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effects are also apparent from sequence comparison studies of human genes and
pseudogenes (Blake and Hess, 1992; Hess
et al
., 1994).
The mutation rate in higher organisms has long been assumed to be a compro-
mise between keeping the frequency of deleterious substitutions low at the same
time as not completely abolishing the potential for generating adaptive variation.
One prediction of this
trade-off theory
is that a lower equilibrium mutation rate
should evolve if the deleterious effect of mutation is increased. To examine the
validity of this postulate, McVean and Hurst (1997) compared rates of synony-
mous nucleotide substitution in 33 X-linked genes and 238 autosomal genes in
mouse and rat. Since the X chromosome is hemizygous in male mammals, delete-
rious recessive mutations arising on it might reasonably be expected to have a
greater effect on fitness than those arising on the autosomes. If, however, synony-
mous substitutions were completely neutral with respect to fitness, then they
should accumulate at a rate equal to the mutation rate and could be used directly
to estimate mutation rates. McVean and Hurst (1997) found that the X-linked
genes exhibited significantly lower rates of synonymous substitution than their
autosomal counterparts and this was held to be explicable in terms of the X-chro-
mosomal mutation rate being reduced by natural selection.
Mutational pressure may have influenced the evolution of the eukaryotic
genetic code in that the code's organization at least appears to provide at least
some protection against the deleterious consequences of single base-pair substitu-
tions (Goldman, 1993; Haig and Hurst, 1991; Jukes, 1993; Kuhn and Waser, 1994;
Osawa and Jukes, 1988; see Section 7.2). However, the converse argument is more
persuasive: that the design of the genetic code and the functional similarity (or
dissimilarity) of amino acids to one another may have affected the relative muta-
bilities of individual codons during evolution. Codon usage varies quite widely
between different vertebrates (Nakamura
et al
., 1998; CUTG Database at
http://www.dna.affrc.go.jp/~nakamura/CUTG.html
), a finding which may be
related to the influence of the codon frequencies of highly expressed genes on
translation efficiency via tRNA pools (Britten, 1993). Codon usage may also vary
between different genes in the same species. In humans, such a finding has been
suggested to be related to chromosomal location (D'Onofrio
et al
., 1991; see
Section 7.4).
7.1.5 The deleterious mutation rate in humans
Man's yesterday may ne'er be like his tomorrow;
Nought may endure but mutability.
Percy Bysshe Shelley (1816)
Mutability
It has been suggested that humans may experience a high deleterious mutation
rate (Crow, 1997; Kondrashov and Crow, 1993). If a significant proportion of these
mutations were even mildly deleterious, such lesions would tend to accumulate in
populations with small effective sizes or in which selection had been relaxed.
Eyre-Walker and Keightley (1999) estimated the human deleterious mutation rate
per diploid genome per generation,
U
, by comparing the expected and observed
rates of nonsynonymous substitution in 46 orthologous gene pairs from human
and chimpanzee. Under conservative assumptions of 60 000 genes in the human
