For the first time, genes chemically silenced by stress during life have been shown to remain silenced in eggs and sperm, possibly allowing the effect to be passed down to the next generation.
The finding, obtained from detailed DNA scans in developing mouse eggs and sperm, backs up mounting indirect evidence that the genetic impacts of environmental factors such as smoking, diet, stressed childhoods, famine and psychiatric disease can be passed down to future generations through a process called epigenetic inheritance. Many geneticists had considered this an impossibility.
Genes can be switched off by altering DNA through a chemical process called methylation, in which enzymes respond to environmental factors by marking genes with methyl groups that prevent them from working.
But the idea that genes carrying these epigenetic markings could be inherited is controversial. Previous studies had shown that as sperm and eggs develop, any markings added during life are erased to provide a genetic “blank slate” from which the next generation develops. Any remaining marks were also thought to be erased when an egg is fertilized.
Now a team led by Jamie Hackett at the University of Cambridge has challenged this picture. The researchers extracted the DNA from mouse primordial germ cells — the precursors to sperm and eggs — at various stages of development and used markers to spot any methylated genes.
They found that a tiny number of methylated gene regions survived unerased: an average of just 233 of approximately 25,000 in the germ cells examined. Still, the work clearly shows that traits resulting from the surviving markings might be passed on. “What we’ve found is a potential way things can get through, whereas before, everything was considered to be erased,” Hackett says.
Do the markings survive simply because the erasure process may not always work properly, or are they deliberately spared so that the information they carry is passed to the next generation? The finding “doesn’t solve this question,” Hackett says. “But it’s a proof of principle for one possible mechanism by which traits might be inherited epigenetically.”
Those skeptical of epigenetic inheritance are adamant that even if some methylated DNA makes it through, this is likely to be because of faulty erasure.
“The idea that what’s left carries information about the environment is sufficiently far-fetched to demand much more evidence of its importance,” says Adrian Bird of the University of Edinburgh. “I’d say [the erasure] is an inefficient process, and what’s left doesn’t matter.”
Researchers who claim to have demonstrated that epigenetic traits can be passed down were more enthusiastic. Isabelle Mansuy of the Swiss Federal Institute of Technology in Zurich has found that in mice, the effects of stress in infancy can be passed from one generation to at least the next two.
“The paper demonstrates there are regions which do escape reprogramming,” she says. “This is fundamental to the idea of epigenetic inheritance of acquired traits that so many people are reluctant to accept, because it does indicate that it is possible to maintain some marks intact from parents to offspring.”
Hackett says that he and his colleagues plan to repeat the experiment in human cells and that they hope to resolve the question of whether some genes escape demethylation through luck or design.