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expression levels (Bosse et al., 2006). However, in vitro, all GATA factors
bind the proximal sites with similar affinity, and it has been found that
GATA-5 and HNF-1
are capable of co-operating to stimulate expression
from the proximal promoter in this context (Krasinski et al., 2001).
While the identified recognition sites and the corresponding transcrip-
tion factors of the proximal LCT promoter are undoubtedly important in the
basal regulation of lactase expression, they are, as discussed above, not
sufficient for the correct temporal and spatial expressions of the gene, and
hence this region is not thought to be involved in causing lactase persistence.
Indeed, sequencing of LCT and the immediate promoter region in Europeans
showed no nucleotide changes that were absolutely associated with persis-
tence/non-persistence (Boll et al., 1991; Lloyd et al., 1992; Poulter et al.,
2003).
Subsequent research has, therefore, focused more intensely on the
upstream regions of LCT, looking for regulatory elements that influence
the lactase persistence phenotype. Interestingly, many enhancer motifs
occur upstream of the proximal promoter, which are different depending on
the species, and are recognised by various transcriptional regulators (includ-
ing Cdx-2, HNF-1
and GATA factors) (Troelsen, 2005; Lewinsky et al.,
2005). One such highly variable region was identified
900 bp upstream of
the lactase start site (Harvey et al., 1995; Hollox et al., 1999). A nucleotide
change, C-958T, was found to affect greatly interaction with an unidentified
DNA-binding protein. However, this polymorphism was not considered to be
causal of lactase persistence because the ancestral allele, C, was present in
both lactase-persistent and non-persistent people. If functional in vivo, this
SNP may perhaps affect the timing of down-regulation or spatial expression
along the length of the intestine or modulate the effect of other nucleotide
changes.
In fact, several polymorphisms exist across the 50 kb LCT gene and
association studies revealed that very few haplotypes (i.e. a particular combi-
nation of alleles at each SNP) occur in most of the human populations tested,
although greater diversity was observed in African populations (Hollox et al.,
2001). One particular combination of alleles, designated the 'A' haplotype, is
particularly common in northern Europe and is found to associate with
lactase persistence (Harvey et al., 1998).
6.7.
Identification of Causal Variations
A putative causative single nucleotide polymorphism (-13910C
>
T) has been
described 13.9 kb upstream of the LCT transcription initiation site (Enattah
et al., 2002). It is located in an intron of an adjacent gene, MCM6, and occurs
