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Embryos at the two-cell stage, represented in this illustration, need an unusual mobile DNA sequence to keep developing.

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Don’t call it junk—this ‘jumping’ gene may be why you made it past an embryo

At one point in your life, you were a two-celled embryo tumbling toward a soft landing in the uterus. You may have only been able to get past this rudimentary stage, a new study suggests, thanks to a type of DNA many scientists once wrote off as junk.

“It’s a very impressive paper,” says Cedric Feschotte of Cornell University, who wasn’t connected to the study.

Your many thousands of genes only account for a small part of your genome. Much more common are transposons, DNA sequences also known as “jumping genes” because they can relocate or introduce copies of themselves into a different location in the genome. About half our DNA consists of transposons, and researchers once assumed they were genomic parasites that reproduced themselves but served no purpose for their host.

However, scientists now think the sequences have been crucial for evolution. Researchers have found that about 25% of the regulatory sequences that help switch our genes on or off include bits of transposons, suggesting they have provided new DNA we have adopted as our own. That said, transposons often behave like unwelcome houseguests. When a transposon barges into a new location in the genome, for example, it finds a nice home, but it can also cause a mutation that leads to cancer.

Developmental biologist Miguel Ramalho-Santos and colleagues wanted to determine whether the transposon LINE1, which accounts for 17% of our DNA, was purely selfish or provided any benefits during embryonic development. To reproduce, LINE1 first produces an RNA copy of itself. An enzyme later transforms this RNA back into DNA, which inserts somewhere in the genome. The transposon was puzzling, says Ramalho-Santos, who is in the process of jumping from the University of California, San Francisco, to the University of Toronto in Canada, because it moves around early in embryonic development, when DNA alterations could be disastrous. Cells can often restrain transposons, but the early embryos seem to unleash them. “Are cells completely crazy and playing with fire, or is there something more to it?” he asks.

Transposons (glowing dots) are prevalent in this two-celled mouse embryo.

Ramalho-Santos Lab

Ramalho-Santos and colleagues found a way to short-circuit LINE1’s jumping mechanism and put that question to the test. The researchers designed small molecules that blocked the process and slashed the amount of LINE1 RNA in cells by 80% to 90%. The scientists then tested the effect of shackling LINE1 in mouse embryonic stem cells. These cells divide to produce specialized body cells, but they also need to produce more embryonic stem cells so that development can continue. Removal of LINE1 RNA dramatically reduced the cells’ ability to replenish themselves, the team found.

LINE1 had another, separate function during natural embryonic development, however. When LINE1 RNA was scarce, mouse embryos stalled at the two-cell stage, the team reports today in Cell. Humans reach this stage before the embryo beds down in the wall of the uterus. If an embryo can’t progress beyond this stage, it won’t give rise to an offspring.

Although transposons are famous for their ability to insert themselves into the genome, LINE1’s embryonic roles have no connection to this ability, the scientists report. Instead, the transposon’s RNA teams up with two proteins to allow the two-celled embryos to continue developing.

The findings suggest that LINE1 transposons have a good side in the embryo, Ramalho-Santos says. “They are not simply selfish, parasitic elements. They are endogenous to our beings, and we would not be able to do without them.” By helping its host cells, Feschotte says, the transposon achieves its selfish ends. “It looks like it’s indispensible for development. You can’t get rid of it.”

Some researchers are skeptical, however. About 500,000 copies of LINE1 are strewn around our genome, many of which are inside genes, notes molecular human geneticist Haig Kazazian of Johns Hopkins University School of Medicine in Baltimore, Maryland. The technique researchers used to block production of LINE1 RNA might also shut down these genes, he says. Thus, the effects the scientists observed might be due to inactivation of these genes, not the reduction in LINE1 RNA. “You may be knocking down some key genes in early development,” he says.