The −14010*C variant associated with lactase persistence is located between an Oct-1 and HNF1α binding site and increases lactase promoter activity

Abstract

In most people worldwide intestinal lactase expression declines in childhood. In many others, particularly in Europeans, lactase expression persists into adult life. The lactase persistence phenotype is in Europe associated with the -13910*T single nucleotide variant located 13,910 bp upstream the lactase gene in an enhancer region that affects lactase promoter activity. This variant falls in an Oct-1 binding site and shows greater Oct-1 binding than the ancestral variant and increases enhancer activity. Several other variants have been identified very close to the -13910 position, which are associated with lactase persistence in the Middle East and Africa. One of them, the -14010*C, is associated with lactase persistence in Africa. Here we show by deletion analysis that the -14010 position is located in a 144 bp region that reduces the enhancer activity. In transfections the -14010*C allele shows a stronger enhancer effect than the ancestral -4010*G allele. Binding sites for Oct-1 and HNF1α surrounding the -14010 position were identified by gel shift assays, which indicated that -14010*C has greater binding affinity to Oct-1 than -14010*G.

Tracing Pastoralist Migrations to Southern Africa with Lactase Persistence Alleles

“…The LP trait, as well as LP alleles, is strongly associated with pastoralism worldwide [19–21], including in eastern Africa [8]. Eastern African pastoralist groups have relatively high frequencies of unique LP alleles that enhance lactase expression in vitro and exhibit strong signals of recent positive selection [6–8]. Thus, one would predict LP alleles of eastern African origin in southern African groups whose ancestors included immigrant eastern African pastoralists.…”

“…This allele was first reported in Kenya and Tanzania, at overall frequencies of 28% and 32%, respectively [8], but is rare or absent in other populations (Figure 2A). The −14010* C allele is associated with the lactase persistence phenotype in eastern Africa, where it shows a strong signal of recent positive selection [8], and it significantly increases lactase expression in vitro [6, 8]. …”

“…Eastern Africa harbors distinctive lactase persistence (LP) alleles [6–8], and therefore LP alleles in southern African populations may be derived from this eastern African pastoralist migration. We sequenced the lactase enhancer region in 457 individuals from 18 Khoisan and seven Bantu-speaking groups from Botswana, Namibia, and Zambia and additionally genotyped four short tandem repeat (STR) loci that flank the lactase enhancer region.…”

Stronger signal of recent selection for lactase persistence in Maasai than in Europeans

“…10,13,14 Both of these LP polymorphisms (European À13910C-T and East African À14010G-C) have been directly attributed to the enhancement of transcription of the LCT gene, by means of binding affinity and reporter gene assays. [15][16][17] In addition to the two polymorphisms mentioned above, three other polymorphisms within the adjacent MCM6 gene have also been linked to the lactase persistent trait in specific groups of people. The compound À13712C, À13915G allele has a role in LP in the Middle East, 4 while the À22018G-A SNP is linked to the trait in certain northern European populations 5 and the À13907C-G SNP is linked to the trait in some Sudanese populations.…”

Gene–environment interactions in human health: case studies and strategies for developing new paradigms and research methodologies

“…For example, in some South Africans, the -14010 ∗ C allele, is associated with LP (Jensen et al, 2011). In East Africa, the primary mutation appears to be (-13907G; Enattah et al, 2008).…”