). The further evolution of the code has mainly served to increase the number of
functional hydrophilic amino acids, since there has not been a great advantage in increasing the number of structural,
hydrophobic amino acids. At some stage during the evolution of the genetic code, double-stranded DNA was
introduced as a maximally safe genetic copy of RNA. This required the action of highly specific enzymes, and was
therefore preceded by the refinement of the genetic code. As a conclusion of this evolutionary scheme, it can be
inferred that, in general only the sense strand encodes proteins. © 1999 Elsevier Science Ireland Ltd. All rights
reserved.

Keywords: Genetic code; Nonsense; Antisense

1. Introduction

* Tel.: +45-3268-3276; fax: + 45-3268-3149. The diversity of living organisms reflects the
E-mail address: gh@ssi.dk (G. Houen) complexity of the earth as an open nonequi-

0303-2647/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 0 3 - 2 6 4 7 ( 9 9 ) 0 0 0 5 6 - 8
40 G. Houen / BioSystems 54 (1999) 39–46

librium thermodynamic system (Nicolis and Pri- According to this theory, the complementarity
gogine, 1977), in which a complex phylogenetic between the sense and nonsense strands of DNA
evolution has taken place. Despite this complexity is revealed in a complementarity between for ex-
all living organisms use essentially the same ge- ample receptors and peptide hormones (Bost et
netic code for storing and retrieving information, al., 1985a,b; Blalock and Bost, 1986; Carr et al.,
and therefore this code must have evolved at a 1986; Weigent et al., 1986; Brentani, 1988;
relatively early stage of evolution and then re- Brentani et al., 1988; Baranyi et al., 1995) and a
mained unchanged after its ‘perfection’ (Crick et high affinity of peptides for their antisense pep-
al., 1961; Crick, 1968; Orgel, 1968; Eigen et al., tides (Shai et al., 1987; Fassina et al., 1989;
1989; Osawa et al., 1992). Pasqualini et al., 1989; Shai et al., 1989). While
Crick (1968) has discussed two fundamentally this theory may hold for some peptides and anti-
different theories of genetic code evolution: 1, the sense peptides, it can be shown to have no struc-
‘frozen accident theory’, postulating that amino tural basis in the genetic code. Instead, the genetic
acids became linked to codons purely by chance; code evolved as a maximally effective information
and 2, the ‘stereochemical principle’, which as- transfer system, based on RNA, amino acids and
sumes that stereochemical constraints guided the DNA.
association of amino acids with codons. Wong
(1975) has proposed a co-evolution theory of the
genetic code which postulates that ‘the codon 2. The sense, antisense, nonsense and antinonsense
system is primarily an imprint of the prebiotic genetic codes
pathways of amino acid formation’.
In addition to these theories, a theory has been From the DNA double helix three different
put forward about a possible complementarity transcription reading frames can be defined in
between the putative protein products of the two addition to the genetic code. These four codes are
complementary strands of DNA: the molecular logical transformation of each other as shown
recognition theory (Blalock and Smith, 1984; below.
A: The genetic code (the sense code) trans-
Blalock and Bost, 1986; Zull and Smith, 1990).
lates the sense strand into protein by read-
Table 1 ing the codons in 5% –3% direction and using
The genetic code matrix the genetic code matrix (Table 1).
B: The antisense code is obtained by reading
U C A G codons in the opposite (3% –5%) direction
(Table 2).
U Phe Ser Tyr Cys U
Phe Ser Tyr Cys C C: The nonsense code is obtained by reading
Leu Ser End End A complementary codons in the 5% –3% direc-
Leu Ser End Trp G tion (Table 3).
C Leu Pro His Arg U D: The antinonsense code is obtained by
Leu Pro His Arg C reading complementary codons in the 3% –
Leu Pro Gln Arg A 5% direction (Table 4).
Leu Pro Gln Arg G The genetic code (Table 1) groups the amino
A Ile Thr Asn Ser U acids into two major groups: hydrophobic (first
Ile Thr Asn Ser C column) and hydrophilic (columns 2–4). This
Ile Thr Lys Arg A
grouping can be realized either by visual inspec-
Met Thr Lys Arg G
tion of the amino acids or by constructing a
G Val Ala Asp Gly U hydrophobicity matrix from the genetic code ma-
Val Ala Asp Gly C
Val Ala Glu Gly A
trix using any set of hydrophobicity/hydrophilic-
Val Ala Glu Gly G ity values (Table 5). The first column only
contains amino acids with very hydrophobic side
 G. Houen / BioSystems 54 (1999) 39–46 41

