Global Patterns of Human Epigenetic Variation

A study of five far-flung human populations gives clues to adaptations to environmental pressures.

Aug 28, 2017
Ashley Yeager

ISTOCK, BESTDESIGNSDNA methylation—changes to the activity of a DNA segment without changing the sequence—may be a rich source of raw material for natural selection, say the authors of a new study that analyzed DNA methylation, genotype, and gene expression data from five diverse human populations. They found that population-wide epigenetic changes happen much faster than changes in the DNA sequence. 

The result, published August 28 in Nature Ecology & Evolution, may offer insight into how human populations respond to environmental pressures via epigenetic responses.

The epigenome is at the interface between the genome and the environment, so studying it offers clues about different ways in which human populations respond to their surroundings, says Lluis Quintana-Murci, a human evolutionary geneticist at the Pasteur Institute in Paris who was not involved in the study. One way to adapt is through DNA sequence variation, which can be the substrate of natural selection. For instance, a mutation conferring increased resistance to malaria can increase in frequency in a given population through positive selection. But populations can respond, or possibly adapt, to environmental challenges through DNA methylation variation, too. When DNA methylation variation is under genetic control, it can be passed on through generations and participate in human adaptation, says Quintana-Murci.

“Understanding the factors driving variation in DNA methylation among populations is crucial to understanding the relationship between epigenetic diversity and phenotypic diversity, including how that diversity is related to disease,” he adds.

Research on global patterns of epigenetic diversity can be challenging to conduct, study coauthor Hunter Fraser, a geneticist at Stanford University, explains by email. For example, although scientists know that epigenetic variation plays a key role in regulating transcription, they still do not know which specific regions of the genome are involved for any given gene, and they don’t know the consequences of altering epigenetic marks such as DNA methylation, he says.

The team wanted to determine how epigenetic diversity relates to patterns of variation in DNA and gene expression at a global scale. So Fraser and colleagues looked at genetic and epigenetic data, specifically, DNA methylation at CpG sites—regions of DNA where a cytosine nucleotide occurs next to a guanine—from individuals representing five populations: six Siberian Yakuts, seven Cambodians, seven Pakistani Pathans, seven Algerian Mozabites, and seven Mexican Mayans. These are highly distinct groups, which helped the team associate epigenetic patterns to genetic and transcriptional profiles, says Holger Heyn of the Centre Nacional d'Anàlisi Genòmica in Barcelona who was not part of the research.

The results revealed a strong link between population-specific DNA methylation, mRNA levels, and genotypes. However, the CpG sites where methylation occurred that had the highest degree of population specificity were more strongly associated with a local variation in a single nucleotide (SNP) compared with the association of mRNA levels with local SNPs. Population-specific DNA methylation patterns are therefore explained better by local genetic variants than population-specific expression levels, the team says.

Because the DNA methylation variation appears to be under genetic control, it could greatly affect human adaptability. Fraser notes, however, that the consequences of methylation still aren’t clear. “It is likely that most of the variation we measured is not having any important impact, so the challenge is to figure out which genomic regions are important and how their DNA methylation impacts human traits,” he says.

To answer that question and others about epigenetic diversity, researchers will need to better understand how populations with shared environments yet different genetic backgrounds behave in terms of DNA methylation variation. They will also need to examine populations with similar genetic backgrounds but exposed to very different environments, Quintana-Murci says, adding that there’s “lots of work to be done.” As Heyn points out, “we still do not fully understand the mechanisms that drive epigenetic variation in populations.”

O. Carja et al., “Worldwide patterns of human epigenetic variation,” Nature Ecology & Evolution, doi:10.1038/s41559-017-0299-z, 2017.