Biology Reference
In-Depth Information
Splice site differences between orthologous genes.
In an evolutionary
context, gene inactivation is likely to be a relatively rare occurrence and alter-
ations in splice junction sequences are more often to be found associated with
more subtle changes in mRNA processing such as alternative splicing. A number
of examples have been noted in orthologous genes (Chapter 3, section 3.2). Thus,
in the erythroid 5-aminolevulinate synthase (
ALAS1
; 3p21.1) gene, exon 4 is
involved in alternative splicing in the human but not in the dog or mouse
(Conboy
et al.
, 1992). Conversely, the alternative splicing of the 45 bp exon 3 of the
murine
Alas1
gene utilizes a major upstream splice site (85% of mRNAs) and a
minor downstream site (15% of mRNAs). This is not found in human owing to an
A
splice site
thereby preventing the possibility of alternative splicing (Conboy
et al.
, 1992).
Finally, the alternative splicing pathway involving the mutually exclusive exons
6A and 6B of the
G transition which abolishes the consensus sequence of the 3
-tropomyosin (
TPM2
; 9q13) gene differs between chicken, rat
and
Xenopus
(Pret and Fiszman, 1996). The chicken
-tropomyosin exon 6A is
flanked by stronger splicing signals than its rat counterpart and this has been
related to inter-specific differences in both the donor and acceptor splice sites
(Pret and Fiszman, 1996). A chicken-specific pyrimidine-rich splicing enhancer
present upstream of exon 6A may also play a role.
Splice site differences between paralogous genes.
Evidence for splice site
mutations having occurred during evolution has also come from the study of par-
alogous genes. The human glycophorin B (
GYPB
; 4q28.2-q31) gene lacks exon 3
by comparison with the related glycophorin A (
GYPA
; 4q28.2-q31) gene owing to
a G
T transversion at the exon 3 donor splice site (Kudo and Fukuda, 1989).
Comparison with the
GYPB
gene has identified an A
T substitution in the first
base of exon 5 of the
GYPA
gene which leads to the alternative use of an acceptor
splice site 9 bp upstream and the incorporation of nine extra bases into the
GYPA
coding sequence (Kudo and Fukuda, 1989).
The human genes encoding interleukin-1
β
(
IL1B
: 2q13-q21) and interleukin-1 receptor antagonist (
IL1RN
; 2q14.2) are evo-
lutionarily related members of the interleukin family which remain closely linked
on the long arm of chromosome 2. The first exon of
IL1RN
(encoding a leader
peptide) is homologous to the untranslated first exon of
IL1B
but the
IL1RN
gene
lacks the exons corresponding to the first three expressed exons of the
IL1A
and
IL1B
genes. Hughes (1994) suggested that the common ancestor of the
IL1B
and
IL1RN
genes was an alternatively spliced gene: one transcript could have
included exons 1-7 encoding the ancestral IL1B protein whereas the other tran-
script may have included exons 1 and 5-7 encoding the IL1RN protein. The
duplication of this ancestral gene would have freed one copy from functional con-
straints so that it could encode IL1RN only. Selection would no longer have been
able to conserve the intron-exon junctions involved in the splicing of exons 2-4 of
the
IL1RN
gene. Consistent with this view of events, the region of the
IL1B
gene
between exons 1 and 5 is more than twice the length of the analogous region of the
IL1RN
gene.
Finally, the pituitary-expressed growth hormone (
GH1
; 17q22-q24) gene differs
from the closely linked placentally-expressed growth hormone (
GH2
) gene in its
pattern of splice site selection. Whereas 9% of
GH1
mRNA transcripts contain
(
IL1A
; 2q13-q21), interleukin-1
