Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging

Abstract

Inability to digest lactose due to lactase non-persistence is a common trait in adult mammals, with the exception of certain human populations that exhibit lactase persistence. It is not clear how the lactase gene can be dramatically downregulated with age in most individuals, but remains active in some. We performed a comprehensive epigenetic study of the human and mouse intestine using chromosome-wide DNA modification profiling and targeted bisulfite sequencing. Epigenetically-controlled regulatory elements were found to account for the differences in lactase mRNA levels between individuals, intestinal cell types and species. The importance of these regulatory elements in modulating lactase mRNA levels was confirmed by CRISPR-Cas9-induced deletions. Genetic factors contribute to epigenetic changes occurring with age at the regulatory elements, as lactase persistence- and non-persistence-DNA haplotypes demonstrated markedly different epigenetic aging. Thus, genetic factors facilitate a gradual accumulation of epigenetic changes with age to affect phenotypic outcome.

Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

“…Probes were synthesized using a programmable microfluidic platform (Custom Array, Inc.) and prepared as previously described 77,79 . Fine-mapping of DNA methylation at enhancers using bisulfite padlock probes was performed 77,79 . For each sample, genomic DNA was bisulfite converted and purified using the EZ DNA Methylation-Lightning Kit…”

Global variation in gene expression and the value of diverse sampling

“…Moreover, these variants reside in an intronic region of the neighboring gene, MCM6 , acting over a considerable genomic distance. Evidence suggests that the causal genetic variants primarily act by altering epigenetic mechanisms during development and aging [3]. Finally, the lactase enzyme is specifically expressed in enterocytes of the small intestine, and the trait is only apparent when individuals actually consume lactose, highlighting that population differences can be cell-type specific and condition dependent.…”

“…We note, however, that this is an area of active research and the limits to this approach are currently not well known. Combining this approach with technologies for introducing population or region specific genetic variants in vitro , such as CRISPR/Cas9 technology, could be a promising route [3,4] for examining cross-population differences in gene expression regulation in diverse tissues that obviates many of the difficulties in tissue collection across ethnically diverse populations.…”

Inferences of African evolutionary history from genomic data

“…LP confers the ability to digest lactose (the sugar present in milk) during adulthood, giving a selective advantage to those individuals who can consume dairy products as a source of nutrition and hydration. Four alleles associated with LP have been demonstrated to be functional, and they are located in a regulatory region in intron 13 of the MCM6 gene, an enhancer of the lactase gene ( LCT ) [63,64 •• ]. The variant T-13910 is common in Europe but is also present at low levels in the Middle East and in Central and Western Africa where it was introduced due to migration [49,61].…”