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BioSystems 54 (1999) 39–46 www.elsevier.com / locate / biosystems Evolution of the genetic code: the

BioSystems 54 (1999) 39–46

BioSystems 54 (1999) 39–46 www.elsevier.com / locate / biosystems Evolution of the genetic code: the nonsense,

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, Artilleri ej 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

* Tel.: +45-3268-3276; fax: + 45-3268-3149. E-mail address: gh@ssi.dk (G. Houen)

1. Introduction

The diversity of living organisms reflects the

nonequi-

complexity

of

the

earth

as

an

open

0303-2647/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.

PII: S0303-2647(99)00056-8

40

G. Houen / BioSystems 54 (1999) 39–46

librium thermodynamic system (Nicolis and Pri- gogine, 1977), in which a complex phylogenetic evolution has taken place. Despite this complexity all living organisms use essentially the same ge- netic code for storing and retrieving information, and therefore this code must have evolved at a relatively early stage of evolution and then re- mained unchanged after its ‘perfection’ (Crick et al., 1961; Crick, 1968; Orgel, 1968; Eigen et al., 1989; Osawa et al., 1992). Crick (1968) has discussed two fundamentally different theories of genetic code evolution: 1, the ‘frozen accident theory’, postulating that amino acids became linked to codons purely by chance; and 2, the ‘stereochemical principle’, which as- sumes that stereochemical constraints guided the association of amino acids with codons. Wong (1975) has proposed a co-evolution theory of the genetic code which postulates that ‘the codon system is primarily an imprint of the prebiotic pathways of amino acid formation’. In addition to these theories, a theory has been put forward about a possible complementarity between the putative protein products of the two complementary strands of DNA: the molecular recognition theory (Blalock and Smith, 1984; Blalock and Bost, 1986; Zull and Smith, 1990).

Table 1 The genetic code matrix

 

U

C

A

G

U

Phe

Ser

Tyr

Cys

U

Phe

Ser

Tyr

Cys

C

Leu

Ser

End

End

A

Leu

Ser

End

Trp

G

C

Leu

Pro

His

Arg

U

Leu

Pro

His

Arg

C

Leu

Pro

Gln

Arg

A

Leu

Pro

Gln

Arg

G

A

Ile

Thr

Asn

Ser

U

Ile

Thr

Asn

Ser

C

Ile

Thr

Lys

Arg

A

Met

Thr

Lys

Arg

G

G

Val

Ala

Asp

Gly

U

Val

Ala

Asp

Gly

C

Val

Ala

Glu

Gly

A

Val

Ala

Glu

Gly

G

According to this theory, the complementarity between the sense and nonsense strands of DNA is revealed in a complementarity between for ex- ample receptors and peptide hormones (Bost et al., 1985a,b; Blalock and Bost, 1986; Carr et al., 1986; Weigent et al., 1986; Brentani, 1988; Brentani et al., 1988; Baranyi et al., 1995) and a high affinity of peptides for their antisense pep- tides (Shai et al., 1987; Fassina et al., 1989; Pasqualini et al., 1989; Shai et al., 1989). While this theory may hold for some peptides and anti- sense peptides, it can be shown to have no struc- tural basis in the genetic code. Instead, the genetic code evolved as a maximally effective information transfer system, based on RNA, amino acids and DNA.

2. The sense, antisense, nonsense and antinonsense genetic codes

From the DNA double helix three different transcription reading frames can be defined in addition to the genetic code. These four codes are logical transformation of each other as shown below. A: The genetic code (the sense code) trans- lates the sense strand into protein by read- ing the codons in 5 –3 direction and using the genetic code matrix (Table 1). B: The antisense code is obtained by reading codons in the opposite (3 –5 ) direction (Table 2).

The nonsense code is obtained by reading

complementary codons in the 5 –3 direc- tion (Table 3). D: The antinonsense code is obtained by reading complementary codons in the 3 – 5 direction (Table 4). The genetic code (Table 1) groups the amino acids into two major groups: hydrophobic (first column) and hydrophilic (columns 2–4). This grouping can be realized either by visual inspec- tion of the amino acids or by constructing a hydrophobicity matrix from the genetic code ma- trix using any set of hydrophobicity/hydrophilic- ity values (Table 5). The first column only contains amino acids with very hydrophobic side

C:

G. Houen / BioSystems 54 (1999) 39–46

41

Table 2 The antisense genetic code matrix

 

U

CAG

 

