Scientists find mating can cause epigenetic changes that last for 300 generations

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UMD researchers have found that the same gene to express a red fluorescent protein is always expressed (ON), when inherited from the mother, but when inherited from the father, it can lose its expression (turn off ) forever if the mother does not have the gene. Credit: Antony José / UMD

Scientists at the University of Maryland find that match matters: The right combination of parents in nematode worms can turn off a gene indefinitely.

Evidence suggests that what happens over the course of a generation – diet, exposure to toxins, trauma, fear – can have lasting effects on future generations. Scientists believe these effects result from epigenetic changes that occur in response to the environment and turn genes on or off without altering the genome or DNA

DNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).
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But how these changes are passed down from generation to generation has not been understood, in part because scientists have not had a simple way to study the phenomenon. A new study by researchers at the University of Maryland provides a potential tool to unravel the mystery of how experiments can cause hereditary changes in an animal’s biology. By mating nematode worms, they produced permanent epigenetic changes that lasted for over 300 generations. The research was published on July 9, 2021 in the journal Nature Communication.

“There is a lot of interest in inherited epigenetics,” said Antony Jose, associate professor of cell biology and molecular genetics at UMD and lead author of the study. “But getting clear answers is difficult. For example, if I am on a diet today, how does it affect my children and grandchildren and so on? No one knows, because so many different variables are involved. But we found this very simple method, through mating, to turn off a single gene for multiple generations. And it gives us a huge opportunity to study how these stable epigenetic changes occur. “

In the new study, Jose and his team discovered while breeding nematode worms that certain matings resulted in epigenetic changes in the offspring that continued to be passed down through as many generations as scientists continued to breed. This discovery will allow scientists to explore how epigenetic changes are passed on to future generations and what characteristics make genes sensitive to permanent epigenetic changes.

Jose and his team began this work in 2013, while working with nematode worms, Caenorhabditis elegans (C. elegans), a species often used as a model for understanding animal biology. Scientists noticed that the worms reproduced to carry a gene they called T, which produces fluorescent proteins, sometimes bright and sometimes not. It was confusing because Glowers and non-Glowers had almost identical DNA.

“It all started when we came across a rare gene that has undergone a permanent change for hundreds of generations simply by mating. We could have easily missed it, ”said Sindhuja Devanapally (Ph.D. ’18, biological sciences), co-lead author of the study who is now a postdoctoral fellow at Columbia university.

To better understand the phenomenon, the researchers carried out breeding experiments in which only the mother or the father carried the fluorescent gene. The team expected that regardless of which parent carried the gene, the offspring would shine. Instead, they found that when the mother carried the fluorescent gene, the offspring always glowed, meaning the gene was always on. But when the father carried the gene, the offspring usually glowed weakly or did not glow at all.

“We found that there are these RNA-based on signals controlling gene expression, ”said Jose. “Some of these signals silence the gene and some of them are protective signals that prevent silence. These signals clash as the offspring develop. When the gene comes from the mother, the protective signal always wins, but when the gene comes from the father, the silence signal almost always wins.

When the silence signal wins, the gene is silenced for good, or for at least 300 generations, which is how long Jose and his colleagues have been following their lab-reared worms. The previous examples of epigenetic changes were more complex or did not last more than two generations. Researchers don’t yet know why the silence signal wins only part of the time, but this new discovery puts them in a much better position to explore the details of epigenetic inheritance than ever before.

“Although we have found a set of genes that can be almost permanently silenced, most of the other genes are not affected in the same way,” the study’s other lead co-author said, Pravrutha Raman (Ph.D. ’19, Biological Sciences), who is now a postdoctoral fellow at the Fred Hutchinson Cancer Research Center. “After being silenced, they bounce back and express themselves in future generations. “

With their new findings, the researchers now believe that some genes may be more vulnerable to permanent epigenetic changes while other genes recover within a few generations. While studies in worms are not the same as in humans, the research provides a window into biological processes that are likely shared, at least in part, by all animals.

“The two big advantages we now have from this work are that this long lasting epigenetic change is easy to induce by mating and occurs at the single gene level,” said Jose. “Now we can manipulate this gene and control everything about it, which will allow us to determine what characteristics make a gene susceptible or resistant to hereditary epigenetic change. “

Jose and his colleagues expect that future studies may one day help scientists identify human genes that are vulnerable to long-lasting epigenetic changes.

Reference: “Mating can initiate stable RNA silencing that overcomes epigenetic recovery” by Sindhuja Devanapally, Pravrutha Raman, Mary Chey, Samual Allgood, Farida Ettefa, Maïgane Diop, Yixin Lin, Yongyi E Cho and Antony M Jose, July 9 2021, Nature Communication.
DOI: 10.1038 / s41467-021-24053-4

This work was supported by the National Institutes of Health (award # R01GM111457 and R01GM124356). The content of this article does not necessarily reflect the views of this organization.

Other authors of the UMD study include a doctorate in biological sciences. candidate Mary Chey, Samual Allgood (BS ’15, biological sciences), Farida Ettefa (BS ’18, biochemistry), Maïgane Diop (BS ’20, biological sciences), Yixin Lin (BS ’19, biological sciences; M.Ed. ’20), Yongyi E Cho (BS ’20, biological sciences; BA ’20, philosophy).


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