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Exploring the Possibilities, One Generation to the Next
CHORI Scientists First to Demonstrate Inheritance of Environmentally-Influenced Epigenetic State in a Specific Gene

In a ground-breaking new study in the November 14th issue of Proceedings of the National Academy of Sciences, which was accompanied by a special editorial commentary, CHORI scientists David Martin, MD and Kenneth Beckman, PhD, provide for the first time evidence that exposure to environmental agents in one generation can affect that generation’s grandchildren.

In this case, the environmental agent was dietary supplementation, and Drs. Martin and Beckman were able to induce an epigenetic modification at a specific gene that was maintained for a generation after the dietary supplement was withdrawn. This indicates that the germ-line of the mice was affected.

Everyone knows that the phenotypes seen in different individuals – their hair or eye color, for example – are the result of which genotypes, or sequences of DNA, they have inherited from their parents. Epigenetics, loosely defined, describes the phenomenon of the same DNA sequence behaving in different ways in different cells or different individuals.

“Inheritance is far more complex than the transmission from generation to generation of the simple DNA sequence,” explains Dr. Martin. “There is increasing evidence that epigenetic modifications are inherited along with the DNA sequence.”

These epigenetic modifications are complex in molecular terms, but in simplified terms can be thought of as resulting in one of two epigenetic states. The DNA may either be active – the DNA sequence is accessible and genes on it expressed – or silent, a state in which the DNA is not accessible and genes on it are not expressed. Evidence has suggested that these epigenetic states can be inherited in the germ line as well.

“The germ line represents the cells — egg and sperm progenitors — that are set aside very early in development, that create the next generation,” explains Dr. Beckman. “During fertilization, you have only one cell. It then splits into two, and then each of those cells splits, and so on and so forth. At some point, some cells branch off and are set aside as germ cells.”

While many studies in humans have hinted that environmental agents – such as diet, or exposure to toxins – could also result in changes to epigenetic states, none of these studies had the genetic backing to prove it.

“In all of those cases, the genes that might be mediating the effects were not known, which leaves the whole theory open to question,” says Dr. Beckman.

In the mouse model used in the PNAS study, however, researchers are able to clearly track epigenetic modifications to a specific gene through multiple generations.

In addition to demonstrating transgenerational inheritance of an acquired epigenetic state, the study also illustrates another complexity for the first time: that the parental origin of the gene can determine its ability to respond to an environmental agent.

“The origin of allele matters,” says Dr. Beckman. “When the affected allele comes from the mother, the environmental agent doesn’t influence the allele in the next generation. But when the allele comes from the father, it does. What this suggests is an environmental effect that only seems to operate when the chromosome comes from the father.”

As Dr. Martin confirmed, “The gene knows whether it came from the father or the mother.”

While the study is a landmark in many ways, it was not a complete surprise to Dr. Martin. If anything, it confirmed what he had long believed, that epigenetic traits may be heritable and play a key role in variation between individuals.

“You have your genes, and you have environmental impacts,” says Dr. Martin. “But what this study quite clearly demonstrates is that there is another layer, interposed between these two things. The behavior of a gene is not fixed, it can change. What we can see is that it’s probably a mixture of all three – genetics, environment and epigenetics. The patterns that are possible are infinite.”

Luckily, researchers like Drs. Martin and Beckman continue to explore those infinite possibilities, and by doing so, continue to bring us closer to understanding the complexities of inheritance – how and why we are who we are.

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Monday, May 16, 2011 11:33 PM

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