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mates but there was essentially no overlap with the normal human range, findings
also reported by Limprasert et al . (1996). The AR gene was also found to be poly-
morphic in nonhuman primates but with minimal overlap with the normal
human range (Djian et al ., 1996). For the SCA1 gene, the average repeat copy
numbers exhibited by Pan , Gorilla , Hylobates , Macaca, and Cercopithecus were
within the normal human range but were lower than the modal number in
humans (Djian et al ., 1996). Thus, for these four loci, CAG copy number is lower
in nonhuman primates than in humans. From what we know of the propensity of
CAG repeats to expand, this is much more likely to be due to a higher rate of
expansion in humans than the alternative: contraction in the other primate
species. In the case of the HD gene, this interpretation is supported by the finding
of a similar number of CAG repeats in the murine Hd gene to that found in the
nonhuman primate HD genes (Lin et al ., 1994). The high number of CAG repeats
in the human HD gene is therefore due primarily to expansion within the human
lineage. This contrasts with the expansion of CAG number in the AR gene which
began earlier in hominoid evolution; the great apes contain an expanded CAG
repeat not found in rodents (Choong et al ., 1998; Djian et al ., 1996). Thus, the AR
CAG repeat expansion began prior to ape-human divergence but continued in
human after divergence from the great apes.The most dramatic example of CAG
expansion is however that of the involucrin ( IVL ; 1q21) gene which is so rich in
CAG repeats and codons derived from CAG that it is likely that it is descended
from a simple poly (CAG) sequence (see Section 8.9.5 below).
The CGG repeat in the 5
UTR of the FMR1 gene has been studied in 44 mam-
malian species from 8 different orders (Eichler et al ., 1995). The presence of this
repeat in all species examined indicates that the CGG repeat has been conserved
for over 150 Myrs and is therefore likely to be have some functional significance
(reviewed by Eichler and Nelson, 1998). Repeat length was found to be similar
among the 24 nonprimate species, ranging from 4 to 12 units (mean 8.01 ± 0.8).
By contrast, the mean length of the repeat among the 20 primate species examined
was 20.1 ± 2.3. Copy number polymorphism was not found to be limited to
human, with Ornythorhyncus (platypus), Artibeus (phyllostomid bat) and Pan
(chimpanzee) all possessing polymorphic repeats. Parsimony analysis predicted
that the early mammalian CGG repeat was short (4-9 units) and uninterrupted,
whereas an increase in copy number beyond ~20 repeats appears to have occurred
at least three times independently in the Catarrhini ( Figure 8.13 ). These expan-
sions in the hylobatid apes, great apes and the cercopithecoid monkeys were asso-
ciated with the addition of specific interspersions, CGA, AGG and CGGG
respectively ( Figure 8.13 ). These interspersions are unlikely to have arisen
through DNA polymerase slippage and may have been mediated by unequal
crossing over or gene conversion.
A comparison of trinucleotide repeats in human versus rodent coding
sequences has indicated that, by and large, orthologous repeats have not been con-
served for long periods of evolutionary time, either in terms of their size or loca-
tion (Stallings, 1994). As yet, there are no known pathological equivalents of
human dynamic mutations in other species but this may merely reflect bias of
ascertainment. Thus, nonhuman examples of disease-associated triplet repeat
expansions may not yet have come to our attention and it may be that these expan-
 
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