Biology Reference
In-Depth Information
Various examples of the recruitment of metabolic enzymes to a novel lens-spe-
cific role have been documented among the taxon-specific crystallins (see Chapter
4, section 4.2.1,
Crystallin genes
). Recruitment of these genes to a new lens function
has been achieved by acquiring the potential for lens expression by the develop-
ment of novel promoter elements. Two strategies appear to have been employed
viz. the modification of (i) distinct regions of the same non-functional intronic
sequence to perform a role in lens-specific expression and (ii) pre-existing pro-
moters previously utilized for nonlens tissue expression (see Chapter 4, section
4.2.1,
Crystallin genes
).
Not surprisingly, some differences between orthologous promoters are appar-
ently neutral and do
not
obviously affect promoter function. One example of this
is the 54 bp insert in the promoter of the human liver arginase (
ARG1
; 6q22.3-
q23.1) gene which is absent from the same gene in macaques (Goodman
et al
.,
1994).
Not all regulatory sequences occur upstream of the transcriptional initiation
site. Some occur in introns (Chapter 3, section 3.1) but such regulatory elements
are not necessarily conserved between orthologous genes. Thus, the 83 bp intron
1 of the human
CD68
(17p13) gene contains a macrophage-specific enhancer but
the equivalent intron of the orthologous murine (macrosialin;
Ms
) gene does not
despite ~80% nucleotide sequence homology (Greaves
et al
., 1998).
5.1.5 Bidirectional promoters
There is now a growing list of divergently transcribed gene pairs arranged in
head-to-head fashion separated by a bidirectional promoter. Such an organization
has often but not always arisen through a process of gene duplication followed by
inversion. In true cases of a bidirectional promoter, the gene promoters overlap
and contain common elements that can allow the coordinate regulation of expres-
sion of both genes. Bidirectional promoters are often associated with CpG islands
which therefore serve as useful markers for their location (Brenner
et al
., 1997;
Lavia
et al
., 1987).
Examples of bidirectional promoters are thought to include the human histone
H2A
and
H2B
(1q21-q23) genes (Hentschel and Birnstiel, 1981), type IV collagen
(
COL4A1
and
COL4A2
, 13q34,
Figure 5.2
;
COL4A3
and
COL4A4
, 2q36-q37;
COL4A5
and
COL4A6
, Xq22) genes (Schmidt
et al
., 1993; Oohashi
et al
., 1995),
and the
TAP1
and
LMP2
(6p21.3) genes (Wright
et al
., 1995). These gene pairs
encode proteins that are involved in the same biological processes whether as
components of multi-chain proteins (collagens) or protein complexes (histones)
or as proteins with associated functions (both TAP1 and LMP2 have a role in
antigen processing). This is no coincidence since evolutionarily related pairs of
genes that have arisen by a process of gene duplication/inversion would be pre-
dicted to have similar functions. As a consequence of their mode of creation, they
will often possess the potential for coordinate regulation as long as the promoter
region(s) are still intact and the genes remain closely linked. In principle, the
newly created functional redundancy of the promoter elements (Section 5.1.11)
can be reduced by element removal and subsequent element sharing while still
retaining the potential for coordinate regulation (Section 5.1.14). Alternatively,
