Biology Reference
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contained CCTGCTG, CCTGGCC and GCTGGCC heptameric repeats. Ohno
(1987) showed that the gene encoding porcine muscarinic acetylcholine receptor
still contains many of these oligomeric repeats. The original heptameric repeats
appear to be more stringently conserved in those portions of the gene encoding
the seven transmembrane domains whereas new repeat units comingle with old
repeats in those portions that encode the extracellular and intra-cytoplasmic
domains.
8.6.5 Intragenic duplicational polymorphisms
Partial internal duplications of genes can also occur as polymorphic variants. A
particularly dramatic example is provided by the human apolipoprotein(a) (
LPA
;
6q27) gene. This gene possesses at least 34 different alleles containing a variable
number (between 12 and 51) of tandemly repeated kringle IV-encoding domains.
Each allele gives rise to a different apolipoprotein(a) isoform thereby explaining
the size polymorphism of the protein: 300-800 kDa (Lackner
et al
., 1993;
reviewed by Scanu and Edelstein, 1995). The
LPA
gene has been described as a
'plasminogen gene gone awry'; an apt description in that the closely linked and
evolutionarily related plasminogen (
PLG
; 6q27) gene encodes a protein with only
5 kringles (Ichinose, 1992; Magnaghi
et al
., 1994). The
LPA
gene is thought to
have arisen between 40 Myrs (McLean
et al
., 1987) and 90 Myrs ago (Pesole
et al
.,
1994) during the adaptive radiation of the mammals. At least ten kringle IV-
encoding domains are present in rhesus macaque suggesting that kringle number
may have expanded progressively during primate evolution (Pesole
et al
., 1994).
Although the
LPA
gene was originally thought to be confined exclusively to pri-
mates, it has also been found in hedgehogs in which it possesses 31 kringle-encod-
ing domains (Lawn
et al
., 1997). Since these are kringle III repeats, we must
surmise that an apolipoprotein(a)-like gene arose independently from a plas-
minogen-like gene in this insectivore (~80 Myrs ago) and experienced a similar
expansion of a subset of its kringle repeats to that found in humans - a remarkable
example of
convergent evolution
. In humans, the
LPA
kringle repeat number poly-
morphism may not be without clinical significance because (i) there is an inverse
relationship between apolipoprotein(a) isoform size and plasma apolipoprotein(a)
levels (van der Hoek
et al
., 1993) and (ii) elevated levels of apolipoprotein(a) are
associated with an increased risk of atherosclerosis and cardiovascular disease
(Byrne and Lawn, 1994).
Several human mucin genes exhibit highly polymorphic tandemly repetitive
regions, for example
MUC1
(1q21; Gengler
et al
., 1990),
MUC2
(11p15; Toribara
et al
., 1991), and
MUC4
(3q29; Nollet
et al
., 1998). Intragenic repeat copy number
polymorphisms are also evident in the human proline-rich protein (
PRH1
;
12p13.2) gene where alleles vary in terms of the number of copies of a 63 bp repeat
in exon 3 (Azen
et al
., 1987; Kim
et al
., 1993) and the complement receptor type 1
(
CR1
; 1q32) gene where the two most common alleles differ in terms of the pres-
ence of a long homologous repeat of ~450 amino acids (Wong
et al
., 1989). Finally,
in the human filaggrin (
FLG
; 1q21) gene, a length polymorphism of 10, 11, or 12
copies of a 972 bp repeat occurs within its polyprotein precursor which is subse-
quently cleaved into individual functional filaggrin molecules (Gan
et al
., 1991).
