Biology Reference
In-Depth Information
Expansion of unstable repeat sequences.
A recently recognized mutational
mechanism involves the instability of certain specific trinucleotide repeat
sequences (reviewed by Timchenko and Caskey, 1996). This mechanism was first
reported as a cause of the fragile X mental retardation syndrome. The brain-
expressed
FMR1
gene responsible was found to contain an ususual (CGG)n repeat
which exhibited copy number variation of between 6 and 54 in normal healthy
controls, between 52 and >200 in phenotypically normal transmitting males (the
'premutation') and between 300 and >1000 in affected males (the 'full mutation').
Expansion of premutations to full mutations occurs only during female meiotic
transmission whilst the probability of repeat expansion correlates with repeat
copy number, consistent with a mechanism of slipped mispairing during replica-
tion. Expansion of a sequence can thus itself lead to further expansion, a process
termed 'dynamic mutation' by Richards
et al
. (1992). The discovery of this novel
mutational mechanism soon led to the recognition that the expansion of unstable
repeats is responsible for a number of other human inherited diseases, almost all
neuromuscular (see Chapter 8, section 8.9.1).
The triplet repeats (CGG)n and (CAG)n are very abundant in the human
genome (Stallings, 1994; Han
et al
., 1994). A considerable number of human
genes, both ubiquitously expressed and tissue-specific, have now been identified
as containing such triplet repeats (Riggins
et al
., 1992; Karlin and Burge, 1996).
Many of these repeats are highly polymorphic and may thus represent examples
of more subtle triplet repeat expansions. Whether specific polymorphic alleles are
associated with any particular phenotype, however, remains to be seen.
This chapter has attempted to provide the reader with a brief introduction to what
is known of structure-function relationships in the human genome. Specific DNA
sequences have clearly evolved for different cellular functions. Some sequences rep-
resent gene coding regions that contain the genetic information necessary to direct
the synthesis of proteins. Other sequences in gene promoter or untranslated regions
serve to direct appropriate gene expression or are involved in mRNA processing, sta-
bility and nucleocytoplasmic transport. Some highly repetitive sequences may play
an important role in chromosome architecture whereas others may almost be com-
mensally parasitic in that they cohabit in the genome having increased in copy num-
ber under their own mutational momentum. Some sequences are modified by DNA
methylation which itself may influence function. Other sequences, by their very
nature, are more mutable than others and may be capable of rapid change. Whatever
their cellular role, many DNA sequences are able to interact with proteins or mRNA
molecules in order to effect their function. It follows that the imminent analysis of
the human genome sequence should reveal the existence of new sequence codes (and
perhaps codes within codes) to add to that first elucidated in the early 1960s.
References
Adachi Y., Käs E., Laemmli U.K.
(1989) Preferential, cooperative binding of DNA topoisomerase II
to scaffold-associated regions.
EMBO J.
8
: 3997-4006.
Adams M.D.
et al
.
(1995) Initial assessment of human gene diversity and expression patterns based
upon 83 million nucleotides of cDNA sequence.
Nature
377
Suppl.: 3-174.
