Promoters and transcription factors - Human Gene Evolution - page 244

acquiring different promoters (Adey et al ., 1994a). These regulatory sequences
may then confer a novel specificity of expression upon genes with which they
become associated. Thus, a LINE element at position

800 in the human factor
IX ( F9 ; Xq27.1-q27.2) gene promoter has been implicated in conferring high
level liver-specific expression on the F9 gene (Kurachi et al ., 1997). An enhancer
some 20 kb 5 to the apolipoprotein(a) gene ( LPA ; 6q27) which contains binding

sites for Ets and Sp1 transcription factors, also resides within a LINE element
(Yang et al ., 1998).
The polyadenylation signal of the murine thymidylate synthase ( Tyms ) gene has
been derived from an inserted LINE element (Harendez and Johnson, 1990).
Similarly, the polyadenylation sites of several human genes including the -tubu-

lin ( TUBB ; 6p21.3) gene have been derived from MIR elements, mammalian
wide interspersed repeats (Murnane and Morales, 1995).
As we have seen (Chapter 1, section 1.4.3), only a proportion of LINE elements
are transpositionally active, the remainder having been inactivated by truncation
and rearrangement. Adey et al . (1994b) performed phylogenetic analysis to deduce
the sequence of an ancestral murine transpositionally active LINE element. This
element was then 'resurrected' by chemical synthesis and shown in vitro to possess
promoter activity.

Minisatellites and microsatellites. Several minisatellites are known to have
become recruited as gene regulatory elements. These include minisatellites 1 kb
3

to the polyadenylation signal of the human HRAS proto-oncogene (11p15.5; 28
bp repeat unit; Green and Krontiris 1993), 600 bp 5 of the transcriptional initia-

tion site of the human insulin ( INS ; 11p15.5; 14 bp repeat unit; Catigani-
Kennedy et al ., 1995) gene and 4.1 kb upstream of the human insulin-like growth
factor II ( IGF2 ; 11p15; Paquette et al ., 1998) gene, and the minisatellite in the
D H /J H intron of the human immunoglobulin heavy chain ( IGHD / IGHJ ;
14q32.33) gene cluster (Treppicchio and Krontiris, 1992). The HRAS minisatel-
lite binds members of the rel /NF B family (Treppicchio and Krontiris, 1993)

whilst the INS minisatellite binds the transcription factor Pur-1 (Kennedy et al .,
1995). The IGHD / IGHJ minisatellite binds a mycHLH protein closely related to
USF/MLTF (Treppicchio and Krontiris, 1992). This element may influence
IGHD / IGHJ gene expression since sequestration of the transcription factor by
the minisatellite inhibits transcriptional activation through a bone fide USF
enhancer element. Since the HRAS , INS and IGHD / IGHJ minisatellites are
absent from the analogous positions in orthologous non-primate genes, it would
appear that evolution has recruited these elements during primate evolution.
Such minisatellites may have provided the raw material for promoter and
enhancer sequences which have then been optimized by selection. Alternatively,
if transcriptional effects emanating from these sequences are comparatively
minor, selection would probably have been unable either to improve or remove
them and they would have remained as transcriptional control elements with
minor effect.
Microsatellites can also serve as regulatory elements and indeed some are con-
served at orthologous positions in the genomes of different species (Meyer et al .,
1995; Moore et al ., 1991; Stallings, 1994, 1995; Stallings et al ., 1991). One example