From the color of our eyes to our odds of developing cancer, we are 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.
The study, published in the journal Cell, was led by a team of scientists at the Salk Institute in La Jolla, California. 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.
The study and its implications
Thus, the scientists created mice that were obese or had high cholesterol, not by modifying the animals’ genome, but by making small modifications of the molecules located on the genes (this is epigenetics), which caused the genes to be silenced. That is, two genes related to obesity and high cholesterol were inactivated without modifying their genetic sequence, but only by modifying their epigenetic marks. But the surprising thing is not this, which has already been possible for some time, but that they observed that both these epigenetic modifications and their metabolic effects were passed down for at least three to six generations, something scientists once assumed was impossible.
It is 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 Izpisua Belmonte, lead author of the study. “The knowledge gained from our research may be useful for increasing disease diagnostic tools, estimating disease risk, or prevention of hereditary human diseases”.
Transgenerational epigenetics and the evolutionary controversy
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 this, 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.
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.
However, it is still too early to reformulate the currently accepted evolutionary theories. “The problem is to learn whether these types of ‘experimental’ modifications — therefore directed — occur in nature. That is, to determine their incidence and frequency of occurrence and their value as a mechanism of modification with evolutionary effect, taking into account that, in any event, the DNA sequences in the genes are not changed, and the epigenetic modifications are reversible”, explains Dr. Nicolás Jouve, professor emeritus of genetics at the University of Alcalá de Henares (Madrid, Spain). “This should not be used to think that the environment alters the genome and allows a Lamarckian interpretation of evolution. In no case are the mutations (in this case epimutations) pre-adaptive. If there really is transgenerational epigenetics and the epimutations produce effects on the expression of mammalian genes, they will then have to go through the filter of natural selection, or permanence through mechanisms of genetic drift. If the changes are good they will be selected for and maintained, and if they are not, they will be lost. This is not demonstrated in Belmonte’s work, and therefore neither invalidates Darwin’s sound theory of natural selection, nor endorses Lamarck’s theory of the action of the environment as a molder of acquired characteristics”.
These discoveries in transgenerational epigenetics have ethical implications in relation to gene editing, i.e., modification of the genome for therapeutic purposes. Thus, it was considered that modulating gene expression by altering epigenetic patterns was safer than modifying the gene sequence and in no case has it been related to germline gene editing, which is the most controversial form of gene editing as it involves the transmission of genetic changes to offspring, among other things. Nevertheless, the new findings have led us to reassess the concept of germline genetic modification. Accordingly, close attention will have to be paid to advances in the field of transgenerational epigenetics from bioethics when evaluating proposed therapeutic interventions on humans that involve an epigenetic modification.
Lucía Gómez Tatay
Bioethics Observatory – Institute of Life Sciences
Catholic University of Valencia