A new DNA map, published in 'Nature Genetics', provides the first large-scale study of biological inheritance in humans that is not DNA-sequence based. The map of human chromosomes 6, 20 and 22 shows that as many as one in six human genes might be subject to modifications that could alter their activity by epigenetic changes - under the influence of the environment. Understanding these modifications will be important in diagnosis, drug development and disease study.
Epigenetic changes include modification of DNA bases, through addition or removal of simple chemical tags, such as a methyl group, and similar changes of the proteins that are closely entwined with DNA to form chromatin, the functional form of the genome. Collectively, these modifications are also referred to as the 'epigenetic code' which researchers believe defines how different genetic programmes can be executed from the same genome in different tissues.
To examine how and where DNA modification might vary, the team from the Wellcome Trust Sanger Institute and Epigenomics AG measured levels of DNA methylation across three chromosomes in twelve different tissues. The results, from almost two million measurements, looked for differences between tissues as well as differences that might be linked to age or sex.
Although DNA methylation can vary over a wide dynamic range, the study revealed the majority of sites to have on/off status (e.g. being unmethylated or methylated) and identified distinct regions in the genome where methylation differs between tissues but no significant differences were found between two age groups - average age 26 years old and average age 68 years old.
Age has been suspected to influence the plastic changes in methylation, and perhaps influence disease processes, but these remarkable results suggest methylation states are more stable than previously thought. The authors do emphasise that discrete changes may occur in regions or tissues not examined here.
Moreover, the two sexes showed indistinguishable patterns of methylation of regions not on the sex chromosomes, X and Y, or part of imprinted regions that are known to have parent-of-origin specific methylation patterns. Except for those regions, the global patterns of methylation are thus the same in males and females.
"There is much less noise in the system than we feared," explained Dr Stephan Beck, project leader at the Wellcome Trust Sanger Institute. "Our data show DNA methylation to be stable, specific and essentially binary (that is, on or off) - all key hallmarks of informative clinical markers. Our conclusion is that epigenetic markers will be a powerful addition to the current repertoire of genetic markers for future disease association studies, particularly where non-genetic factors are known to play a role, for example in cancer, and where they are suspected, as in autoimmune disease."
Analysis of the global epigenetic landscape revealed methylation to be tissue- and cell-type specific with sperm showing the greatest difference (up to 20 per cent) when compared to other cell types, emphasising the extensive epigenetic reprogramming during production of the gametes.
The team found that tissue-specific methylation of one in three genes they studied was associated with changed levels of gene activity. Intriguingly, tissue-specific differences were enriched in regions called evolutionary conserved regions, lying distant from genes, out in the 'junk' DNA. Evolutionary conserved regions were more often differentially methylated than regions close to genes, suggesting they might have an undiscovered role in gene or chromosome activity.
The study also looked at predicted genes that have decayed and appear to have lost function - so-called pseudogenes - or lack experimental verification. The control regions for almost 90 per cent were methylated, suggesting that methylation plays a role in silencing such genes and that many of the predicted genes might also be non-functional.
In 70 per cent of cases, the patterns of methylation were also conserved between mouse and human tissues. Less than 5 per cent differed to a great extent, supporting previous studies that suggest some epigenetic states to be conserved between these two species.
Image: DNA fragments by electrophoresis, courtesy of Neil Leslie
Eckhardt F et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 2006;38(12):1378-85. Abstract