Why and when was lactase persistence (LP) selected for? Insights from Central Asian herders and ancient DNA ..

To answer your question, Doron, the authors simply raised a philosophical (perhaps anthropomorphic?) question that cannot be answered, i.e. why Mother Nature has chosen this (genetic) form of evolutionary adaptation (for most northern Europeans) — instead of the “simpler” (at least, in our tiny human brains) “cultural adaptation” — is her secret. 😉

To answer the question from “Anonymous” — this is not a naïve question; it’s an exciting question.😊 Regulation of LCT gene expression is a fascinating story. The LCT gene is transcribed into messenger-RNA (mRNA), and then translated into a protein called “pre-pro-lactase”; this remains anchored in the endoplasmic reticulum (ER) membrane. Several subunits of pre-pro-lactase are cleaved off. The immature protein dimerizes (i.e. attaches to another copy of itself) within the ER. Then a transport vesicle, containing pro-lactase, splits off the ER and travels into the Golgi apparatus; once there, the “pro” subunit prevents degradation and ensures proper folding of lactase into its mature quaternary structure. Finally, a vesicle containing mature lactase travels to the external brush border membrane of gastrointestinal (GI) epithelial cells (enterocytes) — where the enzyme functions, to break down dietary lactose.

In most mammals (including ~65% of humans), levels of LCT gene expression in enterocytes decrease dramatically after weaning; this is because mammals do not typically consume milk after childhood — thus, maintaining enzymes to digest milk is unnecessary (it is ‘energetically wasteful’). Age-dependent lactase regulation occurs at the level of transcription. Transcription factors (TFs) are proteins that bind to a specific piece of DNA (usually 4-20 base-pairs), influencing a gene’s transcription frequency; once bound to DNA, a TF either attracts or repels the molecular machinery necessary for transcription. TFs often attract other TFs — to form large transcription complexes. TF “activators” bind to specific enhancer sites (on the DNA), and participate in initiating transcription by binding to RNA polymerase and other proteins used in transcription (this type of TF therefore increases expression of a gene; other TFs influence the probability and frequency of transcription by binding to TFs at enhancer sites). Enhancer sites can be far away from the start of a gene — but DNA can form large loops, allowing distant enhancers to come into contact with the transcription complex (this increases the frequency of transcription of the gene and, by extension, increases the expression of a gene).

Several TFs — that regulate the amount of lactase mRNA an enterocyte produces, over the course of its life — have been identified; these TFs bind to DNA ~14,000 base-pairs (bp) upstream of the LCT gene, within an intron (non-protein-coding region) of the upstream neighboring gene, MCM6. Thus, most research (concerning evolution of LP in humans) focuses on mutations not in the LCT gene, but rather on mutations in enhancers within introns of the MCM6 gene. Several single-nucleotide variants (SNVs) are associated with LP — all of which increase or decrease a TF’s ability to bind to DNA within specific response elements. For the most-thoroughly studied SNV 13,910 bp upstream of the LCT, a thymine base (T) has been substituted into the DNA sequence in place of a cytosine (C); this C>T mutation increases the binding affinity for the TF, POU2F1 (POU class 2 homeobox-1; formerly called ‘Oct-1’). POU2F1 acts as an activator (i.e. increases the transcription-complex binding to the promoter, thereby enhancing production of lactase mRNA).

Regulation of a gene via TF-binding site(s) in a neighboring gene is not that uncommon. For example, the human NFKB1 and SLC39A8 genes are located adjacent to one another on Chr 4q24, and they exhibit reciprocal regulation. NFKB1 (which is a TF) can activate SLC39A8, which results in enhanced influx of zinc (Zn) into many cell types; this leads to the coordinated NFKB1-mediated transcription of other inflammatory-factor genes. The Chr 4 g.102532378C>T NFKB1 intronic variant represents an expression quantitative-trait locus (eQTL), which causes decreased SLC39A8 mRNA expression in monocytes and macrophages; reciprocally, the SLC39A8-mediated higher Zn levels stimulate NFKB1 gene transcription, functioning negatively to down-regulate pro-inflammatory responses [via Zn-mediated down-regulation of IκB kinase (IKK) activity]. This example reflects a negative feedback loop involving SLC39A8 that directly controls innate immune function — through coordination of Zn metabolism and NFKB1 gene transcription.

Dear Anonymous, this might be a longer answer than you really wanted to know.😉 But regulatory interactions of neighboring genes along the same chromosome — are one of my favorite topics to read and learn about. 😊


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