Biology Reference
In-Depth Information
1991), the composite
EPRS
gene would appear to represent the consequence of an
ancient gene fusion.
The human quiescin Q6 (
QSCN6
; 1q24) gene also appears to represent the prod-
uct of an ancient gene fusion that occurred during metazoan evolution (Coppock
et
al
., 1998). The N-terminal portion of the quiescin Q6 protein is related to the
thioredoxin family (human members include thioredoxin (
TXN
; 9q31) and prolyl-
4 hydroxylase
polypeptide (
P4HB
; 17q25)) whilst the C-terminal is related to the
yeast
Erv1
growth regulatory gene (human homologue,
GFER
, 16p13).
The human lamin B receptor is an integral protein of the inner nuclear mem-
brane encoded by a gene (
LBR
) on chromosome 1q42.1. The
LBR
gene comprises
13 protein coding exons, the first four of which encode the N-terminal domain
and the remainder the C-terminal sterol reductase-like domain (Holmer
et al
.,
1998). A relatively large intron separating exons 4 and 5 is suggestive of an ancient
recombination between two genes, one encoding a basic nuclear protein, the other
a sterol reductase. Consistent with this interpretation, the 3
end of the
LBR
gene
is structurally homologous with two other human genes viz. the transmembrane
protein TM7SF2 (
TM7SF2
; 11q13) and 7-dehydrocholesterol reductase
(
DHCR7
; 11q13) (Holmer
et al
., 1998).
A highly unusual example of gene fusion is provided by the human
HLA-
DRB6
(6p21.3) gene. This gene had represented something of a paradox in that
although both exon 1 and the promoter region are absent in the orthologous
human, chimpanzee and rhesus macaque genes, these genes are still capable of
being transcribed. This apparent paradox has now been resolved by the elucida-
tion of the molecular basis of the change: the insertion of a retroviral (mouse
mammary tumor virus) LTR into intron 1 of the primate
HLA-DRB6
gene >23
Myrs ago, prior to the divergence of the Old World monkeys from the human-ape
lineage (Mayer
et al
., 1993; see Chapter 5, section 5.1.12,
Endogenous retroviral ele-
ments
). Whether the exon/promoter deletion accompanied or instead followed the
LTR insertion is unclear. What is clear is that an open reading frame for a new
exon was created by the insertion which serendipitously encoded a hydrophobic
sequence that was able to function as a leader for the truncated
HLA-DRB6
pro-
tein. The new exon provided a functional donor splice site at its 3
end which
potentiated in-register splicing with exon 2 of the
HLA-DRB6
gene. The LTR
also provided a substitute promoter region essential for the transcription of the
downstream gene. Thus, this case not only provides an example of the
de novo
cre-
ation of an exon but also illustrates a potential evolutionary mechanism to retar-
get proteins within the cell. The incorporation of a novel leader peptide into, for
example, a cytoplasmic protein that previously lacked one could result either in
an alteration in the cellular localization of the protein or its conversion into a
secreted protein.
The mammalian defensins constitute a family of microbicidal and cytotoxic pep-
tides made by neutrophils. In humans, they are encoded by a gene cluster (
DEFA1
,
DEFA3
,
DEFA4
,
DEFA5
,
DEFA6
,
DEFB1
) at chromosome 8p23 (Bevins
et al
.,
1996; Liu
et al
., 1997). After a primordial defensin gene had duplicated to yield two
genes ancestral to extant
DEFA5
and
DEFA6
, an unequal crossing over event gen-
erated a novel hybrid defensin gene which was the ancestor of the present day
hematopoietic defensin genes
DEFA1
,
DEFA3
,
DEFA4
(
Figure 9.5
).
