Biology Reference
In-Depth Information
7.4 Equilibrium of synonymous codon substitutions
Single base-pair substitutions in coding regions that do not change the encoded
amino acid sequence can be assumed to be comparatively free of selectional con-
straints (Creighton, 1993). Although it cannot be entirely excluded that these syn-
onymous (silent) changes might influence gene expression via effects on mRNA
translation (e.g. via alterations in RNA secondary structure or local imbalances in
the tRNA reservoir of a cell), the probability of survival and ultimate population
fixation should in general be much higher for silent mutations than for missense
mutations (Nei, 1987). This view is consistent with the fact that the vast majority
of evolutionarily stable base substitutions in coding regions of human genes have
taken place at the wobble positions of degenerate codons (Wilbur, 1985).
There are 19 groups of triplets which encode the same amino acid such that the
constituent triplets of each group can be replaced by each other via single base-
pair substitution (see
Table 7.1
; Krawczak and Cooper, 1996b). If mutations that
cause an amino acid exchange are ignored, the mutation dynamics within each
group of codons can be modelled by a simple system of linear equations involving
the relative rates of different single base-pair substitutions. With evolutionary
time, this system will approach an equilibrium state and the equilibrium codon
frequencies within each group can be determined by solving this system of equa-
tions. As can be inferred from
Table 7.1
, the actual frequencies within degenerate
codons are still some distance from equilibrium in humans.
When a similar analysis is performed for other vertebrate species with known
codon usage (Wada
et al
., 1991), it turns out that humans are not the closest to
their own equilibrium. In 17/19 cases,
Xenopus laevis
ranks first whereas humans
and rodents form a second group of species, all ranking equally low (Krawczak
Table 7.1.
Euclidean distance between the vectors of current and equilibrium frequencies
within degenerate codons of human genes (from Krawczak and Cooper, 1996b)
Encoded
Euclidean
amino acid
Codon group
distance
Glu
GAA GAG
0.083
Lys
AAA AAG
0.088
Asp
GAT GAC
0.164
Asn
AAT AAC
0.173
Tyr
TAT TAC
0.196
His
CAT CAC
0.222
Pro
CCT CCC CCA CCG
0.240
Thr
ACT ACC ACA ACG
0.275
Gln
CAA CAG
0.294
Ser
TCT TCC TCA TCG
0.295
Cys
TGT TGC
0.311
Gly
GGT GGC GGA GGG
0.314
Ala
GCT GCC GCA GCG
0.318
Phe
TTT TTC
0.367
Arg
CGT CGC CGA CGG AGA AGG
0.371
Ser
AGT AGC
0.416
Leu
TTA TTG CTT CTC CTA CTG
0.431
Val
GTT GTC GTA GTG
0.444
Ile
ATT ATC ATA
0.540