U

Phe

Ser

Tyr

Cys

U

Leu

Pro

His

Arg

C

Ile

Thr

Asn

Ser

A

Val

Ala

Asp

Gly

G

C

Phe

Ser

Tyr

Cys

U

Leu

Pro

His

Arg

C

Ile

Thr

Asn

Ser

A

Val

Ala

Asp

Gly

G

A

Leu

Ser

End

End

U

Leu

Pro

Gln

Arg

C

Ile

Thr

Lys

Arg

A

Val

Ala

Glu

Gly

G

G

Leu

Ser

End

Trp

U

Leu

Pro

Gln

Arg

C

Met

Thr

Lys

Arg

A

Val

Ala

Glu

Gly

G

Table 3 The nonsense genetic code matrix

 
 

U

C

AG

 

U

Lys

Arg

Ile

Thr

U

Glu

Gly

Val

Ala

C

End

End

Leu

Ser

A

Gln

Arg

Leu

Pro

G

C

Lys

Arg

Met

Thr

U

Glu

Gly

Val

Ala

C

End

Trp

Leu

Ser

A

Gln

Arg

Leu

Pro

G

A

Asn

Ser

Ile

Thr

U

Asp

Gly

Val

Ala

C

Tyr

Cys

Phe

Ser

A

His

Arg

Leu

Pro

G

G

Asn

Ser

Ile

Thr

U

Asp

Gly

Val

Ala

C

Tyr

Cys

Phe

Ser

A

His

Arg

Leu

Pro

G

chains and with no ionizable groups in the side chains. Columns 2–4 contain amino acids with hydrophilic side chains or side chains of very low hydrophobicity (Pro and Ala). Only Tyr, Trp and Cys present exceptions to this pattern and they are not purely hydrophobic due to ionizable side

chains (Cys and Tyr) or a high dipole moment (Trp). Thus with only minor exceptions the genetic code divides the amino acids into two major groups (hydrophobic and hydrophilic), a basic pattern which has a direct correlation with the folding pattern of proteins: a hydrophobic core

Table 4 The antinonsense genetic code matrix

 

UCA

G

U

Lys

Arg

Ile

Thr

U

Lys

Arg

Met

Thr

C

Asn

Ser

Ile

Thr

A

Asn

Ser

Ile

Thr

G

C

Glu

Gly

Val

Ala

U

Glu

Gly

Val

Ala

C

Asp

Gly

Val

Ala

A

Asp

Gly

Val

Ala

G

A

End

End

Leu

Ser

U

End

Trp

Leu

Ser

C

Tyr

Cys

Phe

Ser

A

Tyr

Cys

Phe

Ser

G

G

Gln

Arg

Leu

Pro

U

Gln

Arg

Leu

Pro

C

His

Arg

Leu

Pro

A

His

Arg

Leu

Pro

G

Table 5 The genetic code hydrophobicity a matrix

9.2

6.5

1.9

1.4

9.2

6.5

1.9

1.4

9.2

6.5

9.2

6.5

10.0

9.2

2.1

2.1

4.2

9.2

2.1

2.1

4.2

9.2

2.1

6.0

4.2

9.2

2.1

6.0

4.2

8.0

5.2

7.0

6.5

8.0

5.2

7.0

6.5

8.0

5.2

5.7

4.2

4.2

5.2

5.7

4.2

3.7

2.1

10.0

5.7

3.7

2.1

10.0

5.7

3.7

2.1

7.8

5.7

3.7

2.1

7.8

5.7

a HPLC derived hydrophobicity values (Parker et al., 1986).

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G. Houen / BioSystems 54 (1999) 39–46

Table 6 The nonsense genetic code hydrophobicity matrix.

5.7

4.2

8.0

5.2

7.8

5.7

3.7

2.1

9.2

6.5

6.0

4.2

9.2

2.1

5.7

4.2

4.2

5.2

7.8

5.7

3.7

2.1

10.0

9.2

6.5

6.0

4.2

9.2

2.1

7.0

6.5

8.0

5.2

10.0

5.7

3.7

2.1

1.9

1.4

9.2

6.5

2.1

4.2

9.2

2.1

7.0

6.5

8.0

5.2

10.0

5.7

3.7

2.1

1.9

1.4

9.2

6.5

2.1

4.2

9.2

2.1

Table 7 Sum of genetic code hydrophobicity matrix and nonsense code hydrophobicity matrix

