Biology Reference
In-Depth Information
the recipient proteins. One of the first examples of exon shuffling to be recognized
was from the human low density lipoprotein receptor (
LDLR
; 19p13.3) gene which
contains eight contiguous exons encoding epidermal growth factor (EGF)-like
domains as well as seven repeats corresponding to LDL-binding domains (Südhof
et al
., 1985a,b). Other examples include the human hemopexin (
HPX
; 11p15.4-
p15.5) gene which contains 10 exons each of which encodes a 45 amino acid repeat
(Altruda
et al
., 1988) and the human factor XIII b subunit (
F13B
; 1q31-q32;
Bottenus
et al
., 1990) gene which encodes a protein with ten 60 amino acid comple-
ment B-type ('sushi') domains each encoded by a single exon. A large number of
other human genes possess multiple copies of exons encoding specific domains.
These encode proteins of the extracellular matrix (e.g. laminins, collagens), the ser-
ine proteases of coagulation (see Section 3.6.3), a variety of receptors (e.g. integrins)
and the immunoglobulins among many others (reviewed by Patthy, 1996). Exon
shuffling is therefore a widely used evolutionary strategy although it appears to be
confined to the genes of higher eukaryotes.
Until recently, exon shuffling was considered to result solely from intron-medi-
ated recombination (Patthy, 1995; Strelets and Lim, 1995). However, an alterna-
tive mechanism,
LINE element-mediated recombination
, now appears to be capable
of linking previously unlinked genomic DNA segments and may represent a
novel means to bring about exon shuffling. Moran
et al
. (1999) have shown that
LINE elements are capable of transducing exons from a downstream gene to new
genomic locations thereby creating novel genetic combinations. This mechanism
requires readthrough of the relatively weak LINE element polyadenylation signal
by RNA polymerase to yield a processed mRNA transcript containing the LINE
element fused to one or more exons from the neighboring gene. Readthrough is
made possible by the presence of more potent polyadenylation signals 3
to the
LINE element and Moran
et al
. (1999) have shown that this can occur with high
efficiency. The chimeric transcript then serves as a template for reverse transcrip-
tase and if the resulting cDNA is subsequently integrated into the intron of a
recipient gene, it may be recruited by that gene. This may help to explain why 3
terminal exons are often much longer than internal exons (Hawkins, 1988).
Inefficient mRNA cleavage/polyadenylation might however lead to alternative
splicing (Section 3.2). A possible example of this process occurred about 10 Myrs
ago during the evolution of the great apes: the co-transduction and integration of
a LINE element and a fragment containing exon 9 of the cystic fibrosis trans-
membrane conductance regulator (
CFTR
; 7q31) gene (Rozmahel
et al
., 1997).
Since some 6% of LINE element insertions occur within genes (Moran
et al
.,
1999), it could be that this mechanism has played an important role in shuffling
exons between genes, and may therefore have been central to the creation of the
mosaic structures characteristic of so many genes in higher animals.
3.6.2 The phase compatibility of introns
Only a limited proportion of exons can be utilized for exon shuffling since the
splice junctions of the shuffled exon must be phase compatible with their flank-
ing exons in order to maintain the reading frame. As we have seen in Chapter 1,
section 1.2.1, introns are classified as phase 0 if the intron lies between two