Promoters and transcription factors - Human Gene Evolution - page 235

near highly conserved sequence motifs. It may be some time before the precise
sequence changes responsible for the change to fetal expression are unequivocally
determined.
One way of approaching this question has been through the use of 'differential
phylogenetic footprinting' (Section 5.1.1) and gel retardation analysis. By these
means, Gumucio et al . (1994) identified several proteins (G1, G2, G3, and G4) that
bound the galago sequence but did not bind the corresponding human sequence.
Phylogenetic reconstruction and gel retardation analysis were used to demon-
strate that the promoter sequence of the embryonically expressed

-globin gene of
the primate common ancestor would have bound proteins G1 and G2 some 4-6-
fold more strongly than the promoter of the fetally expressed simian ancestor
(Gumucio et al ., 1994). The binding strength of these proteins correlated with
repression of promoter activity in vitro , suggesting that the loss of the binding sites
for these proteins in the ancestral simian -globin gene could have potentiated the

conversion of this gene to a fetal onset of expression (Gumucio et al ., 1994).

5.1.9 Promoter polymorphisms

Promoter polymorphisms affecting the expression of the downstream gene are
probably not infrequent. However, as yet, relatively few examples of promoter
polymorphisms in human genes have been properly characterized by means of
functional (e.g. reporter gene) studies. Examples of such polymorphisms include
plasminogen activator inhibitor type 1 ( PAI1, 7q21.3-q22.1; Dawson et al ., 1993),
tumor necrosis factor ( TNF ; 6p21.3; Wilson et al ., 1997), apolipoprotein AI

( APOA1, 11q23.3; Angotti et al ., 1994), lipoprotein(a) ( LPA, 6q27; Suzuki et al .,
1997; Wade et al ., 1993), lipoprotein lipase ( LPL ; 8p22; Hall et al ., 1997), inter-
leukin 6 ( IL6 , 7p21-p15; Fishman et al ., 1998), factor VII ( F7 ; 13q34; Pollak et al .,
1996), hormone-sensitive lipase ( LIPE ; 19q13; Talmud et al ., 1998) and
monoamine oxidase A ( MAOA , Xp11.23; Sabol et al ., 1998). The presence of poly-
morphisms in gene promoter regions is not unusual per se since all gene regions
harbor polymorphisms. Indeed, such variants are quite consistent with, and
explicable in terms of, a neutralist model. However, it is possible that those poly-
morphisms in the promoter region which specifically affect gene expression con-
fer, or have conferred, a selective advantage.
The PAI1 promoter polymorphism constitutes the insertion or deletion of a
single G residue at position 675 (Dawson et al ., 1993). The ins allele contains an

interleukin 1-responsive element which is not present in the del allele suggesting
that individuals homozygous for the del allele may exhibit an altered PAI-1
response during the acute phase reaction (Dawson et al ., 1993). Similarly, a com-
mon insertion polymorphism (G) at position

1607 in the human matrix metal-
loproteinase-1 ( MMP1 ; 11q22-23) gene promoter creates a binding site for
members of the Ets family of transcription factors which results in the increased
transcription of the gene (Rutter et al ., 1998).
A highly unusual 76 bp length polymorphism (f = ~ 0.20/0.80) in the human
antithrombin III ( AT3 ; 1p31.3-qter) gene promoter results from the alternative
presence of two apparently distinct sequences of 108 bp (L) and 32 bp (S) at the
same position, ~345 bp upstream of the ATG translational initiation codon (Bock