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therefore have been free to pass through a nonfunctional state in which several
base changes accumulated, resulting eventually in a change in splicing phenotype.
Whether selection or genetic drift could have been responsible was unclear.
Unfortunately in this context, the authors did not see fit to discuss the intron
phase of the added/removed exons.
Evidence for intergenic differences in alternative splicing during evolution has
also come from the study of paralogous genes. Although the intron-exon distribu-
tion in the human annexin VI (
ANX6
; 5q32-q34) gene conforms exactly to that
found in the human annexin I (
ANX1
; 9q11-q22) and II (
ANX2
; 15q21-q22)
genes, exon 21 of the annexin VI gene (encoding 6 amino acids) is alternatively
spliced (Smith
et al
., 1994). Similarly, the human chloride channel gene
CLCN6
(1p36) contains an alternatively spliced 167 bp exon that is absent in the evolu-
tionarily related
CLCN1
(7q32-qter),
CLCN5
(Xp) and
CLCN7
(16p13) genes
(Eggermont 1998). The genetic basis of these examples of gene-specific alternative
splicing has however not yet been elucidated. Known examples of single base-pair
substitutions in paralogous genes responsible for the emergence of alternative
splicing are discussed in Chapter 7, section 7.5.3.
Alternative processing may become redundant after gene duplication as exem-
plified by the troponin I gene which encodes one of the three subunits of the tro-
ponin complex of the thin filaments of vertebrate striated muscle. Invertebrates
and ascidians possess a single troponin I gene (Hastings, 1997) and this is alter-
natively spliced to generate proteins that differ in their N-terminal regions. By
contrast, the three troponin I genes in the human genome (
TNNI1
, 1q31;
TNNI2
,
11p15;
TNNI3
, 19q13) and in the genomes of other vertebrates do not undergo
alternative splicing although the 'extra' exon in the
TNNI3
gene (as compared
with the
TNNI1
and
TNNI2
genes) is thought to correspond to the exon which is
alternatively spliced in ascidians and invertebrates (Hastings, 1997).
A database of alternatively spliced genes (ASDB) is available online at
http://cbcg.nersc.gov/asdb
and contains information about alternatively spliced
genes in different organisms and in different tissues.
Alternative transcripts may also be generated by the differential utilization of
polyadenylation sites (
Figure 3.1
). The differential utilization of two distinct
polyadenylation sites in the plasminogen activator inhibitor 1 (
PAI1
; 7q22) gene
(yielding two mRNA species of 2.6 kb and 3.6 kb) has been conserved between
humans, orangutans and African green monkeys (Cicila
et al
., 1989). However,
only one
PAI1
mRNA species is apparent in lower primates and nonprimate
mammals (Cicila
et al
., 1989) consistent with the acquisition of an extra
polyadenylation site during primate evolution. The evolution of alternative pro-
cessing may have come about through the differential utilization of polyadenyla-
tion sites via the newly described mechanism of LINE element-mediated
recombination described in Section 3.6.1). Finally, alternative transcripts may
also arise through alternative promoter usage. There is very little information on
inter-specific differences in promoter site selection: the example of the insulin-
like growth factor II gene is cited in Section 3.7.
Herbert and Rich (1999) have stressed the potential importance of RNA process-
ing in evolutionary processes. Their perspective, which deserves close examination,
was elegantly summarized in one of their introductory paragraphs:
