Biology Reference
In-Depth Information
Te
l o m
e r e
FLN1
EMD
Proximal repeat
48
30 27 22
10
3
1
1
6
Distal repeat
Figure 9.1.
Structure of the Xq28 region containing the human emerin (
EMD
) and
filamin (
FLN1
) gene loci (from Small
et al.,
1997). The exons of the
EMD
and
FLN1
genes are indicated by black boxes, some of which are numbered for orientation. The
direction of transcription for each gene is indicated by small arrows below. The thick
black arrows represent the 11.3 kb inverted repeats. The black circle represents the
centromere and the position of the telomere is indicated.
1p21; Groot
et al
., 1990) and the
-fibrinogen (
FGB
and
FGG
; 4q31; Kant
et al
., 1985) genes. Genes which are divergently transcribed, evolutionarily related
and which share bidirectional promoters (see Chapter 5, section 5.1.5) are likely
to have arisen by a process of duplication and inversion. Other genes have clearly
evolved by this same process but are almost certainly too far apart to share pro-
moter elements, for example the serum amyloid A1 and A2 genes (
SAA1
,
SAA2
;
15-20 kb apart on chromosome 11p15) and the GABA receptor
- and
3 and
5 genes
(
GABRB3
,
GABRA5
; 100 kb apart on chromosome 15q11-q12).
9.1.3 Physiological and pathological inversions
Somatic inversions, both relatively small and rather larger involving megabase-
sized DNA fragments, occur physiologically during rearrangement of DNA at the
immunoglobulin
(
TCRB
; 7q35) loci in
human (Weichhold
et al
., 1990). In human pathology, sporadic chromosomal
inversions are not uncommon although each type of inversion is likely to be indi-
vidually rare. By contrast, intragenic DNA sequence inversions, occurring as a
result of recombination between inverted repeats in the germline, are highly
unusual. The best known example is that found in the factor VIII (
F8C
) gene
causing hemophilia A: this rearrangement occurs in about 40% of severely
affected patients and recurs at high frequency (Lakich
et al
., 1993; Naylor
et al
.,
1993). The mechanism responsible is thought to be homologous intrachromoso-
mal recombination between a gene (
F8A
) located in intron 22 of the
F8C
gene and
one of two additional homologues of the
F8A
gene situated 500 kb upstream of the
F8C
gene.
(
IGKV
; 2p12) and T cell receptor
9.1.4 Intragenic inversions
Not surprisingly, intragenic inversions occurring during gene evolution are
extremely uncommon. One example is however provided by the family of inter-
-
trypsin inhibitors encoded by four genes in the human genome (
ITIH1
,
ITIH3
,
ITIH4
, 3p21;
ITIH2
, 10p14-p15). The ancestral
ITIH
gene was first duplicated
with one copy being translocated to chromosome 10 about 300 Myrs ago (Diarra-
Mehrpour
et al.
, 1998). Prior to further gene duplication and divergence, the pri-
mordial
ITIH1/ITIH3/ITIH4
gene experienced an inversion of exons 3-13.
