Twin Data Highlight Genetic Changes
Tuesday, July 5, 2005
A mysterious biological mechanism that subtly changes the way people's genes behave may account for many of the surprising differences between identical twins, researchers announced yesterday.
Geneticists said the new work, by an international team of scientists who studied the DNA of more than 40 pairs of twins, strengthens the case that a fledgling research field called epigenetics holds the long-sought answer to one of biology's toughest questions: How do environmental influences, such as exposure to pollutants, consumption of certain foods or perhaps even powerful emotional experiences, produce lasting and potentially life-altering changes in a person's DNA?
Beyond its potential importance for understanding differences in identical twins, epigenetics could explain many of the twists of fate that affect ordinary people -- why one person may be struck by cancer, for example, while another is spared, even though neither's DNA harbors a cancer-causing mutation.
"This is how the environment talks to the genome," said Rudolf Jaenisch, a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Mass., who was not part of the project. "This paper says lifestyle, or environmental influences or whatever you want to call them, have a real influence on your DNA."
Stephen Baylin, a professor of oncology and medicine at Johns Hopkins Medical Institutions in Baltimore, said the new work points to the roots of a host of chronic diseases. "This could lead to far-reaching revelations about how our environment breeds predispositions for lots of diseases, like diabetes, cancer and heart disease."
Human cells have tens of thousands of genes inside them, each with its own job, such as producing energy or overseeing cell division. But only certain genes are active at any given time or in any cell type while the rest are appropriately dormant -- a grand orchestration that adds up to a smooth-running life.
The new research, led by Mario F. Fraga and Manel Esteller of the Spanish National Cancer Center in Madrid, focused on two biological mechanisms that influence gene activity. In one, called DNA methylation, enzymes inside a cell attach a minuscule molecular decoration to a gene, deactivating that gene. In the other, called histone acetylation, a dormant gene is made active again.
These altered genetic settings can last a lifetime (though they are not passed down to a person's offspring) and can be important if, say, the gene turned off is one that protects against cancer. The extent to which epigenetic changes are preprogrammed from birth or spurred by factors outside the body has been unclear.
In the new work, described in today's issue of Proceedings of the National Academy of Sciences, researchers measured the extent to which twins of various ages, from 3 to 74, differed in the number and variety of genes that had been either turned on or shut down by epigenetic processes. They found that young twins had almost identical epigenetic profiles but that with age their profiles became more and more divergent.
In a finding that scientists said was particularly groundbreaking, the epigenetic profiles of twins who had been raised apart or had especially different life experiences -- including nutritional habits, history of illness, physical activity, and use of tobacco, alcohol and drugs -- differed more than those who had lived together longer or shared similar environments and experiences.
Small epigenetic events before birth probably account for many of the minor distinguishing differences in the appearance, personality and general health of young twins, Estella said, and a lifetime of further epigenetic changes gradually increases individuality.
"Both nature and nurture are acting on these twins," Estella said. "Epigenetics is the bridge or the interplay between them."
Francis Collins, director of the National Human Genome Research Institute, said the work adds to an emerging recognition that scientists must move beyond their long-standing focus on the inherited spelling of people's DNA code and the occasional mutation or outright "misspelling." Epigenetic changes do not alter genetic spellings but may account for as many cases of cancer and other diseases as full-blown gene mutations, he said.
"Here's something where Mendel, Watson and Crick all seem to have missed some crucial goodies," said Collins, referring to pioneers of genetic research. Collins's institute, along with the National Cancer Institute and others, intends to launch a major effort to identify the many epigenetic changes that contribute to cancer.
Scientists want to identify the epigenetic changes wrought by specific environmental exposures -- whether dietary factors, environmental toxins or more nuanced influences such as persistent stress -- and develop drugs that can reverse those alterations.
Peter Jones, director of the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, likened epigenetic alterations to the clothes worn by genes. "The clothes are really what determine how the genome works," he said. "The clothes can get tattered by these changes, which can lead to different susceptibilities to disease."