New mouse study shows genes aren’t only way to pass obesity to next generation

From the color of our eyes to our odds of developing cancer, we’re all shaped by the genetic legacy of our ancestors. But a new study in mice provides the clearest evidence yet that acquired traits can be passed down from one generation to the next in mammals without DNA changes, challenging centuries of evolutionary dogma and raising fresh questions about the factors that affect our health.

Scientists created mice that were obese or had high cholesterol, not through tinkering with the animals’ genetic code, but by making little chemical modifications that changed which genes were active without altering the DNA sequence. Both these modifications and their metabolic effects were shown to have passed down for at least three to six generations — something scientists once assumed was impossible.

The study, published Tuesday in the journal Cell, was led by a team of Salk Institute scientists who have now joined Altos Labs. Their findings provide further support for the fast-growing field of transgenerational epigenetics: the study of traits that pass from one generation to the next without being inscribed into our genetic code.

What researchers have already found is raising questions and concerns: Rats with fertility issues after their great-great-grandmothers were exposed to pesticides. Mice suffering from obesity and liver disease five generations after an ancestor drank water laced with a chemical used to coat ship hulls. And all without detectable genetic changes.

It’s unclear whether such inheritance happens in people, too, despite early hints suggesting it’s plausible. Studying intergenerational effects is inherently time-consuming, so the best current evidence in mammals comes from animal studies. But these studies raise the possibility that our health could be molded in part by what happened to our distant ancestors during their lifetimes — what they ate, drank, and breathed — and that we could have a similar impact on our descendants.

“It could contribute for instance to heritable susceptibility to cancer, obesity, as well as other disease risks,” said Juan Carlos Izpisúa Belmonte, the study’s senior author and leader of the San Diego division of Altos Institutes of Science.

“The knowledge gained from our research may be useful for increasing disease diagnosis tools, estimating disease risk, or prevention of hereditary human diseases.”

Transgenerational epigenetics is a young field based on an ancient idea that was once widely accepted, then seen as laughable, and which has now gained new life — that acquired traits can be passed down to the next generation. The best-known proponent of this hypothesis was 19th century French naturalist Jean-Baptiste Lamarck, who famously mused that giraffes evolved their distinctive necks by straining to reach high-up branches, causing each generation to grow slightly longer necks.

That idea was soon discredited. Gregor Mendel, an Austrian monk with a penchant for breeding pea plants, found that traits such as height, pod shape, and flower color depended on “invisible characteristics” the plants inherited and passed down — and that these inherited characteristics weren’t changed by the environment. The eventual discovery of DNA and genes reinforced those findings.

But in 2005, a team of scientists at Washington State University noticed something that didn’t add up. A postdoctoral researcher found that male rats whose great-great-grandmothers had been injected with methoxyclor and vinclozolin, common pesticides, were infertile. That might have been explained by a genetic change in these descendants, but there was no sign of mutations in these mice.

Researchers published the findings in the journal Science. And other teams have reported similar effects from DDT, jet fuel and a growing list of chemicals, all without DNA changes. What they’ve found instead are so-called epigenetic changes, chemical modifications that control which genes are turned on or off.

This latest study took a more controlled approach to examine this pattern of inheritance. Researchers planted precise epigenetic changes near two genes associated with obesity and high cholesterol, Ankrd26 and Ldlr. To do so, scientists manipulated embryonic stem cells to trigger a chemical modification known as methylation in DNA regions that control the activation of both genes.

Methylation silences genes. If DNA is the book of life, methylation marks are notes in the margins telling you to skip a paragraph. And researchers found that male and female mice passed down these silencing marks for three to six generations.

These changes also had clear metabolic effects. Animals with silenced Ankrd26 were consistently obese and had higher levels of leptin, an appetite-suppressing hormone that rises during obesity to counter increased body fat. And mice with silenced Ldlr had high cholesterol.

The researchers then focused on how these methylation patterns were passed down to the next generation. The changes would have to make it into a mouse’s sperm or eggs, but these cells go through a process known as reprogramming that wipes clean any epigenetic marks. That happens a second time shortly after sperm and egg fuse.

Scientists found that the methylation marks regulating Ankrd26 and Ldlr went through reprogramming, too. But after being erased, these changes sprang back.

This is a very significant step, to demonstrate that there is some epigenetic memory and that cells are able to identify those regions that were methylated in the past and that can be re-methylated later on,” said Raquel Chamorro-Garcia, a transgenerational epigenetics researcher at the University of California, Santa Cruz who was not involved in the study.

Exactly how the modifications resurface — and why they weaken after several generations — remain questions researchers don’t fully understand. But Belmonte said that regulatory RNA molecules and a class of proteins known to control gene silencing likely shape this process.

It’s not the first time his team’s research has made headlines. Belmonte’s lab at the Salk Institute created pig-human chimeras, discovered new types of stem cells, and increased the lifespan of mice by reprogramming their cells to a more youthful state.

He’s now one of the top scientists at Altos Labs, a biotech that launched last year with $3 billion and an ambitious plan to reverse a range of diseases by rejuvenating cells. Belmonte said in an email that his team’s transgenerational epigenetics work, conducted while at the Salk, doesn’t reflect his current research program at Altos.

For researchers actively working in the field, there are plenty of puzzles to pursue. One is whether transgenerational epigenetic inheritance takes place in people. The answer will likely require more long-term studies of events such as the Dutch Hunger, a brutal famine triggered in part by Nazi Germany cutting off food supplies to part of the Netherlands, forcing millions of people to live on as little as 400 to 800 calories a day.

Researchers have discovered that the descendants of pregnant mothers who were affected by the famine were more likely to be obese or have heart disease. And there’s some evidence that the grandchildren of these famine survivors are at higher risk of being overweight.

Further evidence could come from similar ongoing studies, such as the Child Health and Development Studies Cohort, which began in 1959 with the recruitment of 15,000 Bay Area families. Researchers are just beginning to study the grandchildren of the original participants to study the multigenerational impacts of industrial chemicals and other stressors.

Meanwhile, Chamorro-Garcia says another open question is whether chemicals, dietary changes, and other environmental exposures can trigger precise, heritable epigenetic changes similar to those found in the recent study.

“The field is now shifting. For a long time, the focus was into describing [traits] that could be propagated across generations,” she said. “Now there is a lot of pressure to understand how the information is provided from one generation to the next.”

This story has been corrected to accurately describe the role of leptin.