Great-grandpa’s genes gone, effects stay

Removing anti-obesity DNA from a mouse lineage doesn’t stop descendants from staying thin

VANCOUVER — Great-grandfathers may impart more than engraved watches. A sugar-regulating gene that made a brief appearance in a lineage of mice but wasn’t passed on seems to have made animals up to four generations later resistant to obesity, research presented March 30 at the annual conference on Research in Computational Molecular Biology shows.

“This changes the way we think about the inheritance of disease,” said study coauthor Joseph Nadeau of the Institute for Systems Biology in Seattle. The results may force researchers to grapple with complicated transgenerational gene influences.

The surprising effect was caused by the single-generation appearance of a genetic variation that affects the maintenance of blood sugar, Nadeau and his colleagues reported.

In the experiments, researchers allowed two inbred strains of mice to eat as many of the mouse equivalent of double cheeseburgers as they wanted. One type of mice grew obese on the diet and developed a suite of accompanying health problems, such as insulin resistance, high blood pressure and cardiovascular disease. The other type didn’t gain weight, even though these mice ate more than the first type and exercised less.

By swapping a part of the skinny mouse’s DNA that includes the glucose-related gene into the obesity-prone mouse, the researchers could cause mice to stay slim on the high-fat diet.

But here’s where the story gets strange: Even if this piece of DNA was swapped into a mouse but then not passed on to descendants, the effect was still evident generations later. The original mouse’s great-grandchildren remained slender, even on a high-fat diet. Though these mice didn’t inherit the actual gene, they did inherit some ghostly imprint of it. “The reason they are the way they are isn’t in them,” Nadeau said. “It was in the previous generation.”

The findings are “breathtaking,” says computational biologist Sorin Istrail of Brown University in Providence, R.I., and provide very interesting answers to questions about how genes work. The results might help resolve a genetics mystery: Some traits — including obesity — are known to be strongly inherited. But so far, researchers have been able to identify genes that explain just a tiny part of this total heritability. A gene present generations earlier that left a biochemical mark might explain some of the “missing” effect, Istrail said.

The researchers have found evidence for similar transgenerational genetic effects in testicular cancer and are currently testing for such effects in colon cancer and metabolic disorders.

Nadeau and his colleagues don’t yet understand how the ghostly gene’s effect could persist across generations. One hint comes from preliminary studies that suggest there are changes in the way small pieces of RNA regulate protein production. 

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