Mendel Didn't Have The Whole Picture: Our Genome Changes Over Lifetime, Johns Hopkins Experts Say
Contrary to conventional wisdom, it appears that while the overall health of our genomes is indeed inherited from our parents, chemical marks on our genomes’ DNA sequences actually change as we age, driving increased risk of disease susceptibility for us and similarly for our close family members.
Summarizing results of an international collaborative research project, Andrew Feinberg, M.D., M.P.H., concluded that “we’re beginning to see that changes wrought by these epigenetic marks may help explain why susceptibility to many diseases such as diabetes and cancer increases with age.”
Feinberg, a professor of molecular biology and genetics and director of the Epigenetics Center at the Johns Hopkins School of Medicine, added that they may also explain why diseases such as diabetes and cancer, in which we know the environment is important, might arise in part because the environment changes the genes themselves. “In this sense, epigenetics probably stands at the center of modern medicine because unlike our DNA sequences, which are the same in every cell, epigenetic changes can occur as a result of dietary and other environmental exposure,” he said.
Reporting results of the new study in this week’s Journal of the American Medical Association, Feinberg said he and an international team embarked on their study to nail down more evidence that epigenetic changes interact with external factors by focusing on a chemical phenomenon called methylation, one particular type of epigenetic mark in which chemical methyl groups attach themselves to DNA in response to various triggers.
“Abnormal methylation levels, either too much, which could turn necessary genes off, or too little, which could turn genes on at the wrong time or in the wrong cell, already have been shown to contribute to cancer and other diseases,” said Vilmundur Gudnason, M.D., Ph.D., a professor of cardiovascular genetics at the University of Iceland, who designed the Reykjavik, Iceland, component of the study.
For the new study, researchers first collected DNA samples collected in 1991 and again between 2002 and 2006 from 600 participants already enrolled in the AGES Reykjavik Study. The AGES study is renowned for its value to genetics research because of the historic isolation and reduced number of genetic “variables” among Iceland’s population, making certain patterns of genetic information easier to identify.
Among the 600, the research team measured the total amount of DNA methylation in each of 111 samples and compared total methylation from DNA collected in 2002 to 2005 to that person’s DNA collected in 1991.
They discovered that in almost one-third of the subjects, methylation changed over that 11-year span, with some gaining DNA methylation and others losing it.
“The key thing this part of the study told us is that levels changed over time, proof of principle that an individual’s epigenetic profile does change with age,” said M. Daniele Fallin, Ph.D., an associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health.
Still a puzzle, though, was why or how, Fallin said, “so we wondered whether the tendency to those changes was also inherited, right along with our DNA sequences. That would explain why certain families are more susceptible to certain diseases.”
To that end, the team measured total methylation changes in a different set of DNA samples collected from Utah residents of northern and western European descent. These DNA samples were collected over a 16-year span from 126 individuals from two- and three-generation families.
Similar to the Icelandic population, the Utah family members also showed varied methylation changes over time. But they found that family members tended to have the same kind of change: If one individual lost methylation over time, they saw similar loss in other family members.
“It seems,” said Fallin, an epidemiologist interested in patterns of disease among populations, “that epigenetic changes could be an important link between environment, aging and genetic risk for disease.”
Feinberg said interest in the field of epigenetics is growing because “the more we learn about the genetic contribution to aging, health and disease, the more we understand that the DNA sequences we inherit at conception are not the whole story.
“If it were the whole story,” he added, “then such things as susceptibility would not vary so much or change over time. We know that changes to the genome must occur but that nature protected that genome from easy alteration. Methylation is nature’s work-around.”
The research was funded by the National Institutes of Health, Swedish Cancer Foundation, Icelandic Parliament, Huntsman General Clinical Research Center, W. M. Keck Foundation, George S. and Delores Doré Eccles Foundation, Fulbright Foundation and the Icelandic Student Innovation Fund.
Authors on the paper are Hans Bjornsson, Martin Sigurdsson, Rafael Irizarry, Hengmi Cui, Wenqiang Yu, Michael Rongione, Fallin and Feinberg, all of Hopkins; Thor Aspelund, Gudny Eiriksdottir and Vilmundur Gudnason of Hjartavernd, Reykjavik, Iceland; Tomas Ekstrom of Karolinska Institute, Stockholm, Sweden; Tamara Harris and Lenore Launer of the National Institute on Aging, Bethesda, Md; Mark Leppert of University of Utah, Salt Lake City; and Carmen Sapienza of Temple University Medical School, Philadelphia, Pa.