Table 2 chains (Cys and Tyr) or a high dipole moment

The antisense genetic code matrix
(Trp).
U C A G Thus with only minor exceptions the genetic
code divides the amino acids into two major
U Phe Ser Tyr Cys U groups (hydrophobic and hydrophilic), a basic
Leu Pro His Arg C
pattern which has a direct correlation with the
Ile Thr Asn Ser A
Val Ala Asp Gly G folding pattern of proteins: a hydrophobic core
C Phe Ser Tyr Cys U
Leu Pro His Arg C Table 4
Ile Thr Asn Ser A The antinonsense genetic code matrix
Val Ala Asp Gly G
U C A G
A Leu Ser End End U
Leu Pro Gln Arg C
U Lys Arg Ile Thr U
Ile Thr Lys Arg A
Lys Arg Met Thr C
Val Ala Glu Gly G
Asn Ser Ile Thr A
G Leu Ser End Trp U Asn Ser Ile Thr G
Leu Pro Gln Arg C
C Glu Gly Val Ala U
Met Thr Lys Arg A
Glu Gly Val Ala C
Val Ala Glu Gly G
Asp Gly Val Ala A
Asp Gly Val Ala G

Table 3 A End End Leu Ser U

The nonsense genetic code matrix End Trp Leu Ser C
Tyr Cys Phe Ser A
U C A G Tyr Cys Phe Ser G
G Gln Arg Leu Pro U
U Lys Arg Ile Thr U Gln Arg Leu Pro C
Glu Gly Val Ala C His Arg Leu Pro A
End End Leu Ser A His Arg Leu Pro G
Gln Arg Leu Pro G
C Lys Arg Met Thr U
Glu Gly Val Ala C Table 5
End Trp Leu Ser A The genetic code hydrophobicitya matrix
Gln Arg Leu Pro G
−9.2 6.5 −1.9 1.4
A Asn Ser Ile Thr U −9.2 6.5 −1.9 1.4
Asp Gly Val Ala C
−9.2 6.5 – –
Tyr Cys Phe Ser A −9.2 6.5 – −10.0
His Arg Leu Pro G
−9.2 2.1 2.1 4.2
G Asn Ser Ile Thr U −9.2 2.1 2.1 4.2
Asp Gly Val Ala C −9.2 2.1 6.0 4.2
Tyr Cys Phe Ser A −9.2 2.1 6.0 4.2
His Arg Leu Pro G
−8.0 5.2 7.0 6.5
−8.0 5.2 7.0 6.5
−8.0 5.2 5.7 4.2
chains and with no ionizable groups in the side −4.2 5.2 5.7 4.2
chains. Columns 2– 4 contain amino acids with −3.7 2.1 10.0 5.7
hydrophilic side chains or side chains of very low −3.7 2.1 10.0 5.7
−3.7 2.1 7.8 5.7
hydrophobicity (Pro and Ala). Only Tyr, Trp and −3.7 2.1 7.8 5.7
Cys present exceptions to this pattern and they
are not purely hydrophobic due to ionizable side a
HPLC derived hydrophobicity values (Parker et al., 1986).
42 G. Houen / BioSystems 54 (1999) 39–46

