Biology Reference
In-Depth Information
islands tend to lose their methylation upon transcription. CpG islands some-
times also occur within the coding regions of genes as in the case of the human
apolipoprotein E (
APOE
; 19q13) gene in which exon 4 constitutes a 940 bp
CpG island. Other examples of human genes with CpG islands within their
coding regions are the
CDKN2A
(9p21),
MYOD1
(11p15.4), and
PAX6
(11p13)
genes.
CpG islands are predominantly found in early replicating (R band) as opposed
to late replicating (G band) regions of the genome (Craig and Bickmore, 1994).
They may be considered to be the last remnants of the unmethylated domains
that once dominated the vertebrate genome. The evolution of the heavily methy-
lated vertebrate genome has been accompanied by a progressive loss of CpG din-
ucleotides as a direct consequence of their methylation in the germline. Although
CpG islands are usually unmethylated and therefore relatively immune to muta-
tional decay (Luoh
et al
., 1995; see section 1.1.3,
CpG suppression in the vertebrate
genome and its origin
), there is nevertheless some evidence for their gradual erosion
over evolutionary time (Matsuo
et al
., 1993).
CpG suppression in the vertebrate genome and its origin.
Methylation of
cytosine results in a high level of mutation due to the propensity of 5mC to
undergo deamination to form thymidine. Deamination of 5mC probably does not
occur during the enzymatic replication of the methylation pattern which appears
to be a high fidelity process. Indeed, 5mC deamination probably occurs with the
same frequency as the deamination of cytosine to uracil. However, whereas uracil
DNA glycosylase activity in eukaryotic cells is able to recognize and excise uracil,
thymine being a 'normal' DNA base is thought to be both less readily detectable
and removable by cellular DNA repair mechanisms.
One consequence of the hypermutability of 5mC is the paucity of CpG in the
genomes of many eukaryotes (Setlow, 1976), the heavily methylated vertebrate
genomes exhibiting the most extreme 'CpG suppression' (Bird, 1980; Jabbari
et
al
., 1997; Schorderet and Gartler, 1992). A first estimate of the
in vivo
rate at
which 5mC is deaminated and fixed as thymidine was arrived at by extrapolation
from
in vitro
data (Cooper and Krawczak, 1989). To this end, the deamination rate
of 5mC as measured under laboratory conditions in single stranded DNA, was
modified so as to be consistent with the observed spectrum of point mutations
found to have caused human genetic disease. The rate estimate of 1.66 ×
10
-16
sec
-1
was consistent with the rate calculated from the evolutionary pattern of
CpG substitution exhibited by
-globin gene and pseudogene sequences in
human, chimpanzee and macaque (Cooper and Krawczak, 1989). Mathematical
modelling allowed a detailed study of the dynamics underlying the CpG sup-
pression currently found in the bulk DNA of vertebrate genomes (Cooper and
Krawczak, 1989). It was inferred that the time span required in order to create
the currently observed CpG frequency (0.01) was 50 to 100 Myrs. On the other
hand, the process of CpG loss must have lasted for approximately 450 Myrs in
order for the mononucleotide frequencies to have attained their present levels.
This time span corresponds closely to the estimated time since the emergence
and adaptive radiation of the vertebrates and thus coincides with the probable
advent of heavily methylated genomes. These data are therefore consistent with
