Gross gene rearrangements - Human Gene Evolution - page 389

duplicate of cluster A, comprises ZNF11B , ZNF33B, and ZNF37B and is located
on chromosome 10q11.2. Duplicated gene clusters are usually contiguous but these
ZNF clusters are located on opposite sides of the centromere consistent with their
involvement in a pericentric inversion subsequent to the duplication. Tunnacliffe
et al . (1993) proposed that this event took place during primate evolution.
The human genes encoding NADP-dependent malate dehydrogenase ( ME1 ;
6q12), glutathione S -transferase 2 ( GSTA2 ; 6p12) and phosphoglucomutase 3
( PGM3 ; 6p12) form part of a chromosome 9 syntenic group in mouse (Kasahara
et al ., 1990). The extension of this syntenic group across the centromere of chro-
mosome 6 in human is indicative of a pericentric inversion which must have
occurred since the divergence of rodents and humans. Other examples of inferred
pericentric inversions that have occurred during primate evolution involve the -

casein ( CSN2 ; 4q13-q21; McConkey et al ., 1996) gene, the GLI oncogene on chro-
mosome 12q13 (Conte et al ., 1998), the fibroblast growth factor genes FGF3 and
FGF4 on chromosome 11q13 (Conte et al ., 1998) and the steroid sulfatase
pseudogene ( STSP ; Yq11; Yen et al ., 1988). Finally, a Y-specific pericentric inver-
sion occurs as a polymorphism among Gujarati Indians (Spurdle and Jenkins,
1992).
Pericentromeric regions appear to be particularly prone to rearrangement
(Eichler, 1998) and this genetic instability could be related to the presence of spe-
cific repetitive sequences (Wöhr et al ., 1996).

9.1.2 Paracentric inversions

An example of a human-specific paracentric inversion is that involving the short
arm of the Y chromosome (Schwartz et al ., 1998). A single contiguous segment of
Xq21 is homologous to two noncontiguous segments of Yp and it is likely that the
transposition of a ~4 Mb segment from the X to the Y chromosome ~3-4 Myrs
ago after the divergence of human from chimpanzee was followed by an inversion
of the sequence. Schwartz et al . (1998) suggested that this inversion could have
been mediated by recombination between two LINE elements misaligned at
homologous CATTATTCT motifs. Since humans from different racial groups
(Caucasian, African, and Asian) have all been found to possess this Yp inversion,
the rearrangement must have occurred prior to the radiation of the human racial
groups.
Another rather different type of paracentric inversion is exemplified by the
Xq28 inversion polymorphism involving the Emery-Dreyfuss muscular dystro-
phy ( EMD ) and filamin ( FLN1 ) genes. Recombination between two large 11.3 kb
inverted repeats (with >99% sequence homology) flanking these genes has been
responsible for a frequent and clinically asymptomatic inversion of the 48 kb
FLN1 / EMD region (Small et al ., 1997; see Figure 9.1 ). The inversion polymor-
phism may have resulted either from inter- or intra-chromatid exchange between
misaligned repeats. Whichever, it is very common in the general population
occurring in the heterozygous state in 33% of females and 19% of males (18% of
human X chromosomes surveyed).
Other regionally localized paracentric inversions may be inferred from the
presence of long inverted repeat regions containing homologous but divergently
transcribed genes. Examples of this include the

-amylase ( AMY1A and AMY1B ;