Biology Reference
In-Depth Information
gene coding region (
Table 8.2
). This is thought to constitute a gain-of-function
mutation through the incorporation of a polyglutamine tract into the protein prod-
uct (Houseman, 1995). Several factors are known to influence the stability of triplet
repeats viz. the type of sequence, length of repeat, whether the repeat is interrupted
or not, and the orientation of the repeat relative to the origin of replication
(Andrew
et al
., 1997). The removal of interrupting point mutations from repeat
arrays is thought to be very important in promoting triplet repeat expansion
(Eichler
et al
., 1994) and is significant in an evolutionary context as well as in cases
of disease. Removal of these point mutations could occur simply by single base-
pair substitution or by gene conversion or unequal crossing over. Other inherited
conditions result from expansion of a triplet repeat in the 3
untranslated region
(myotonic dystrophy;
DMPK
) and an intron (Friedreich ataxia;
FRDA
) (
Table 8.2
)
and the resulting mechanisms of disease are consequently different.
8.9.2 Nature and distribution of triplet repeats in the human genome
Trinucleotide repeats are 10-100-fold less frequent than (AC)n repeats (Gastier
et
al
., 1995) and different types of trinucleotide repeat occur at different frequencies.
Thus repeats (AAT)n and (AAC)n are the most frequent trinucleotide repeats
found in the human genome (Gastier
et al
., 1995; Stallings 1994), with (AAT)n
exhibiting a high degree of copy number polymorphism (Gastier
et al
., 1995).
Both (CAG)n and (CCG)n repeats appear to be over-represented in the human
genome (Han
et al
., 1994), the former being polymorphic in number in the
genomes of humans and non-human primates (Sirugo
et al
., 1997). (CAG)n
repeats are rare in intronic regions, possibly because of their similarity to the
acceptor splice site consensus, CAGG (Stallings, 1994). Long homopeptides are
present in 1.7% of human protein-coding sequences (Karlin and Burge, 1996).
A number of human genes contain polymorphic triplet repeats (e.g. cadherin 2
(
CDH
; 18q12), breakpoint cluster region (
BCR
; 22q11), glutathione-
S
-trans-
ferase (
GSTA1
; 6p12), Na
+
/K
+
ATPase
1-subunit (
ATP1B1
; 1q22-q25) but these
repeats are not known to exert any pathological effect (Li
et al
., 1993; Riggins
et
al
., 1992). Other genes have been identified solely on account of their possession
of polymorphic trinucleotide repeats and these genes represent candidate loci for
involvement in complex diseases (Breschel
et al
., 1997; Néri
et al
., 1996).
Trinucleotide repeat containing genes are also found in other species, including
mouse (Kim
et al
., 1997), but no nonhuman example of triplet repeat expansion as
a cause of a genetic disease has yet been documented.
Replication slippage involving short GC-rich motifs ('expansion segments') has
occurred during the evolution of the vertebrate genes encoding the 28S and 18S
ribosomal RNAs (Hancock, 1995a; Hancock and Dover, 1988). Interestingly, dif-
ferent segments of the 28S rRNA subunit gene appear to have coevolved by 'com-
pensatory slippage' allowing RNA secondary structure to be conserved as a
consequence of runs of sequence motifs in one region being compensated for by
complementary motifs in another (Hancock and Dover, 1990).
8.9.3 Origin of expanded triplet repeats
In myotonic dystrophy, all Caucasian and Japanese DM chromosomes possess a
specific haplotype (Deka
et al
., 1996; Imbert
et al
., 1993; Tishkoff
et al
., 1998;
