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findings. First, substitutions of hydrophilic and polar amino acid residues could
have resulted in more severe and/or variable consequences for the phenotype than
other types of substitution during most of the time period that the DNA repair
mechanisms were evolving. Second, it has been observed that, during evolution,
the effect of an amino acid change in the hydrophobic protein core is often com-
pensated for by another change in the immediate vicinity (Schirmer, 1979). Thus,
any selective pressure acting upon the organism to avoid substitutions at
hydrophobic core residues may have been balanced by the requirement for evolu-
tionary fixation of a second compensatory mutation. Finally, the majority of adap-
tive events shaping the eukaryotic DNA repair process will have occurred in
organisms other than human. It therefore follows that, were current clinical
observation likelihoods to be specific to human, this could have obscured any cor-
relation between mutation generation likelihoods and the phenotypic conse-
quences of substitutions at hydrophobic or nonpolar residues.
If mutations in human genes are biased against amino acid replacements with a
high present day probability of resulting in a disease phenotype, the question arises
as to whether such a bias might also be reflected in the evolutionary history of pro-
tein sequences. To explore this possibility, Krawczak and Cooper (1996a) calculated
a quantity termed the
relative evolutionary acceptability
for each possible amino acid
substitution from the data of Collins and Jukes (1994) who had reported the num-
bers and types of amino acid mismatches deduced from the alignment of 337 pairs
of human-rodent cDNA sequences. Krawczak and Cooper (1996a) found that clini-
cal observation likelihoods were negatively correlated with evolutionary acceptabil-
ity values. This implied that the more likely a given amino acid substitution was to
result in a disease phenotype (at least in contemporary humans), the less often has
it been tolerated during the evolution of mammalian protein sequences.
In summary, it is evident that the evolutionary requirement to avoid a deleteri-
ous phenotype has left its footprints in the mechanisms of mutation generation.
In this context, the most promising target for selection would appear to be the
intracellular DNA repair mechanism. Although the effect of a given amino acid
replacement upon protein structure is known to be heavily dependent upon its
precise location within the tertiary structure of the molecule (Alber, 1989; Pakula
and Sauer, 1989; Wacey
et al
., 1994), some basic rules which relate local causes and
consequences may nevertheless be perceived (De Filippis
et al
., 1994). If the effi-
ciency of mutation removal were directed by the immediate DNA sequence con-
text of a lesion, it may be that this has facilitated the avoidance during evolution
of hazardous amino acid replacements by consideration of the genetic code.
7.3 The importance of evolutionary conservation in the
study of pathological mutations at the protein level
using human factor IX as a model
The nature, frequency and location of gene lesions causing human genetic disease
are highly specific and, as outlined in Chapter 1, section 1.5, are determined in
part by the local DNA sequence environment. Once a given mutation has arisen,
however, the likelihood that it will come to clinical attention is a complex
