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evolution. One consequence of this fusion process would be the frequent occur-
rence of methionine-encoding ATG triplets at the borders between unit length
sequence segments, a prediction which has been bourne out by statistical analysis
(Kolker and Trifonov, 1995). This positional preference of methionines testifies to
the excision-reinsertion mechanism of protein construction and means that these
internal methionines can justifiably be termed the 'fossils of gene fusion.'
Further, it illustrates the probable importance of gene fusion events in the evolu-
tionary construction of extant gene sequences.
9.3.3 Fusion gene polymorphisms
Some fusion genes occur in the human genome as polymorphic variants. One
example is the red and green visual pigment genes (
RCP
,
GCP
; Xq28). Normal
human males with trichromatic vision typically possess one
RCP
gene, one, two
or more
GCP
genes plus an
RCP
/
GCP
hybrid gene (
Figure 9.6
; Neitz
et al
., 1995;
see Chapter 7 section 7.5.2,
The visual pigments
). In some individuals, the
RCP
genes contain a substantial amount of
GCP
sequence e.g. exon 4 of the
GCP
gene
(individuals 23, 26, 03, 27, and 21 in
Figure 9.6
). Other individuals possess
RCP
genes that contain 5
sequences derived from
GCP
genes (individuals 07, 09, 14,
25, 06, 22, 20, 04, 08, 19, 18, 01 in
Figure 9.6
). The degree of polymorphism is dra-
matic in that ~70% of individuals with normal trichromatic color vision possess
one or other type of fusion gene (
Figure 9.6
). Other gene fusions have occurred as
a result of unequal homologous crossing over to generate polymorphic variants in
the MNS (
GYPA
; 4q31; Huang and Blumenfeld, 1991) and ABO blood group sys-
tems (
ABO
; 9q; Olsson
et al
., 1997).
9.3.4 Fusion splicing
Although gene fusion can arise through deletion or translocation, it need not
invariably occur as a result of DNA rearrangement. Gene fusion can, in functional
terms, also be brought about by the
fusion splicing
of mRNA transcripts derived
from two closely linked but unrelated genes. Evidence for such a mechanism has
come from the cotranscription of two human genes encoding galactose-1-phos-
phate uridylyl-transferase (
GALT
) and interleukin-11 receptor
-chain (
IL11RA
)
which are closely linked (separated by only 4 kb) on chromosome 9p13
(Magrangeas
et al
., 1998). GALT is a 43 kDa enzyme required for the conversion
of galactose to glucose and is encoded by a gene which comprises 11 exons span-
ning 4 kb and which specifies a 1.4 kb mRNA. The
IL11RA
gene, a member of the
hematopoietin receptor superfamily, comprises 13 exons spanning 8 kb and
encodes a 48 kDa protein. Magrangeas
et al
. (1998) demonstrated that the two
genes are sometimes cotranscribed in normal human cells and that the 3 kb fusion
mRNA encodes an 85 kDa protein of unknown function and biological signifi-
cance. The in-frame fusion transcript probably results from a combination of
inefficient RNA polymerase II termination of
GALT
gene transcription and an
alternative splicing event between exon 10 of the
GALT
gene and exon 2 of the
IL11RA
gene.
Magrangeas
et al
. (1998) speculated that fusion splicing could represent an
'exploratory event for evolution'; fusion proteins thus formed might initially be
