If epigenetics has taught us anything, it’s that genes are not our destiny. Even though aberrant patterns of epigenetic marks have been caught at the scene of the crime in many disease states, we know relatively little about their natural variation and how this influences human health. That may be about to change however with a new study by researchers from the University of Otago, New Zealand who report surprisingly high levels of natural DNA methylation variation in human leukocytes that may influence genomic output.
“We know that the extent of genetic variation is too small to explain the diversity of phenotype we see within and between species” says first author Aniruddha Chatterjee. “Variation in DNA methylation patterns in healthy individuals has been hypothesized to alter human phenotypes including susceptibility to common diseases and response to drug treatments” he adds.
Yet, studies examining inter-individual differences in DNA methylation have used mixed cell populations (like whole blood), and, therefore, the situation remains a little fuzzy.
Chatterjee, Morison and the team turned to an easy to access and purify cell population, neutrophils, which make up around 60% of whole blood. Using reduced representation bisulfite sequencing (RRBS), they generated base-pair resolution DNA methylation maps of neutrophils from 11 healthy individuals (six women and five men), divided the genomes up into manageable fragments for ease of comparison, and ran some pretty neat bioinformatics analyses:
- This identified around 13,000 autosomal fragments showing significant differences in methylation between individuals, which they named inter-individual variably-methylated fragments (iVMFs).
- Sex did not account for differences in methylation on autosomes.
- Promoters were the least variable regions of the genome and, instead, a whopping 50% of iVMFs mapped to gene bodies.
- Repetitive elements were also significantly enriched in iVMFs.
- Importantly, some iVMFs overlapped with differentially expressed exons, and their methylation correlated with exon inclusion, suggesting that iVMFs affect splicing.
- Variably methylated genes were enriched for functions related to genome regulation.
Chatterjee continues “This extent of variation has never been reported before. With projects such as the International Human Epigenome Consortium picking up pace, we will soon have a large enough number of epigenomes with which to test the functional association between variable DNA methylation, chromatin marks or whatever, and susceptibility to particular diseases”
For more information, head on over to Scientific reports, November 2015.