The molecular basis of lactase persistence: Linking genetics and epigenetics

Abstract

Lactase persistence (LP) - the genetic trait that determines the continued expression of the enzyme lactase into adulthood - has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single-nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age-related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct-1 (encoded by the gene POU2F1) and neighbouring TFs GATA-6 (GATA6), HNF-3A (FOXA1) and c-Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs.

Keywords: epigenetics; gene expression; lactase persistence; methylation; multiple alleles; transcription factors.

FIGURE 1

Schematic MCM6 intron 13 lactase persistence (LP) enhancer region as identified by Troelsen et al. (2003). The light grey box with coloured segments represents the sequence from −13,800 bp (GRCh38 chr2:135,850,966) to −14,030 bp (GRCh38 chr2:135,851,196) of LCT. The coloured boxes and corresponding annotations are transcription factor binding sites, and the red lines and annotations are LP‐associated SNPs with their positions (not to scale) (Jensen et al., ; Lewinsky et al., ; Liebert et al., 2016).

FIGURE 2

Known lactase persistence (LP) alleles and frequencies in Europe, Asia and Africa. These represent an estimation of allele frequencies in each continent based on samples from different countries. The African pie chart also includes populations from the Arabian Peninsula. Adapted from Swallow (2015).

FIGURE 3

Flowchart of proposed genetic and epigenetic mechanisms causing lactase persistence (LP). LP‐associated alleles enhance Oct‐1 binding and possible interactions with demethylating transcription factors (TFs) such as C‐ets‐1, GATA‐6 and HNF‐3A. These likely act against age‐related methylation in the LCT enhancer, allowing for continued Oct‐1‐mediated enhancer activity and LP.

FIGURE 4

Schematic of putative LCT–MCM6 methylation‐altering activity of transcription factors (TFs) bound to MCM6 intron 13 via chromatin looping in lactase persistence (LP) individuals. Light and dark grey boxes represent the MCM6 and LCT genes; dark grey regions represent regions differentially methylated with age between LP and lactase non‐persistence (LNP) individuals (specifically −13910*TT and CC homozygotes). The black connecting line is the intergenic region. Coloured triangles are TFs, which all bind at MCM6 intron 13 in LP individuals and carry out demethylating activity partly via GATA‐6 and HNF‐3A recruitment of TET demethylating enzymes shown as red circles and slight demethylating activity shown in black dashed arrows.