Table 6 corresponding amino acid side chains. On the

The nonsense genetic code hydrophobicity matrix.
contrary, the different codes pair very different
5.7 4.2 8.0 5.2 side chains with each other, e.g. in first column
7.8 5.7 −3.7 2.1 rows 5–8:
– – −9.2 6.5
6.0 4.2 −9.2 2.1 sense nonsense antisense Antinonsense
5.7 4.2 −4.2 5.2 Leu Lys Phe Glu
7.8 5.7 −3.7 2.1 Leu Glu Leu Glu
– −10.0 −9.2 6.5 Leu End Ile Asp
6.0 4.2 −9.2 2.1
Leu His Val Asp
7.0 6.5 −8.0 5.2
10.0 5.7 −3.7 2.1
Some ‘complementarity’ is observed when com-
−1.9 1.4 −9.2 6.5
2.1 4.2 −9.2 2.1 paring the code with the antisense code, and when
comparing the nonsense code with the antinon-
7.0 6.5 −8.0 5.2
10.0 5.7 −3.7 2.1
sense code due to the fact that residues only
−1.9 1.4 −9.2 6.5 change positions within columns. This is, how-
2.1 4.2 −9.2 2.1 ever, only a mathematical property of the genetic
code and reflects its general property of a maxi-
mally safe and effective information transfer
Table 7 system.
Sum of genetic code hydrophobicity matrix and nonsense code
Another way of analyzing possible relations
hydrophobicity matrix
between the sense and nonsense codes is by com-
−3.5 10.7 −9.9 6.6 paring the sense genetic code hydrophobicity ma-
−1.4 12.2 −4.6 3.5 trix (Table 5) with the nonsense genetic code
– – – – hydrophobicity matrix (Table 6). When these ma-
−3.2 10.7 – −7.9
trices are added, a matrix is obtained which de-
−3.5 6.3 −2.1 9.6 scribes possible physical interactions between
−1.4 7.8 −1.6 6.3 amino acid residues and the corresponding non-
– −7.9 −3.2 10.7
−3.2 6.3 −3.2 6.3
sense residues (Table 7). Table 7, however, shows
no signs of complementarity between sense and
−1.0 11.7 −1.0 11.7
2.0 10.9 3.3 8.6
nonsense residues. Hydrophobic residues would
−9.9 6.6 −3.5 10.7 be expected to interact primarily with hydropho-
−2.1 9.4 −3.5 6.3 bic nonsense residues, and this should give a more
3.3 8.6 2.0 10.9 negative sum. Hydrophilic residues should inter-
6.3 7.8 6.3 7.8 act preferentially with hydrophilic nonsense
−5.6 3.5 −1.4 12.2 residues by hydrogen bonds and ionic interac-
−1.6 6.3 −1.4 7.8 tions, thus giving rise to a more positive sum.
None of this is observed, but a more or less
random appearing sum matrix is obtained.
surrounded by a hydrophilic surface (Bajaj and
Blundell, 1984).
When the genetic code matrix is compared with 3. The primordial genetic code
its antisense (Table 3), nonsense (Table 4) and
antinonsense (Table 5) codes, the grouping into Several reviews summarizing current knowledge
hydrophobic and hydrophilic amino acids is con- of codon specificities have been published, and
served. However, there is no complementarity be- many authors have integrated this knowledge
tween the code and the nonsense code in terms of with different theories of genetic code evolution
possible attractive physical forces between the (Crick, 1968; Jukes, 1973, 1978; Wong, 1975,
 G. Houen / BioSystems 54 (1999) 39–46
1988; Kocherlakota and Acland, 1982; Macchiato
and Tramontano, 1982; Soto and Toha, 1985;
Cedergren et al., 1986; Figureau, 1987, 1989; Os-
awa and Jukes, 1988, 1989; Lehmann and Jukes,
1988; Di Guilio, 1989a,b; Osawa et al., 1992;
Baumann and Oro, 1993).
Presumably, the code evolved from a primitive
form, but no matter how the code reached its
present form the grouping of the amino acids into
two major groups cannot be accidental, but rather
reflects an important property of the genetic code:
U as second base determines that a codon will
code for a very hydrophobic amino acid. With
this notion a simple genetic alphabet can be
constructed:
U C/A/G
N (U/C/A/G) Hydrophobic Hydrophilic N
This simple code contains the central property
of a protein folding code: the ability to discrimi-
nate between a structural, hydrophobic amino
acid which tends to be in the interior of a protein,
and a functional, hydrophilic amino acid, which
tends to be at the surface of a protein. This
self-folding property of proteins, sometimes
named ‘the second alphabet’ of the genetic code
(Jaenicke, 1987; Levitt, 1991), is strongly con-
served in the genetic code. Mutations at position 3
result in an identical or very similar amino acid
while mutations at position 1 result in a similar
amino acid.
In principle, the simple code described above
could have generated primitive folded proteins
(Brack and Orgel, 1975), which catalyzed evolu-
tion of the code by stabilizing some RNAs rela-
tive to others.
The instability of RNA, which is today a major
problem in studying many processes in living
cells, favoured evolution of the protective action
of proteins, and the limited catalytic capabilities
of RNA favoured the evolution of protein en-
zymes. This process required the establishment of
a genetic code for reading the encoded
information.
At this stage it is difficult to envisage stero-
chemical constrains on the association of RNAs
with amino acids and it seems more likely that a
43
few amino acids were selected by availability and
by their ability to catalyze chemical evolution.
From this point, evolution proceeded by increas-
ing the number of amino acids and the complexity
of the protein synthetic machinery.
4. Refining the genetic code
In the present genetic code only three amino
acids have six codons: Leu, Ser and Arg. These
three amino acids makes a set containing all
properties for protein hydrophobic core structure
(Leu), interaction with nucleic acids (Arg) and
catalysis of chemical reactions (Ser). Ser and Arg
are further related by their coexistence in the
fourth column rows 5–8. The primitive code
could therefore have been:
