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pattern of inheritance (Metneki et al., 1984). Further evidence that lactase
persistence is a genetic trait, and more specifically that it is caused via a cis-
acting element was produced in the early 1980s. Ho et al. (1982) reported a
trimodal distribution of lactase:sucrase ratios in British natives. Both lactase
and sucrase were extracted from autopsy material (from individuals without
gastrointestinal disease) with the sucrase activity serving as an internal stan-
dard correcting for non-genetic variation. The trimodal distribution was
interpreted to represent individuals homozygous for lactase persistence (high-
est lactase activity), heterozygotes (mid-level activity) and non-persistent
homozygotes (low-lactase activity) (Ho et al., 1982). The intermediate lactase
activity observed in the heterozygotes indicated that only one copy of the
lactase gene was being fully expressed, and concordant results were subse-
quently obtained for individuals of German ancestry (Flatz, 1984). Confir-
matory evidence for the cis-acting nature was obtained from mRNA studies.
Allelic variants of exonic single nucleotide polymorphisms (SNPs) were used
to identify particular transcripts and their expression levels. Europeans of the
persistent phenotype who were heterozygous for exonic polymorphisms were
used to demonstrate monoallelic expression at the mRNA level (Wang et al.,
1995).
Studies of the LCT immediate promoter show a conserved
150 bp
region that exists in human, rat, pig and mouse, suggesting that key regula-
tory elements important for lactase expression are encoded within this small
region (Troelsen, 2005). This region has been shown to drive low-level expres-
sion in an intestinal cell line (Troelsen et al., 1992), while transgenic mouse
experiments using rat and pig promoter constructs of different sizes show that
elements outside this conserved 150-bp region are required for high and
tissue-specific expression of lactase (Troelsen et al., 1994; Krasinski et al.,
1997; Lee et al., 2002; Wang et al., 2006). A 1 kb pig promoter construct is
sufficient to mimic endogenous gene expression in transgenic mice (Troelsen
et al., 1994). However, a 2 kb rat promoter is required to produce the same
effect (Lee et al., 2002). In addition, the different enhancer sites encoded
within the upstream regions are thought to make distinct contributions to
the spatial and temporal expressions of LCT (Wang et al., 2006). The differ-
ence in promoter structure outside the proximal region in different species
demonstrates the difficulty of finding a suitable model organism in which to
replicate the lactase persistence phenotype.
A number of transcription factors have been identified that are impor-
tant for lactase expression (Figure 6.2) (Troelsen, 2005). The transcription
factor Cdx-2 is implicated in the regulation of many intestinally expressed
genes (Freund et al., 1998; Beck, 2004) and has a number of binding sites
upstream of the LCT initiation codon, including two within the 150 bp
conserved proximal promoter region (Troelsen et al., 1997). Cdx-2 has been
