Biology Reference
In-Depth Information
CYP21P
,
C4A
and
C4B
genes at human chromosome 6p21.3 (Collier
et al
., 1989;
Figueroa, 1997;
Figure 8.10
). Another example of a duplicational polymorphism is
that of three members (one potentially functional) of the olfactory receptor
(
OLFR
) gene family which occur in tandem within a block that is duplicated at 14
different subtelomeric locations in the human genome (Trask
et al
., 1998a). This
results in normal individuals possessing between 7 and 11 copies of this block in
their genomes. Trask
et al
. (1998a) suggested that sub-telomeric regions could
serve as 'nurseries' for the generation of diversity by promoting gene duplication.
Other gross duplicational polymorphisms are found in the immunoglobulin V
H
gene cluster (
IGHV
; 14q32): one of 50 kb in length is present in 73% of individu-
als and results in the gain of 5 functional V
H
segments (Walter
et al
., 1993;
Willems van Dijk
et al
., 1992) whilst another of length ~80 kb is present in ~50%
of individuals and involves the gain/loss of two functional V
H
segments (Cook
et
al
., 1994). A third such polymorphism involving only a single additional V
H
seg-
ment has been reported to occur in 27% of individuals (Cook and Tomlinson,
1995). A duplicational polymorphism is also apparent in the C
H
gene cluster: the
IGHG4
gene (14q32) is duplicated in 44% of haplotypes (Brusco
et al
., 1997).
Finally, the partial duplication of the GABA A receptor
5 (
GABRA5
) gene is
polymorphic in that individuals differ with respect to gene copy number (Ritchie
et al
., 1998).
8.6 Intragenic gene duplications in evolution
Numerous examples of human genes have now come to light in which the
encoded proteins have emerged through the introduction of individual exons or
blocks of exons. Some of these exons encode specific protein domains (e.g. zinc
finger, homeobox, immunoglobulin-like, epidermal growth factor-like,
fibronectin, ABC cassette, Sushi, ankyrin, chymotrypsin etc; Doolittle, 1995;
Henikoff
et al
., 1997) which have come to be distributed between a large number
of different proteins through
exon shuffling
(Chapter 3, section 3.6.1). Protein evo-
lution may however also involve the internal duplication or amplification of indi-
vidual exons, blocks of exons or alternatively repetitive sequence motifs within
exons. Some typical examples of such intragenic duplication events are explored
below.
8.6.1 Multi-exon duplications
Some genes encode proteins that comprise two homologous domains and are
therefore likely to have originated through a gross internal duplication. Thus, the
17 exon human transferrin (
TF
; 3q21) gene is thought to have originated by an
internal duplication which may have resulted from an unequal crossing over event
(Park
et al
., 1985;
Figure 8.11
). Similarly, the human angiotensin I converting
enzyme is encoded by a gene (
DCP1
; 17q23) which comprises 26 exons that
encode two homologous domains each containing an active site. Exon number and
size in the
DCP1
gene are consistent with an ancient internal duplication, as are
the codon phases at the exon-intron boundaries (Hubert
et al
., 1991). An ancient
