Biology Reference
In-Depth Information
5.1.10 Promoter duplication
Promoters may occasionally be duplicated in the absence of the duplication of
their associated genes. Thus the BRCA1 (17q21) and 1A1.3b ( M17S2 ; 17q21.1)
gene promoters are duplicated in tandem fashion (Barker et al ., 1996) but the
functional significance of this observation is unknown.
Two copies of a motif known as the hepatic control region (HCR), located,
respectively, 15 kb and 5 kb downstream of the human APOE and APOC1 genes
on chromosome 19q13.2, arose by a regional duplication event which encom-
passed the APOC1 gene ~40 Myrs ago (Raisonnier et al ., 1991; Figure 5.5 ). Whilst
the duplicated APOC1 gene has become a pseudogene ( APOC1P1 ), the dupli-
cated HCR (HCR2) has retained 85% homology with HCR1 and appears to be able
in its new location to direct the transcription (albeit infrequent transcription) of
a sequence resembling an exon which is spliced to APOC4 5
exons even in the
absence of conventional promoter elements (Allan et al ., 1995).
5.1.11 Functional redundancy of promoter elements
The human 7SK RNA gene ( RN7SK ; chromosome 6) contains a proximal
sequence element (PSE) between
49 and
65 and a distal sequence element
(DSE) between
210 which display sequence similarity and functional
homology (Boyd et al ., 1995). The PSE can retain function after extensive muta-
tion but only if the DSE is intact. How this apparent functional redundancy has
been maintained is unclear.
The promoter of the human
243 and
-globin ( HBE1 ; 11p15.5) gene displays functional
redundancy of a different type; it contains eight YY1 binding sites, five binding
sites for a putative stage selector protein and seven binding sites for a hitherto
unidentified protein (Gumucio et al ., 1993). Other probable examples of functional
redundancy include the eight SP1 sites present in the human muscle phospho-
fructokinase ( PFKM ; 12q13.3) gene promoter (Johnson and McLachlan, 1994).
Without detailed functional studies, however, it is unclear if the multiple cis -acting
regulatory elements are truly redundant or if each additional copy leads to an
incremental increase in transcription factor binding potential and hence promoter
strength.
5.1.12 Recruitment of repetitive sequences as promoter and silencer
elements
Alu sequences. A number of examples of the recruitment of repetitive sequence
elements, mostly Alu sequences, as gene promoter and silencer elements have
been studied (reviewed by Britten, 1996; 1997; Robins and Samuelson, 1992;
Table 5.1). Over evolutionary time, the insertion of Alu repetitive sequence ele-
ments in the vicinity of genes has served to introduce different motifs that have
altered the expression level or tissue specificity of the associated gene either
immediately or after subsequent fine tuning by natural selection. One such motif
is a retinoic acid response element (RARE) in the human KRT18 (12q13) gene:
three hexamer half sites, related to the consensus AGGTCA, arranged as direct
repeats with a spacing of 2 bp (Vansant and Reynolds, 1995). These sites are
 
 
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