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Inheritance Is More Than Gene Deep

12 April 2006 (All day)
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Emma Whitelaw laboratory

The same, but different.
Epigenetic inheritance could explain the disparate coat colors of these genetically identical mice.

As Darwin would have loved to have known, genes made of DNA are the basic unit of inheritance. But in recent years, researchers have shown that differences not related to DNA sequence can also be passed down, a phenomenon called epigenetic inheritance. Some studies have implicated chemical groups that bind to genes. A new study in mice, however, suggests other possibilities--some of which could dramatically alter our notions of inheritance.

Epigenetic inheritance has long been known in plants and yeast. In the mustard plant Arabidopsis, for example, epigenetic alterations in leaf and flower shape can be passed on to offspring. But the phenomenon was first demonstrated in mammals only in 1999, by molecular geneticist Emma Whitelaw and her coworkers. They created a strain of genetically identical mice, all of which had a coat color gene called agouti viable yellow (Avy). Despite having exactly the same DNA, the mice had wildly varying coat colors, ranging from yellow to mottled and nearly everything in between. Most dramatically, the color of the mother greatly influenced the color of her pups: Yellow mothers had more yellow offspring and mottled mothers had more mottled offspring. The coat color in turn depended on how many methyl groups were bound to a stretch of regulatory DNA just upstream of the Avy gene, suggesting that the methylation status was inherited epigenetically.

In the new work, Whitelaw--now at Queensland Institute of Medical Research in Brisbane, Australia--and her coworkers investigated what might be behind this inheritance. They found that, during reproduction, methyl groups quickly vanished from Avy genes inherited from the father. Most were gone by the time the sperm and egg had fertilized to form a zygote. Demethylation on the maternal line took place much more slowly. For example, the maternally inherited gene was still heavily methylated at the zygote stage. But by the time the embryo was implanted in the uterus, the maternal Avy gene had also lost all of its methyl groups.

Thus, the methyl groups themselves cannot be the inherited "epigenetic mark" when coat color is passed on, the team reports in this month's issue of PLoS Genetics. Rather, the findings suggest that methylation status may be a byproduct of other changes, such as alterations in proteins associated with the DNA, or even of inheritance via small molecules of RNA. "This is a very exciting possibility," says Whitelaw. "DNA is certainly not all that you inherit from your parents."

Manel Esteller of the Spanish National Cancer Center in Madrid, who studies epigenetic effects in cancer cells, agrees. "[RNA] could be critical in maintaining this epigenetic memory during development," he says, "although we are still in our infancy in understanding this phenomenon." Greg Barsh, a geneticist at Stanford University in California, adds that while DNA methylation may not be the core explanation for this curious inheritance pattern, it's likely part of "multiple mechanisms coming into play."

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