U C/A/G
N L R/S N
Arg was possibly recruited earlier than Ser, due
to its ability to interact with and stabilize nucleic
acids by ionic forces.
Since the third position of the codons is highly
redundant, it is likely that the next step was the
ability of the first base to discriminate between
Ser and Arg. The ability of U or C as first base to
discriminate between Ser and Arg indicates that C
was the second primordial base, and a possible
step in the evolution of the code could have been:
U C
U L S N
C L R N
This code has the ability to distinguish between
a structural hydrophilic amino acid and a cata-
lytic hydrophilic amino acid.
The further evolution of the code must have
been an intimate interplay between proteins and
RNA exploring all possibilities and resulting in
the present amino acids, and the start and stop
codons.
The present code gives some hints about stages
in evolution:
44 G. Houen / BioSystems 54 (1999) 39–46
Codons in first row column 2 – 4 code for hy-
drophilic amino acids with catalytic properties,
whereas the same columns in row two code for
structural amino acids. It can also be seen that the
introduction of A and G added the possibility of
discriminating between uncharged (column 2) and
charged (columns 3 and four) as well as start/
stop, Asp/Glu, etc. This evolutionary scheme is
reflected in the present code since at places where
the third position is important U and C code for
the same amino acid and A and G code for the
same amino acid, eg. Tyr-stop, Cys-stop, His-Gln,
Asn-Lys, Asp-Glu, Ser-Arg.
A possible stage in evolution could thus have
been:
U C A G
U L S stop stop N altered T3 binding capacity (Miyajima et al.,
C L R R R N
A start S R R N
G start S D D N
This relatively simple code contains all informa-
tion for start, stop, structure and function.
Later in evolution Cys and Trp were introduced
at the expense of the number of stop codons.
Since the hydrophobic amino acids have struc-
tural functions, there has not been a great advan-
tage in enlargement of the number of different
hydrophobic amino acids, a notion supported by
the relatively low number of codons for them. The
increase in the number of bases from 2 to 4 has
mainly served to increase the number of func-
tional amino acids.
5. Discussion
Inspection of the genetic code and its derived
hydrophobicity matrix reveals that the code di-
vides the amino acids into two major groups with
hydrophobic and hydrophilic residues. This divi-
sion is directly related to the folding property of
proteins, which have a hydrophobic core and a
hydrophilic surface.
On the basis of this fundamental division, it
seems likely that the genetic code evolved from a
primitive code, which only discriminated between
a hydrophobic and a hydrophilic residue, most
likely Leu and Arg. From this primordial code,
evolution proceeded by introduction of a func-
tional catalytic residue (Ser), and by a further
limited increase in structural hydrophobic
residues, and a larger increase in functional hy-
drophilic residues.
Comparison of the present genetic code and the
nonsense code reveals no complementarity in
terms of possible attractive physical forces, and it
can be concluded, that in general only the sense
strand encodes functional proteins.
Some nonsense messages do code for proteins,
but this is only rarely found and may reflect the
early existence of double-stranded RNA. For ex-
ample, the nonsense strand of the erbA locus has
been found to encode an erbA homologue with
1989).
The conclusion reached above is consistent with
the notion, that RNA was the primordial au-
toreplicative genetic material.
The early chemical evolution may have been
catalyzed by mineral surfaces and metals (Orgel,
1972) and resulted in the formation of simple
relatively stable RNA molecules or precursors of
RNA (Kuhn, 1972; Darnell and Doolittle, 1986).
These RNAs served as templates for polymeriza-
tion of complementary RNAs which again served
as templates for the synthesis of the sense RNA.
The self-replication of RNA implies the exis-
tence of double-stranded RNA, and therefore,
early chemical evolution must have been re-
strained to relatively short RNAs, which ‘melt’
and separate at a reasonable rate at ambient
temperature. Gradually, ribozymes which cata-
lyzed template-directed RNA synthesis emerged
(Ekland et al., 1995; Ekland and Bartel, 1996;
Doudna and Szostak, 1989). Some ribozymes also
catalyzed breakdown of other RNAs (survival of
the most fit RNA) and thus, RNA has all proper-
ties required for ‘Darwinian’ evolution. The insta-
bility of RNA, which is today a major problem in
studying many processes in living cells, favoured
evolution of the protective action of proteins and
the development of a ‘backup system’ in the form
of DNA, and the limited catalytic capabilities of
RNA favoured the evolution of protein enzymes.
 G. Houen / BioSystems 54 (1999) 39–46
Transcription of DNA and the folding and
modification of proteins are catalyzed by en-
zymes, while the translation and maturation of
RNA are catalyzed by ribonucleoproteins. This
organization reflects the evolution of the genetic
code, also implying that ribonucleoproteins cata-
lyzed early evolutionary steps.
The evolution of DNA as a more stable copy of
the information contained in RNA clearly had a
major evolutionary advantage, as all cells use
DNA in this way.
If it is assumed that DNA evolved as a copy of
RNA by the loss of a hydroxyl group, it also
follows that the genetic code was established
solely by RNA–protein interactions.
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