Biology Reference
In-Depth Information
In the first case, a 'short' haplotype lacks
AMY1A
,
AMY1B
and the pseudogene
AMYP1
whilst a 'long' haplotype contains two extra copies of a duplicated fragment
containing
AMY1A
,
AMY1B
, and
AMYP1
. In the second case, the three most com-
mon haplotypes were PGA-A (containing the
PGA3
,
PGA4
, and
PGA5
genes),
PGA-B (containing the
PGA3
and
PGA4
genes) and PGA-C (containing only the
PGA4
gene). Copy number polymorphisms due to gene deletions have also been
reported at the human T-cell receptor
(
TCRB
; 7q35) and
(
TCRG
; 7p15) loci
(Ghanem
et al
., 1989; Rowen
et al
., 1996), the
-globin (
HBZ
; 16p13.3) gene (Felice
et al
., 1986), the rhesus blood group D antigen (
RHD
; 1p34-36.2) gene (Colin
et al
.,
1991), the immunoglobulin heavy chain constant region
4 (
IGHG4
; 14q32) gene
(Rabbani
et al
., 1996) and the complement C4A (
C4A
; 6p21.3) and C4B (
C4B
;
6p21.3) genes (Teisberg
et al
., 1988). In some gene clusters, it can be difficult to ascer-
tain whether polymorphic alleles have arisen by gene deletion or duplication; some
examples of human duplicational polymorphisms are given in Section 8.5.
8.2 Microdeletions in evolution
Is it possible to extrapolate from lessons learned through the study of microdele-
tions in a pathological context to microdeletions that have occurred during gene
evolution? In particular, can we gain insight into the nature of the generative
mechanism(s) underlying evolutionarily significant microdeletions and the pos-
sible influence of the local DNA sequence environment? Although in principle
the answer to this question is likely to be in the affirmative, in practice the DNA
sequences that were originally responsible for mediating the microdeletions have
often decayed or been lost and it may not always be possible to reconstruct them.
8.2.1 Microdeletions in pathology
Microdeletions (<20 bp) causing human genetic disease were analyzed by Cooper
and Krawczak (1993) in an attempt to relate the presence of specific DNA
sequence motifs in the vicinity of these lesions to possible mechanisms responsi-
ble for their generation. In many cases, slipped mispairing at the replication fork
between homologous sequences in close proximity to one another on comple-
mentary DNA strands appeared to be the causative mechanism. Slipped mispair-
ing probably occurred either between
direct repeats
or through the formation of
secondary structure intermediates potentiated by the presence of
inverted repeats
or
symmetric elements
(Cooper and Krawczak, 1993; Krawczak and Cooper, 1991).
A consensus sequence, TGRRKM, common to pathological deletion hotspots has
been noted in a number of different human genes (Krawczak and Cooper, 1991).
This
deletion hotspot consensus sequence
is similar to the core motifs, TGGGG and
TGAGC, found in immunoglobulin switch (S
) regions (Gritzmacher, 1989) and
to putative arrest sites for DNA polymerase
(Weaver and DePamphilis, 1982).
Cooper and Krawczak (1993) also found that a second motif (polypyrimidine runs
of at least 5 bp; YYYYY) was over-represented in the vicinity of short human
gene deletions whilst Monnat
et al
. (1992) observed a significant association
between
HPRT1
(Xq26.1) gene deletion breakpoints and CTY vertebrate topoi-
somerase I cleavage sites. In principle, such sequence motifs may also have pro-
moted the occurrence of microdeletions during evolution. Indeed, in probably the
