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by exon shuffling (Section 3.6), then novel exon combinations may have been
tested by alternative splicing. If these conferred a selective advantage, then they
could have been fixed by mutation at the appropriate splice junction rendering
them constitutive. Consistent with this view, most alternatively spliced exons
appear to have originated by exon duplication.
There are now several examples of alternative splicing being evolutionarily
conserved in orthologous genes. For instance, exon 9a of the proto-oncogene
MTG8/ETO (
CBFA2T1
; 8q22) is alternatively spliced in both mouse and human
(Wolford and Prochazka 1998). A developmental alternative splicing switch,
involving exon 16 of the erythroid protein 4.1 (
EPB41
; 1p) gene, occurs during
mammalian erythropoiesis and this alternative splice also occurs in
Xenopus
(Winardi
et al
., 1995). The reason for conservation of this switch over 350 Myrs of
evolution probably lies in the fact that it controls the expression of a 21 amino
acid peptide required for the protein's high affinity interactions with spectrin and
actin that help to regulate erythrocyte membrane stability. The alternative splic-
ing of exons 2 and 27 of the neural cell adhesion molecule L1 (
NCAM1
; 11q23-
q24) gene has been conserved in human and the puffer fish (
Fugu rubripes
)
demonstrating evolutionary conservation of the alternative splicing mechanism
over some 430 Myrs (Coutelle
et al
., 1998). In the
-tropomyosin (
TPM1
, 15q22)
gene, alternative splicing to produce tissue-specific isoforms has been conserved
from
Drosophila
to human, corresponding to a timespan of at least 700 Myrs
(Wieczorek
et al
., 1988). Exon 6
of the chromatin condensation regulator gene
(
CHC1
; 1p36.1) is involved in alternative splicing in both humans and hamsters
even though this exon encodes 31 amino acids in human but only 13 in hamster
(a)
Retained intron
(b)
Internal donor site
(c)
Internal acceptor site
TATA
(d)
Alternative promoters
Figure 3.1.
Types of alternative
splicing (redrawn from Li,
1997). Constitutively spliced
exons are denoted by black
boxes and alternatively spliced
exons by shaded boxes.
Splicing patterns are shown by
interrupted diagonal lines.
Alternative promoter and
polyadenylation sites are
denoted by TATA and
AATAAA motifs respectively.
TATA
AATAAA
(e)
Alternative polyadenylation
sites
AATAAA
(f)
Mutually exclusive
(g)
Cassette
