The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element

Abstract

Lactase activity is present at high levels in the small intestine of some human adults and not others. This is due to a genetically determined polymorphism which affects the developmental regulation of the expression of the lactase gene. This polymorphism is of considerable interest in relation to cultural differences in nutrition but despite exhaustive studies, the molecular basis has not yet been found. It has not even been shown whether the sequence differences reside within or adjacent to the lactase gene itself or in a trans-acting factor. We have therefore exploited known DNA 'marker' polymorphisms within the exons of the lactase gene to examine the expression of the individual lactase mRNA transcripts from persistent and non-persistent individuals in order to determine whether the regulation is in cis or trans. Our results show that in certain lactase persistent individuals one allele of the lactase gene is expressed at much lower levels than the other and these individuals tend to have intermediate lactase activities. It is proposed that these people are heterozygous for the lactase persistence and non-persistence alleles and that this means that the nucleotide substitutions responsible for the lactase persistence/non-persistence polymorphism are cis-acting. This narrows down considerably the area of the genome that needs to be searched for the relevant sequence differences.

Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5′ end of the lactase gene on chromosome 2q21

“…The human tissues were as described previously [1,[15][16][17]. Semiquantitative RT-PCR was performed using the method described previously [15] except that the RT was performed at 37°C using 1 Ixg total RNA as starting material for 10 PCR reactions and, for MCM6 only, 30 rounds of amplification (which gave a linear dose response for this transcript).…”

“…In the course of our efforts to identify the cis-acting element which causes the lactase persistence polymorphism in adult humans [1], we have been sequencing upstream of the start of transcription of the lactase gene (LCT). This paper is concerned with the identification of a novel gene in close proximity to LCT, which has a high level of identity to a rat intestinal crypt-cell replication factor [2].…”

Associations of the lactase persistence allele and lactose intake with body composition among multiethnic children

“…This SNP is variable for either cytosine (C) or thymine (T) and is located within intron 13 of the MCM6 gene on chromosome 2 (Wang et al 1995(Wang et al , 1998. The ''C'' variant functions as a cis-element down-regulator by coding for a binding motif that affects an AP2 site on the lactase gene promoter causing delayed transcription and decreased lactase production.…”

Lactase persistence may have an independent origin in Tibetan populations from Tibet, China

“…This trait is caused by genetic differences cis-acting to the lactase gene (LCT). 4 Four causative single-nucleotide polymorphisms (SNPs) B13.9 kb upstream from LCT: À13910C/T (rs4988235), À13907C/G (rs41525747), À13915T/G (rs41380347) and À14010G/C, have been subsequently identified as the candidate cis-acting elements based on genotype-phenotype association analyses and functional experiments during the past decade. 5 The derived allele of À13910*T is associated with LP in European 6 and some Central Asian 7 populations.…”