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September 01, 2014 | By:  Sedeer el-Showk
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How Starvation Causes Heritable Changes

A growing body of evidence is pointing towards unknown inheritance mechanisms that are influenced by what happens during an organism's life. Last summer, I wrote about how crickets whose mother had met a predator were more cautious, and in December the inimitable Virginia Hughes did an amazing job of covering the story about mice inheriting a memory of fear. Now researchers at the Howard Hughes Medical Institute in New York and Tel Aviv University have shown how starvation can cause inherited changes in several generations of the nematode Caenorhabditis elegans even though their DNA stays the same.

An earlier study had already shown that the mother's diet caused changes in gene expression in nematode larvae at a particular stage in their development. However, the research didn't show that the changes continued for several generations, so they couldn't be conclusively called "inherited". After all, it's possible that these changes were because of the mother's direct influence on her embryonic offspring, even though the effects didn't show up until later. In that case, there would be no need for a mysterious new inheritance mechanism; it would just be a malnourished mother affecting her offspring's development. Other studies showed similar effects lasting across several generations, but they didn't unravel the inheritance mechanisms involved.

To get to the bottom of things, the team sequenced RNA from young adult nematodes and from their progeny three generations later. Some of the young adults were starved for six days and others were fed normally, but the three following generations all had a normal diet. While RNA is generally familiar to people as the intermediate molecule in the translation of DNA into proteins, in this case the team was interested in so-called "small RNA", which are short RNA molecules involved in regulating gene expression in various ways. They found a specific set of small RNAs expressed in the adult nematodes that had been starved, but not in the controls. Incredibly, the same small RNAs were expressed in these nematodes' offspring three generations later, even though they had been fed normally (along with the intervening generations). In addition to the changes in small RNAs, the researchers also found nematodes whose great-grandparents had been starved lived for longer than those descended from a line of well-fed nematodes. It's not clear if or how this longevity is connected to the changes in small RNAs, but it's yet another piece of evidence for extra-genetic inheritance over several generations.

Small RNA are often involved in the immune response to viruses, but this experiment showed that they can also act as a mechanism for trans-generational inheritance. How? "We know from other studies that small RNAs can be transported from cell to cell around the body," said Professor Oliver Holbert, who led the study. "So, it's conceivable that the starvation-induced small RNAs found their way into the worms’ germ cells — that is, their sperm or eggs. When the worms reproduced, the small RNAs could have been transmitted generationally in the cell body of the germ cells, independent of the DNA." We still don't know if that's precisely what happened, but now that we know small RNAs are the culprit (at least in this case), researchers will be able to tackle the question with a variety of tools and tease apart what's happening.

"[Our findings] suggest that we should be aware of other things — beyond pure DNA changes — that may have a long-term impact on the health of an organism,” said Hobert. “In other words, something that happened to one generation, whether famine or some other traumatic event, may be relevant to the health of its descendants for generations.” It's becoming clear that our picture of inheritance — which is at the heart of the evolutionary process — is incomplete. We've seen extra-genetic inheritance in a variety of organisms, probably mediated by changes in epigenetic factors like small RNAs and methylation. As geneticists and molecular biologists struggle to understand how this happens, evolutionary biologists will have to start considering its impact. It's a far cry from the simplistic version of Lamarckism taught in schools (one day, I'm going to write a post about what Lamarck really said), but it will still might require some serious rethinking of how evolution works.

Rechavi, O. et al. Starvation-Induced Transgenerational Inheritance of Small RNAs in Caenorhabditis. elegans. Cell, 158:2 (277-287). (2014) doi: 10.1016/j.cell.2014.06.020

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