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within introns have also been characterized, for example in the first introns of the
human Bruton's tyrosine kinase (
BTK
; Xq21.3-q22; Rohrer and Conley, 1998) and
acid maltase (
GAA
; 17q25.2-q25.3; Raben
et al
., 1996) genes. A highly conserved
CCAAT element within intron 1 of the proliferating cell nuclear antigen (
PCNA
;
20p12) gene also appears to act as a negative regulatory element (Alder
et al
., 1992).
Other sequences within introns may affect nucleosome formation (Denisov
et
al
., 1997), or play a regulatory role in the processing of the primary transcript
either by modulating mRNA splicing or by influencing mRNA stability through
RNA-DNA, RNA-RNA or RNA-protein interactions (Mattick, 1994). For exam-
ple, sequences within the second intron of the human
-globin (
HBB
; 11p15.5)
gene are important in promoting efficient 3
end formation and appear to be
essential to the stability of the cytoplasmic
HBB
mRNA (Antoniou
et al
., 1998). A
further fortuitous function of introns may be to act as 'lightning conductors' for
the retrotranspositional insertion of mobile elements thereby protecting the
nearby coding sequences from inactivation (Ferlini and Muntoni 1998). A
glimpse of what surprises introns may have in store for us is to be found within
the introns of the human U22 host gene. Seven fibrillarin-associated small nucle-
olar RNAs (U25-U31), with complementarity to different segments of rRNA, are
encoded within different introns of this gene and are highly conserved between
human and mouse (Tycowski
et al
., 1996). The spliced U22 host gene mRNA
species has by contrast little coding potential, is short lived and is evolutionarily
poorly conserved. The surprise therefore is that in the U22 host gene, it is the
'introns' rather than the 'exons' which appear to specify the functional products.
3.2 The evolution of alternative processing
3.2.1 Alternative splicing
Alternative splicing allows the generation of different mRNAs (and therefore a
diverse array of protein isoforms) from the same gene (
Figure 3.1
). It is therefore an
important mechanism for the tissue-specific or developmental regulation of gene
expression. The potential evolutionary advantages of alternative splicing have
been discussed in detail by Smith
et al
. (1989) and hence will now only be summa-
rized briefly. Unlike gene duplication or rearrangement, alternative splicing does
not change the gene structure or copy number and need not therefore be irre-
versible in genetic terms. Since existing splicing pathways need not necessarily be
discarded in order to employ new ones, alternative splicing is likely to be particu-
larly useful as a means to generate protein diversity during early development and
in very long lived and terminally differentiated cells. The use of alternative splic-
ing may also facilitate the efficient exploitation of intragenic duplications since if
the transcript of the newly duplicated gene were to be alternatively spliced, the
gene could continue to produce the old gene product as well as the new one.
Although alternative splicing implies the existence of cell and developmental
stage-specific splicing factors, it is still unclear whether it is a predecessor or a
refinement of constitutive splicing. Smith
et al
. (1989) argued that the two
processes could have evolved simultaneously. If, indeed, many genes have evolved
