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genome, an average length of protein coding sequence of 1.52 kb, a human-chim-
panzee divergence time of 6 Myrs ago, and an average generation time of 25 years
in the human lineage, Eyre-Walker and Keightley (1999) estimated the rate of
nonsynonymous substitutions,
M
, to be 4.2 ± 0.5 mutations per diploid genome
per generation, and the deleterious mutation rate,
U
, to be 1.6 ± 0.8 mutations per
diploid genome per generation. Estimates of
U
for chimpanzee (1.7 ± 0.8) and
gorilla (1.2 ± 0.6) were found to be similar to that obtained for humans. Eyre-
Walker and Keightley (1999) concluded that the human deleterious mutation rate
is close to the upper limit tolerable by a species with a low reproductive rate. This
implies that in hominids, synergistic epistasis may have occurred between delete-
rious mutations. Further, the level of selective constraint (
U
/
M
) in human protein
coding sequences (0.38 ± 0.17) was judged to be atypically low as were estimates
from chimpanzee (0.53 ± 0.16) and gorilla (0.38 ± 0.17). A large number of
slightly deleterious mutations may therefore have become fixed in the hominids
and the most likely explanation for this, is small long-term effective population
size.
7.2 Mutations in pathology and evolution; two sides of the
same coin
Genotypes never have votes. Phenotypes sometimes do.
A.L. Mackay
In the early days of genetics, many thinkers saw spontaneous variation purely and
simply in terms of its role as the evolutionary fuel for speciation. The first to draw
parallels with disease was probably the British geneticist William Bateson who, at
the turn of the century, maintained that disease presented 'a discontinuity closely
comparable with that of many variations'. Indeed, he speculated
that the problem of species [may well] be solved by the study of pathology; for
the likeness between variation and disease goes far to support the view which
Virchow has forcibly expressed, that 'every deviation from the type of the par-
ent animal must have its foundation on a pathological accident'
Bateson (1894)
Couched in modern terms, single base-pair substitutions in human gene pathol-
ogy and evolution may be viewed as two sides of the same coin. This appealing
supposition has recently been corroborated by an in-depth comparison of muta-
tions causing inherited disease with mutations in noncoding DNA that have
become fixed during the evolutionary divergence of human and other mam-
malian genomes (Krawczak and Cooper, 1996a). Mutations in noncoding DNA
may date back some millions of years and their survival has been independent of
natural selection. By contrast, disease-associated substitutions are of fairly recent
origin by comparison with the evolutionary timescale. This difference notwith-
standing, under the assumption that the underlying molecular mechanisms of
mutation have not changed substantially during mammalian evolution, some
resemblance between the two mutational spectra was to be expected. Consistent
