Biology Reference
In-Depth Information
(Davidson and Peterson, 1997). Fusion could have occurred as a means to allow
coordinate regulation of the three enzymatic activities.
One way in which polycistronic mRNAs might have arisen during evolution is
by inefficient RNA polymerase termination of transcription of one mRNA species
allowing the cotranscription of a second mRNA species from a downstream gene.
Such a phenomenon has been shown to occur in normal human cells and involves
the
fusion splicing
of two adjacent (9p13) genes, those encoding galactose-1-phos-
phate uridylyl-transferase (
GALT
) and interleukin-11 receptor
-chain (
IL11RA
)
(Magrangeas
et al
., 1998).
Some human genes encode
polyproteins
and comprise multiple tandem repeats
of the same coding region on the same transcript, for example those encoding the
ubiquitins (
UBA52
, 19p13;
UBB
, 17p11-p12;
UBC
, 12q24; Wiborg
et al
., 1985)
and filaggrin (
FLG
; 1q21; Gan
et al
., 1990; McKinley-Grant
et al
., 1989).
1.1.3 DNA methylation
5-methylcytosine (5mC) is the most common form of DNA modification in
eukaryotic genomes. Soon after DNA synthesis is complete, target cytosines are
modified by a DNA methyltransferase using S-adenosylmethionine as methyl
donor. In humans, between 70% and 90% of 5mC occurs in CpG dinucleotides, the
majority of which appear to be methylated (Cooper, 1983).
Whereas the vertebrate genome is heavily methylated, methylation is virtually
undetectable in insects and other arthropods (Cooper, 1983). An intermediate
level of methylation is exhibited by the echinoderms, coelenterates and molluscs
whose genomes are characterized by the presence of long methylated and
unmethylated tracts (Cooper, 1983). The transition from a fractional to a global
methylation pattern appears to have occurred close to the origin of the verte-
brates since the cephalochordate
Amphioxus
exhibits a typically invertebrate pat-
tern of genome methylation whereas the jawless vertebrates hagfish and lamprey
possess a vertebrate pattern (Tweedie
et al
., 1997). The increase in size of the
methylated compartment characteristic of vertebrate genomes correlates with
the sharp increase in gene number during the invertebrate-vertebrate transition
(Bird, 1995). DNA methylation may thus have been recruited as a transcriptional
regulatory mechanism (Colot and Rossignol, 1999).
DNA methylation is essential for normal mammalian development (Razin and
Shemer, 1995). It is thought to play a role in both gene regulation (Kass
et al
.,
1997) and imprinting (Jaenisch, 1997; see section 1.1.3,
Imprinting and imprinted
genes
), may serve as a cue for strand specificity in DNA replication and repair
(Hare and Taylor 1988) and could conceivably serve as a self-defence mechanism
to silence transposable elements and proviral DNAs integrated into the genome
during evolution (Yoder
et al
., 1997; Simmen
et al
., 1999). This post-synthetic
modification occurs almost exclusively in CpG dinucleotides of which between
60% and 90% are methylated in mammalian tissues (Jost and Bruhat, 1997).
Although it is as yet unclear how tissue-specific methylation patterns are estab-
lished (Bestor and Tycko 1996; Turker and Bestor, 1997), they are nevertheless
heritable and reproducible after transmission through the germline (Pfeifer
et al
.,
1990; Silva and White, 1988). The establishment of cell type-specific methylation
