Biology Reference
In-Depth Information
The human surfeit 2 and 4 (
SURF2
,
SURF4
; 9q34.1) genes differ from their
murine counterparts in that whilst the mouse genes overlap by 133 bp in their 3
UTRs, the human genes are separated by 302 bp (Duhig
et al
., 1998). The human
SURF2
gene contains two alternative polyadenylation sites resulting in short 3
UTRs of 17 and 25 bp whereas the mouse
Surf2
gene contains a 359 bp 3
UTR.
The much shorter human
SURF2
3
UTR probably accounts for the absence of
overlap with the human
SURF4
gene.
One example of the emergence of a functional difference between the 3
UTRs
of two paralogous human genes is provided by the
-globin (
HBA1
; 16p13.3) and
-globin (
HBZ
; 16p13.3) genes (Russell
et al
., 1998). The
HBA1
and
HBZ
genes
are coexpressed in the embryonic yolk sac. A switch to exclusive expression of the
HBA1
gene in the fetus and adult involves the developmental silencing of the
HBZ
gene. Silencing is achieved both by transcriptional control but also through
a post-transcriptional mechanism that serves to reduce the relative stability of
HBZ
mRNA. The
HBA1
and
HBZ
genes both assemble an mRNP stability-
determining complex on their 3
UTRs but these complexes form with different
affinities on the two genes. The diminished efficiency of complex assembly on the
HBZ
3
G transversion in a polypyrimidine tract that is
common to both genes. This substitution is associated with a shortened poly(A)
tail on the
HBZ
mRNA that may mediate accelerated
HBZ
mRNA decay.
Another example of a functional difference between the 3
UTR results from a C
UTRs of evolution-
arily related human genes is provided by the human alcohol dehydrogenase
(
ADH2
; 4q22) gene which differs from the other paralogous
ADH
family mem-
bers by virtue of a T
to
the gene. This substitution appears to be at least in part responsible for the use of
alternative polyadenylation sites leading to the formation of multiple
ADH2
mRNAs (Trezise
et al
., 1989).
Alterations in the 5
C transition within a canonical polyadenylation site 3
UTR may also influence the expression pathway. For
example, the efficiency of mRNA translation of the renal ornithine decarboxylase
(
Odc
) gene is significantly lower in
Mus pahari
as compared to
Mus domesticus
(Johannes and Berger, 1992). This is thought to be due to the acquisition of sev-
eral single nucleotide substitutions and a 12 bp deletion in the 5
UTR of the
Odc
gene in
M. pahari
. These sequence changes are predicted to alter the secondary
structure of the mRNA molecule and this may influence translation efficiency.
5.1.7 Inter-specific differences in promoter selection
Three distinct mRNA species (L1, M and L2 respectively) are generated from the
human aldolase A (
ALDOA
; 16q22-q24) gene via the differential incorporation of
three exons encoding the 5
UTR (Mukai
et al
., 1991;
Figure 5.3
). The production
of the three mRNAs is controlled by three different promoters (
Figure 5.3
) which
are utilized singly, doubly or all together depending upon the expressing tissue.
The DNA sequences corresponding to these promoters are present in the rat gene
but the L1 promoter is not utilized (Mukai
et al
., 1991). Thus the L1 promoter has
either been acquired in the human lineage or, (perhaps more likely) lost in the rat
lineage since the divergence of primates and rodents.
The vast majority of studies that have mapped transcriptional initiation sites
have been performed on cultured cells and it is by no means clear that those sites
