Early Epigenetic Influence

Random chance, plus small differences in uterine environments, give rise to divergent epigenetic patterns in identical twins.

Jul 16, 2012
Sabrina Richards

Scientists are still teasing out the contributions of genetic and environmental factors to epigenetic marks on the genome. Differences in DNA methylation patterns have been linked to various disease occurrences in genetically identical twins, for example, suggesting an environmental impact. And a new study, out this week (July 15) in Genome Research, extends the influence of the environment in to the uterus by demonstrating that differences between identical twins in methylation are detectable at birth. Surprisingly, methylation patterns between some twins differ more than between unrelated individuals, also suggesting a role for random chance in the development of the epigenome.

“We already know that twins behave differently and look different, and it’s probably due to epigenetics,” said Jeffrey Craig, who led the study with Richard Saffery, both at the University of Melbourne.

Because of their identical genomes, monozygotic twins allow scientists to identify epigenetic differences that may serve as markers for disease. But it wasn’t known when differences in epigenetic patterns emerged between twins, Tadafumi Kato, who studies the molecular basis of bipolar disorder at RIKEN Brain Science Institute in Japan but was not involved in the current study, wrote in an email to The Scientist.

In order to look more closely at epigenetic differences between twins, Craig and Saffery took tissue samples when the children were born and for several months after birth, following epigenetic changes over time. They compared sets of identical twins and fraternal twins, a classic experimental setup used to separate environmental from genetic effects. They then used a chip array to examine DNA methylation at over 27,000 sites in the human genome in each of three tissues: placenta, umbilical cord vascular endothelial cells, and cord blood mononuclear cells. The researchers also compared the newborns’ methylation patterns to those of unrelated infants.

Although DNA methylation patterns tended to be more similar for identical twins, “we were very surprised by the range” of differences, said Craig, “The distribution of monozygotic twins overlapped unrelated newborns, and some twins were more different than unrelated pairs.

The scientists also found that identical twins that shared a placenta—arguably coming as close as possible to sharing similar environments—had epigenetic patterns that differed more than identical twins that didn’t share a placenta, but did share a uterus. This finding highlights “that sharing the same intrauterine environment does not contribute to having more similar DNA methylation patterns,” Esteban Ballestar, who studies the epigenetics of disease at the University of Barcelona, wrote in an email. “Their results would rather suggest that stochastic events could be more relevant in establishing differences between DNA methylation patterns in individuals,” added Ballestar, who was not involved in the work.

Thus, it seems that random changes and environmental factors together influence epigenetic patterns more than twins’ shared genetics. Indeed, when Craig and his colleagues statistically examined how much genetics, environmental factors, and random chance contributed to epigenetic methylation patterns, they found that slight differences in shared intrauterine environments, such as placenta size or where the umbilical cord attaches, and random changes accounted for more of the variance in epigenetic patterns than the underlying DNA sequence. As the children aged, their methylation patterns didn’t continue to diverge, however, suggesting that environmental signals may have less of an influence on epigenetics later in life—a finding that contradicts some earlier studies.

Knowing that low birth weight has been linked to later ill health, the scientists looked more closely at the genes showing differing patterns of methylation. They found that discordantly methylated genes in sets of twins with differing birth weights were often genes encoding proteins involved in metabolism and growth, which suggests to Craig that these pathways can be “nudged” off track early by deleterious patterns of methylation even before birth.

“It’s still a very pilot experiment,” noted Arturas Petronis at the University of Toronto, who pointed out that the 27,000 sites the researchers examined represent only about 0.1 percent of possible methylation sites in the genome. More comprehensive studies will determine how well these findings apply to the whole genome, said Petronis, who did not participate in the study.

In the meantime, Craig and his colleagues are hoping to discover what subtle environmental differences within the uterus can prompt such large epigenetic differences in twins. Placement of the umbilical cord, which can regulate the number nutrients passed from mom to her babies, and even what route they take, could play a role, Craig hypothesized. More importantly, he added, if scientists can identify early epigenetic markers of disease, it may be possible to proactively use epigenetic drugs, such as those already in cancer trials, to “nudge” their methylation patterns back on a healthy track.

L. Gordon, et al., “Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence,” Genome Research, doi: 10.1101/gr.136598.111, 2012.