Genome Transforms as Years Fly By

By Michael Smith
BALTIMORE, 25 june 2008-- -- The individual genome -- far from being stable -- evolves during a lifetime, with changes that could influence disease susceptibility, according to researchers here.
Moreover, the so-called epigenetic changes are similar within families, suggesting that the pattern of alterations might be under genetic control, according to Andrew Feinberg, M.D., of Johns Hopkins, and colleagues.
Such changes might directly affect susceptibility to disease, Dr. Feinberg and colleagues reported in the June 25 issue of the Journal of the American Medical Association.
"We're beginning to see that epigenetics stands at the center of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure," Dr. Feinberg said.
"Epigenetics might very well play a role in diseases like diabetes, autism, and cancer," he added.
Many so-called "epigenetic marks" -- chemical changes to DNA that persist as the cell divides -- are known, but for this study the researchers concentrated on DNA methylation -- the addition of a methyl group to a section of the genome.
DNA methylation usually takes place at so-called "CpG islands" in the genome and changes in methylation can have the effect of turning genes on and off.
The researchers studied DNA from 111 people in an Icelandic cohort, who were sampled on average 11 years apart, as well as from 126 people in a Utah cohort of families who were sampled on average 16 years apart.
In the Icelandic cohort on the whole, Dr. Feinberg and colleagues found, the average individual change in DNA methylation over the 11 years was zero -- consistent with earlier studies.
On the other hand, when the volunteers were looked at individually, the researchers saw a wide range of changes, including gains and losses of methylation of up to 26% and 30% respectively.
The analysis found that:
70 volunteers (63%) had a gain or loss of 5%.
33 individuals (30%) had a change of 10% or more.
Nine (8.1%) had a change of at least 20%.
The results from the Utah cohort -- which consisted of members of 21 families originally part of a larger study of human genetic polymorphisms -- were similar, Dr. Feinberg and colleagues found.
Again there was a wide range of gains and losses, with 50 individuals (40%) showing a change of at least 5%, 23 (18%) with a change of at least 10%, and 13 (10%) with a change of at least 20%.
Because the Utah cohort consisted of family groups, the researchers asked whether the direction of the changes tended to be similar among family members.
In fact, analysis showed that members of the same family were all likely to have either gains or losses in methylation, a finding that was significant at P<0.001.
When one family -- all of whose members had between 40% and 50% losses in methylation -- was excluded, the familial clustering remained significant at P<0.003, the researchers found.
"What we saw was a detectable change over time, which showed us proof of the principle that an individual's epigenetics does change with age," said co-author M. Daniele Fallin, Ph.D., of the Johns Hopkins Bloomberg School of Public Health.
"What we still didn't know was why or how, but we thought 'maybe this, too, is something that's heritable' and could explain why certain families are more susceptible to certain diseases," she said.
They pointed out another potential application of these findings. "These data support the idea of age-related loss of normal epigenetic patterns as a mechanism for late onset of common human diseases (common disease genetic and epigenetic model) which could arise through the loss of functionally important epigenetic modifications as well as through the release of epigenetic buffering of intrinsic genetic variation."
The study was supported by the NIH, the Swedish Cancer Foundation, the Icelandic Parliament, the Huntsman General Clinical Research Center, the W. M. Keck Foundation, the George S. and Delores Doré Eccles Foundation, the Fulbright Foundation, and the Icelandic Student Innovation Fund. The researchers reported no conflicts.
Primary source: Journal of the American Medical AssociationSource reference:Bjornsson HT, et al "Intra-individual change over time in DNA methylation with familial clustering" JAMA 2008; 299(24): 2877-2883.