Gross gene rearrangements - Human Gene Evolution - page 402

produced at low cellular levels but would represent a reservoir of novel functions
which could be called upon to confer a selective advantage under particular con-
ditions. In such a situation, it may be envisaged that a point mutation at the
acceptor splice site or polyadenylation site could then lead to the generation of
much larger amounts of the fusion protein. Such a mutation is evident in the
guinea pig gene that encodes seminal vesicle secretory proteins 1, 3, and 4
(Hagstrom et al ., 1996). The 5 half of this guinea pig gene is homologous to the

human semenogelin II ( SEMG2 ; 20q12-q13) gene. Indeed, sequences related to
the human SEMG2 gene are also found in the first intron of the guinea pig gene
(Hagstrom et al ., 1996). However, the 3

half of the guinea pig gene shares homol-
ogy with the closely linked skin-derived antileukoproteinase/elafin ( PI3 ; 20q12-
q13) gene. It would appear that, as a result of an A G transition, the guinea pig

gene contains a novel AG dinucleotide 7 bp upstream of the 3

splice site used in
the SEMG2 gene. If used as a splice acceptor site, this AG dinucleotide would lead
to a spliced product that is out of frame with the product of the SEMG2 gene, and
the use of a splice acceptor site in the downstream PI3 gene would have been
favored (Hagstrom et al ., 1996). Thus an alternative splicing pathway has led to
the creation of a novel guinea pig gene that presumably encodes a protein with a
new function.
In principle, fusion splicing could also lead to the creation of novel genes
through the germline retrotransposition of the fusion mRNA. Such novel fusion
genes would however be expected to be characterized by the absence of introns
(unlike the case of the guinea pig seminal vesicle secretory protein gene cited
above) and to be chromosomally distant from the parental genes. There are at
least two other possible ways of generating novel genes by fusion splicing. The
first would be via trans -splicing (involving the joining of independently tran-
scribed coding sequences from genetically unlinked loci) followed by retrotrans-
position back into the genome. As yet, however, the available evidence for
trans -splicing in mammalian cells must be regarded as somewhat tentative (Eul et
al ., 1995; Fujieda et al ., 1996). The second mechanism would involve the retro-
transposition of abnormally spliced gene transcripts comprising exons joined in
an order different from that in which they are normally found in the genome
( scrambled exons ). Exon scrambling has been described for at least two human
genes: DCC (18q21; Nigro et al ., 1991) and MLL (11q23; Caldas et al ., 1998).

9.4 Recombination

Mankind…will not willingly admit that its destiny can be revealed by the
breeding of flies or the counting of chiasmata.
C. D. Darlington (1960)

9.4.1 Homologous recombination

Numerous recombination events have now been documented as having occurred
during the evolution of mammalian genes. Indeed, most gene duplication and
amplification events have been mediated by recombination (see Chapter 8,
section 8.5). Examples of the emergence of novel human gene sequences by