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1986) and included cDNA sequences from human, macaque, sheep, pig, rabbit, rat,
mouse, dog, and cow. Conserved cDNA blocks were used as anchors to align inter-
vening non-conserved cDNA blocks for a particular protein, and since protein
function must have been retained during evolution, frameshift mutations were
precluded in all alignments. For each protein, the authors then deduced from the
alignments the most likely cDNA sequence at each node of the mammalian phylo-
genies employed, including the roots representing the respective mammalian
ancestors. A small number of ambiguities remained as to the ancestral mammalian
cDNA sequences. These were resolved by reference to relative nearest neighbor-
dependent mutation rates in humans. Use of human-derived parameters in this
context was justified on the basis of the long-term evolutionary stability of relative
single base-pair substitution rates (Krawczak and Cooper, 1996).
The evolution of a gene family whose members acquire different functions is
invariably accompanied by rapid amino acid sequence divergence in functionally
important regions (Ohta, 1991, 1994). Indeed, specific examples of this phenome-
non include the 'accelerated evolution' (hypervariability) of the reactive center
regions of serine protease inhibitors (Hill and Hastie, 1987) and the active site
regions of some serine proteases (Creighton and Darby, 1989). For humans, the
mutation rates derived during the reconstruction process were found by
Krawczak
et al
. (1996) to be significantly higher in the factor VII, factor X and
protein C lineages than in the factor IX and prothrombin lineages. Similarly in
the dog, the factor VII lineage exhibited a higher mutation rate than that of factor
IX. That factor IX exhibited a lower mutation rate than the other proteins was
indicative of its early emergence. Once adapted to its functions, factor IX would
have had to change rather less over evolutionary time than the other proteins of
more recent origin which still had to adapt to their new-found roles. For factor
IX, protein C and prothrombin, mutation rate differences were also apparent
between species and exhibited an inverse correlation with generation time.
Consistent with previous results (Britten, 1986; Collins and Jukes, 1994), the
mutation rate in humans was much less than that found in rodents.
10.2.3 Evolutionary divergence of the vitamin K-dependent coagulation
factors
Krawczak
et al
. (1996) identified a number of highly conserved regions in their
reconstructed ancestral mammalian cDNA sequences. Mismatches in these
regions were classified on the basis of whether they corresponded to either a silent
or a missense mutation during the process of evolutionary divergence.
Interestingly, the numbers of silent and missense mutations did not correlate with
each other. This finding was interpreted in terms of the existence of two distinct
molecular clocks: one would be based upon silent mutations and would run con-
stantly after the divergence of any two sequences. The other would be based upon
missense mutations which would continue to run immediately after gene dupli-
cation but would stop, or at least be dramatically slowed, once the new protein
product had acquired, and then become adapted to, its new biological function.
Since by far the smallest number of silent mutations in conserved codons had
occurred since the divergence of factors VII and X, Krawczak
et al
. (1996)