3.5

10.7

9.9

6.6

1.4

12.2

4.6

3.5

3.2

10.7

7.9

3.5

6.3

2.1

9.6

1.4

7.8

1.6

6.3

7.9

3.2

10.7

3.2

6.3

3.2

6.3

1.0

11.7

1.0

11.7

2.0

10.9

3.3

8.6

9.9

6.6

3.5

10.7

2.1

9.4

3.5

6.3

3.3

8.6

2.0

10.9

6.3

7.8

6.3

7.8

5.6

3.5

1.4

12.2

1.6

6.3

1.4

7.8

surrounded by a hydrophilic surface (Bajaj and Blundell, 1984). When the genetic code matrix is compared with its antisense (Table 3), nonsense (Table 4) and antinonsense (Table 5) codes, the grouping into hydrophobic and hydrophilic amino acids is con- served. However, there is no complementarity be- tween the code and the nonsense code in terms of possible attractive physical forces between the

corresponding amino acid side chains. On the contrary, the different codes pair very different side chains with each other, e.g. in first column rows 5–8:

sense

nonsense

antisense

Antinonsense

Leu

Lys

Phe

Glu

Leu

Glu

Leu

Glu

Leu

End

Ile

Asp

Leu

His

Val

Asp

Some ‘complementarity’ is observed when com- paring the code with the antisense code, and when comparing the nonsense code with the antinon- sense code due to the fact that residues only change positions within columns. This is, how- ever, only a mathematical property of the genetic code and reflects its general property of a maxi- mally safe and effective information transfer system. Another way of analyzing possible relations between the sense and nonsense codes is by com- paring the sense genetic code hydrophobicity ma- trix (Table 5) with the nonsense genetic code hydrophobicity matrix (Table 6). When these ma- trices are added, a matrix is obtained which de- scribes possible physical interactions between amino acid residues and the corresponding non- sense residues (Table 7). Table 7, however, shows no signs of complementarity between sense and nonsense residues. Hydrophobic residues would be expected to interact primarily with hydropho- bic nonsense residues, and this should give a more negative sum. Hydrophilic residues should inter- act preferentially with hydrophilic nonsense residues by hydrogen bonds and ionic interac- 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.

3. The primordial genetic code

Several reviews summarizing current knowledge of codon specificities have been published, and many authors have integrated this knowledge with different theories of genetic code evolution (Crick, 1968; Jukes, 1973, 1978; Wong, 1975,

G. Houen / BioSystems 54 (1999) 39–46

43

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

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

reflects an important property of the genetic code:

In the present genetic code only three amino

U

as second base determines that a codon will

code for a very hydrophobic amino acid. With

acids have six codons: Leu, Ser and Arg. These three amino acids makes a set containing all

this notion a simple genetic alphabet can be

constructed:

 

properties for protein hydrophobic core structure (Leu), interaction with nucleic acids (Arg) and catalysis of chemical reactions (Ser). Ser and Arg

U

C/A/G

are further related by their coexistence in the

N

(U/C/A/G)

Hydrophobic

Hydrophilic N

fourth column rows 5–8. The primitive code could therefore have been:

This simple code contains the central property

 

of

a protein folding code: the ability to discrimi-

U

C/A/G

nate between a structural, hydrophobic amino

NL

R/S

N

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

of

proteins, and the limited catalytic capabilities

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:

(Brack and Orgel, 1975), which catalyzed evolu-

 

U

C

tion of the code by stabilizing some RNAs rela-

U

L

S

N

tive to others.

C

L

R

N

The instability of RNA, which is today a major problem in studying many processes in living cells, favoured evolution of the protective action

This code has the ability to distinguish between a structural hydrophilic amino acid and a cata- lytic hydrophilic amino acid.

of

RNA favoured the evolution of protein en-

The further evolution of the code must have

zymes. This process required the establishment of a genetic code for reading the encoded

been an intimate interplay between proteins and RNA exploring all possibilities and resulting in

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

the present amino acids, and the start and stop codons. The present code gives some hints about stages in evolution:

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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

a hydrophobic and a hydrophilic residue, most likely Leu and Arg. From this primordial code, evolution proceeded by introduction of a func-

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

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

been:

early existence of double-stranded RNA. For ex- ample, the nonsense strand of the erbA locus has

 

U

CA

G

been found to encode an erbA homologue with

U

L

S

stop

stop

N

altered T 3 binding capacity (Miyajima et al.,

C

L

R

R

R

N

1989).

A

start

SR

R

N

The conclusion reached above is consistent with

G

start

S

D

D

N

the notion, that RNA was the primordial au-

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.

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’

5. Discussion

 

and separate at a reasonable rate at ambient temperature. Gradually, ribozymes which cata- lyzed template-directed RNA synthesis emerged

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

(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

45

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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